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 compared to placebo. SEROQUEL XR (quetiapine
fumarate) is not approved for the treatment of patients with dementia-related
psychosis [see BOXED WARNING].
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal ideation
and behavior (suicidality) or unusual changes in behavior, whether or not they
are taking antidepressant medications, and this risk may persist until significant
remission occurs. Suicide is a known risk of depression and certain other psychiatric
disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have
a role in inducing worsening of depression and the emergence of suicidality
in certain patients during the early phases of treatment. Pooled analyses of
short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
showed that these drugs increase the risk of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults (ages 18-24) with major
depressive disorder (MDD) and other psychiatric disorders. Short-term studies
did not show an increase in the risk of suicidality with antidepressants compared
to placebo in adults beyond age 24; there was a reduction with antidepressants
compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents
with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders
included a total of 24 short-term trials of 9 antidepressant drugs in over 4400
patients. The pooled analyses of placebo-controlled trials in adults with MDD
or other psychiatric disorders included a total of 295 short-term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There
was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger patients for almost all drugs studied. There
were differences in absolute risk of suicidality across the different indications,
with the highest incidence in MDD. The risk differences (drug vs. placebo),
however, were relatively stable within age strata and across indications. These
risk differences (drug-placebo difference in the number of cases of suicidality
per 1000 patients treated) are provided in Table 1.
Table 1
Age Range |
Drug-Placebo Difference in Number of Cases
of Suicidality per 1000 Patients Treated |
|
Increases Compared to Placebo |
< 18 |
14 additional cases |
18-24 |
5 additional cases |
|
Decreases Compared to Placebo |
25-64 |
1 fewer case |
≥ 65 |
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 XR should be written
for the smallest quantity of tablets consistent with good patient management,
in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode
may be the initial presentation of bipolar disorder. It is generally believed
(though not established in controlled trials) that treating such an episode
with an antidepressant alone may increase the likelihood of precipitation of
a mixed/manic episode in patients at risk for bipolar disorder. Whether any
of the symptoms described above represent such a conversion is unknown. However,
prior to initiating treatment with an antidepressant, patients with depressive
symptoms should be adequately screened to determine if they are at risk for
bipolar disorder; such screening should include a detailed psychiatric history,
including a family history of suicide, bipolar disorder, and depression.
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 quetiapine. Rare cases of NMS have been reported with quetiapine.
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 (eg, pneumonia, systemic
infection, etc.) and untreated or inadequately treated extrapyramidal signs
and symptoms (EPS). Other important considerations in the differential diagnosis
include central anticholinergic toxicity, heat stroke, drug fever and primary
central nervous system (CNS) pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic
drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic
treatment and medical monitoring; and 3) treatment of any concomitant serious
medical problems for which specific treatments are available. There is no general
agreement about specific pharmacological treatment regimens for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS,
the potential reintroduction of drug therapy should be carefully considered.
The patient should be carefully monitored since recurrences of NMS have been
reported.
Hyperglycemia 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 (eg, obesity, family
history of diabetes) who are starting treatment with atypical antipsychotics
should undergo fasting blood glucose testing at the beginning of treatment and
periodically during treatment. Any patient treated with atypical antipsychotics
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria,
polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during
treatment with atypical antipsychotics should undergo fasting blood glucose
testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic
was discontinued; however, some patients required continuation of anti-diabetic
treatment despite discontinuation of the suspect drug.
In some patients, a worsening of more than one of the metabolic parameters
of weight, blood glucose and lipids was observed in clinical studies. Changes
in these parameters should be managed as clinically appropriate.
Adults:
Table 2: Fasting Glucose - Proportion of Patients Shifting
to ≥ 126 mg/dL in short-term ( ≤ 12 weeks) Placebo-Controlled Studies
Laboratory Analyte |
Category Change (At Least Once) from Baseline |
Treatment Arm |
N |
Patients n (%) |
Fasting Glucose |
Normal to High ( < 100 mg/dL to ≥ 126 mg/dL) |
Quetiapine |
2907 |
71 (2.4%) |
Placebo |
1346 |
19 (1.4%) |
Borderline to High ( ≥ 100 mg/dL and |
Quetiapine |
572 |
67 (11.7%) |
<126 mg/dL to ≥ 126 mg/dL) |
Placebo |
279 |
33 (11.8%) |
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 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 quetiapine 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).
Table 3 shows the percentage of patients with shifts in blood glucose to ≥
126 mg/dL from normal baseline in MDD adjunct therapy trials by dose.
Table 3: Percentage of Patients with Shifts from Normal Baseline
in Blood Glucose to ≥ 126 mg/dL (assumed fasting) in MDD Adjunct Therapy
Trials by Dose
Laboratory Analyte |
Treatment Arm |
N |
Patients n (%) |
Blood Glucose ≥ 126 mg/dL |
Placebo |
277 |
17 (6%) |
SEROQUEL XR 150 mg |
280 |
19 (7%) |
SEROQUEL XR 300 mg |
269 |
32 (12%) |
Children and Adolescents: Safety and effectiveness of SEROQUEL XR have
not been established in pediatric patients and SEROQUEL XR is not approved for
patients under the age of 18 years. 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.
Hyperlipidemia
Undesirable alterations in lipids have been observed with quetiapine use. Clinical
monitoring, including baseline and periodic follow-up lipid evaluations in patients
using quetiapine is recommended.
In some patients, a worsening of more than one of the metabolic parameters
of weight, blood glucose and lipids was observed in clinical studies. Changes
in these parameters should be managed as clinically appropriate.
Adults
Table 4 shows the percentage of patients with changes in cholesterol and triglycerides
from baseline by indication in clinical trials with SEROQUEL XR .
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 |
Indication |
Treatment Arm |
N |
Patients n (%) |
Total Cholesterol ≥ 240 mg/dL |
Schizophreniaa |
SEROQUEL XR |
718 |
67 (9%) |
Placebo |
232 |
21 (9%) |
Bipolar Depressionb |
SEROQUEL XR |
85 |
6 (7%) |
Placebo |
106 |
3 (3%) |
Bipolar Maniac |
SEROQUEL XR |
128 |
9 (7%) |
Placebo |
134 |
5 (4%) |
Major Depressive Disorder (Adjunct Therapy)d |
SEROQUEL XR |
420 |
67 (16%) |
Placebo |
213 |
15 (7%) |
Triglycerides ≥ 200mg/dL |
Schizophreniaa |
SEROQUEL XR |
659 |
118 (18%) |
Placebo |
214 |
11 (5%) |
Bipolar Depressionb |
SEROQUEL XR |
84 |
7 (8%) |
Placebo |
93 |
7 (8%) |
Bipolar Maniac |
SEROQUEL XR |
102 |
15 (15%) |
Placebo |
125 |
8 (6%) |
Major Depressive Disorder (Adjunct Therapy)d |
SEROQUEL XR |
458 |
75 (16%) |
Placebo |
223 |
18 (8%) |
LDL-Cholesterol ≥ 160 mg/dL |
Schizophreniaa |
SEROQUEL XR |
691 |
47 (7%) |
Placebo |
227 |
17 (8%) |
Bipolar Depressionb |
SEROQUEL XR |
86 |
3 (4%) |
Placebo |
104 |
2 (2%) |
Bipolar Maniac |
SEROQUEL XR |
125 |
5 (4%) |
Placebo |
135 |
2 (2%) |
Major Depressive Disorder (Adjunct Therapy)d |
SEROQUEL XR |
457 |
51 (11%) |
Placebo |
219 |
21 (10%) |
HDL-Cholesterol ≥ 40 mg/dL |
Schizophreniaa |
SEROQUEL XR |
600 |
87 (15%) |
Placebo |
195 |
23 (12%) |
Bipolar Depressionb |
SEROQUEL XR |
78 |
7 (9%) |
Placebo |
83 |
6 (7%) |
Bipolar Maniac |
SEROQUEL XR |
100 |
19 (19%) |
Placebo |
115 |
15 (13%) |
Major Depressive Disorder (Adjunct Therapy)d |
SEROQUEL XR |
470 |
34 (7%) |
Placebo |
230 |
19 (8%) |
a: 6 weeks duration
b: 8 weeks duration
c: 3 weeks duration
d: 6 weeks duration |
In SEROQUEL clinical trials for schizophrenia, the percentage of patients with
shifts in cholesterol and triglycerides from baseline to clinically significant
levels were 18% (placebo: 7%) and 22% (placebo: 16%). HDL-cholesterol and LDL-cholesterol
parameters were not measured in these studies. In SEROQUEL clinical trials for
bipolar depression, the following percentage of patients had shifts from baseline
to clinically significant levels for the four lipid parameters measured: total
cholesterol 9% (placebo: 6%); triglycerides 14% (placebo: 9%); LDL-cholesterol
6% (placebo: 5%) and HDL-cholesterol 14% (placebo: 14%). Lipid parameters were
not measured in the bipolar mania studies.
Table 5 shows the percentage of patients in MDD adjunctive therapy trials with
clinically significant shifts in total-cholesterol, triglycerides, LDL-cholesterol
and HDL-cholesterol from baseline by dose.
Table 5: Percentage of Patients with Shifts in Total Cholesterol,
Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically
Significant Levels in MDD Adjunctive Therapy Trials by Dose
Laboratory Analyte |
Treatment Arma |
N |
Patients n (%) |
Cholesterol ≥ 240 mg/dL |
Placebo |
213 |
15 (7%) |
SEROQUEL XR 150 mg |
223 |
41 (18%) |
SEROQUEL XR 300 mg |
197 |
26 (13%) |
Triglycerides ≥ 200 mg/dL |
Placebo |
223 |
18 (8%) |
SEROQUEL XR 150 mg |
232 |
36 (16%) |
SEROQUEL XR 300 mg |
226 |
39 (17%) |
LDL-Cholesterol ≥ 160 mg/dL |
Placebo |
219 |
21 (10%) |
SEROQUEL XR 150 mg |
242 |
29 (12%) |
SEROQUEL XR 300 mg |
215 |
22 (10%) |
HDL-Cholesterol ≤ 40 mg/dL |
Placebo |
230 |
19 (8%) |
SEROQUEL XR 150 mg |
238 |
14 (6%) |
SEROQUEL XR 300 mg |
232 |
20 (9%) |
a: 6 weeks duration |
Children and Adolescents
Safety and effectiveness of SEROQUEL XR have not been established in pediatric
patients, and SEROQUEL XR is not approved for patients under the age of 18 years.
Table 6 shows the percentage of children and adolescents with shifts in total
cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline
to clinically significant levels by indication in clinical trials with SEROQUEL.
Table 6: Percentage of Children and Adolescents with Shifts
in Total Cholesterol, Triglycerides LDL-Cholesterol and HDL-Cholesterol from
Baseline to Clinically Significant Levels by Indication
Laboratory Analyte |
Indication |
Treatment Arm |
N |
Patients n (%) |
Total Cholesterol ≥ 200 mg/dL |
Schizophreniaa |
SEROQUEL |
107 |
13 (12%) |
Placebo |
56 |
1 (2%) |
Bipolar Maniab |
SEROQUEL |
159 |
16 (10%) |
Placebo |
66 |
2 (3%) |
Triglycerides ≥ 150 mg/dL |
Schizophreniaa |
SEROQUEL |
103 |
17 (17%) |
Placebo |
51 |
4 (8%) |
Bipolar Maniab |
SEROQUEL |
149 |
32 (22%) |
Placebo |
60 |
8 (13%) |
LDL-Cholesterol ≥ 30 mg/dL |
Schizophreniaa |
SEROQUEL |
112 |
4 (4%) |
Placebo |
60 |
1 (2%) |
Bipolar Maniab |
SEROQUEL |
169 |
13 (8%) |
Placebo |
74 |
4 (5%) |
HDL-Cholesterol ≤ 40 mg/dL |
Schizophreniaa |
SEROQUEL |
104 |
16 (15%) |
Placebo |
54 |
10 (19%) |
Bipolar Maniab |
SEROQUEL |
154 |
16 (10%) |
Placebo |
61 |
4 (7%) |
a: 13- 17 years, 6 weeks duration b: 10-17
years, 3 weeks duration |
Weight Gain
Increases in weight have been observed in clinical trials. Patients receiving
quetiapine should receive regular monitoring of weight [see PATIENT INFORMATION].
In some patients, a worsening of more than one of the metabolic parameters
of weight, blood glucose and lipids was observed in clinical studies. Changes
in these parameters should be managed as clinically appropriate.
Adults: Table 7 shows the percentage of adult patients with weight gain
of ≥ 7% of body weight by indication.
Table 7: Percentage of Patients with Weight Gain ≥ 7% of
Body Weight (Adults) by Indication
Vital sign |
Indication |
Treatment Arm |
N |
Patients n (%) |
Weight gain ≥ 7% of body weight |
Schizophreniaa |
SEROQUEL XR |
907 |
90 (10%) |
Placebo |
299 |
16 (5%) |
Bipolar Maniab |
SEROQUEL XR |
138 |
7 (5%) |
Placebo |
150 |
0 (0%) |
Bipolar Depressionc |
SEROQUEL XR |
110 |
9 (8%) |
Placebo |
125 |
1 (1%) |
Major Depressive Disorder (Adjunctive
Therapy)d |
SEROQUEL XR |
616 |
32 (5%) |
Placebo |
302 |
5 (2%) |
a: 6 weeks duration
b: 3 weeks duration
c: 8 weeks duration
d: 6 weeks duration |
In schizophrenia trials, the proportions of patients meeting a weight gain
criterion of ≥ 7% of body weight were compared in a pool of four 3- to 6-week
placebo-controlled clinical trials, revealing a statistically significant greater
incidence of weight gain for SEROQUEL (23%) compared to placebo (6%).
Table 8 shows the percentage of adult patients with weight gain of ≥ 7% of
body weight for MDD by dose.
Table 8: Percentage of Patients with Weight Gain ≥ 7% of
Body Weight in MDD Adjunctive Therapy Trials by Dose (Adults)
Vital sign |
Treatment Arm |
N |
Patients n(%) |
Weight Gain ≥ 7% of Body Weight in MDD Adjunctive Therapy |
Placebo |
302 |
5 (2%) |
SEROQUEL XR 150 mg |
309 |
10 (3%) |
SEROQUEL XR 300 mg |
307 |
22 (7%) |
Children and Adolescents: Safety and effectiveness of SEROQUEL XR have
not been established in pediatric patients and SEROQUEL XR is not approved for
patients under the age of 18 years. In two clinical trials with SEROQUEL, one
in bipolar mania and one in schizophrenia, reported increases in weight are
included in table 9 below.
Table 9 shows the percentage of patients with weight gain ≥ 7% of body weight
in clinical trials with SEROQUEL.
Table 9: Percentage of Patients with Weight Gain ≥ 7% of
Body Weight (Children and Adolescents)
Vital sign |
Indication |
Treatment Arm |
N |
Patients n (%) |
Weight gain ≥ 7% of Body Weight |
Schizophreniaa |
SEROQUEL |
111 |
23 (21%) |
Placebo |
44 |
3 (7%) |
Bipolar Maniab |
SEROQUEL |
157 |
18 (12%) |
Placebo |
68 |
0 (0%) |
a: 6 weeks duration
b: 3 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.
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 XR 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
XR, drug discontinuation should be considered. However, some patients may require
treatment with quetiapine despite the presence of the syndrome.
Orthostatic Hypotension
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 0.3% (5/1866) of the patients treated with SEROQUEL XR across
all indications, compared with 0.2% (2/928) on placebo. Syncope was reported
in 1% (28/3265) of the patients treated with SEROQUEL, compared with 0.2% (2/954)
on placebo. Orthostatic hypotension, dizziness, and syncope may lead to falls.
Quetiapine 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) [see ADVERSE REACTIONS]. 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)
Safety and effectiveness of SEROQUEL XR have not been established in pediatric
patients and SEROQUEL XR is not approved for patients under the age of 18 years.
In placebo-controlled trials in children and adolescents with schizophrenia
(6-week duration) or bipolar mania (3week 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.
Leukopenia, Neutropenia and Agranulocytosis
In clinical trials and postmarketing experience, events of leukopenia/neutropenia
have been reported temporally related to atypical antipsychotic agents, including
quetiapine fumarate. Agranulocytosis (including fatal cases) has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white
cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients
with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia
should have their complete blood count (CBC) monitored frequently during the
first few months of therapy and should discontinue SEROQUEL XR 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 XR and have their WBC followed until recovery [see
ADVERSE REACTIONS].
Cataracts
The development of cataracts was observed in association with quetiapine treatment
in chronic dog studies [see Animal Toxicology]. Lens changes have also
been observed in adults, children, and adolescents during long-term quetiapine
treatment, but a causal relationship to quetiapine 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.
Seizures
During short-term clinical trials with SEROQUEL XR, seizures occurred in 0.05%
(1/1866) of patients treated with SEROQUEL XR across all indications compared
to 0.3% (3/928) on placebo. During clinical trials with SEROQUEL, seizures occurred
in 0.5% (20/3490) of patients treated with SEROQUEL compared to 0.2% (2/954)
on placebo. As with other antipsychotics, quetiapine fumarate 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.
Hypothyroidism
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. In SEROQUEL XR clinical trials across
all indications 1.8% (24/1336) of patients on SEROQUEL XR vs. 0.6% (3/530) on
placebo experienced decreased free thyroxine and 1.6% (21/1346) on SEROQUEL
XR vs. 3.4% (18/534) on placebo experienced increased thyroid stimulating hormone
(TSH); however, no patients experienced a combination of clinically significant
decreased free thyroxine and increased TSH. 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 potentially clinically significant
shifts in thyroid hormones and TSH were*: decrease in free T4, 2.0%
(357/17513); decrease in total T4, 4.0% (75/1861); decrease in free
T3, 0.4% (53/13766); decrease in total T3, 2.0% (26/1312),
and increase in TSH, 4.9% (956/19412). In eight patients, where TBG was measured,
levels of TBG were unchanged.
Table 10 shows the incidence of these shifts in short-term placebo-controlled
clinical trials.
Table 10: Incidence of potentially clinically significant
shifts in thyroid hormone levels and TSH in short term placebo-controlled clinical
trials*
Total T4 |
Free T4 |
Total T3 |
Free T3 |
TSH |
Quetiapine |
Placebo |
Quetiapine |
Placebo |
Quetiapine |
Placebo |
Quetiapine |
Placebo |
Quetiapine |
Placebo |
3.4 % |
0.6% |
0.7% |
0.1% |
0.5% |
0.0% |
0.2% |
0.0% |
3.2% |
2.7% |
(37/1097) |
(4/651) |
(52/7218) |
(4/3668) |
(2/369) |
(0/113) |
(11/5673) |
(1/2679) |
(240/7587) |
(105/3912) |
* 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 < 0.8 x LLN (pmol/L) and shift in TSH is
> 5 mIU/L at any time. |
In short-term placebo-controlled monotherapy trials, the incidence of reciprocal,
potentially clinically significant 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.
Generally, these changes in thyroid hormone levels were of no clinical significance.
Children and Adolescents: Safety and effectiveness of SEROQUEL XR have
not been established in pediatric patients and SEROQUEL XR is not approved for
patients under the age of 18 years. 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 to potentially clinically important
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.
Hyperprolactinemia
Adults: During clinical trials with quetiapine across all indications,
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: Safety and effectiveness of SEROQUEL XR have
not been established in pediatric patients and SEROQUEL XR is not approved for
patients under the age of 18 years. 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 clinically
significant 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 XR 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 Carcinogenesis, Mutagenesis, Impairment of Fertility].
Transaminase Elevations
Asymptomatic, transient and reversible elevations in serum transaminases (primarily
ALT) have been reported. The proportions of patients with transaminase elevations
of > 3 times the upper limits of the normal reference range in a pool of placebo-controlled
trials ranged between 1% and 2% for SEROQUEL XR compared to 2% for placebo.
In schizophrenia trials in adults, the proportions of patients with transaminase
elevations of > 3 times the upper limits of the normal reference range in
a pool of 3- to 6-week placebo-controlled trials were approximately 6% (29/483)
for SEROQUEL compared to 1% (3/194) for placebo. These hepatic enzyme elevations
usually occurred within the first 3 weeks of drug treatment and promptly returned
to pre-study levels with ongoing treatment with quetiapine.
Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event reported in patients treated
with quetiapine especially during the 3-day period of initial dose titration.
In schizophrenia trials, somnolence was reported in 24.7% (235/951) of patients
on SEROQUEL XR compared to 10.3% (33/319) of placebo patients. In a bipolar
depression clinical trial, somnolence was reported in 51.8% (71/137) of patients
on SEROQUEL XR compared to 12.9% (18/140) of placebo patients. In a clinical
trial for bipolar mania, somnolence was reported in 50.3% (76/151) of patients
on SEROQUEL XR compared to 11.9% (19/160) of placebo patients. Since quetiapine
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 quetiapine therapy does not affect them
adversely. Somnolence may lead to falls.
In short-term adjunctive therapy trials for MDD, somnolence was reported in
40% (252/627) of patients on SEROQUEL XR respectively compared to 9% (27/309)
of placebo patients. Somnolence was dose-related in these trials (37% (117/315)
and 43% (135/312) for the 150 mg and 300 mg groups, respectively).
Priapism
One case of priapism in a patient receiving quetiapine was reported prior to
market introduction. While a causal relationship to use of quetiapine has not
been established, other drugs with α-adrenergic blocking effects have
been reported to induce priapism, and it is possible that quetiapine may share
this capacity. Severe priapism may require surgical intervention.
Body Temperature Regulation
Disruption of the body's ability to reduce core body temperature has been attributed
to antipsychotic agents. Appropriate care is advised when prescribing SEROQUEL
XR for patients who will be experiencing conditions which may contribute to
an elevation in core body temperature, eg, exercising strenuously, exposure
to extreme heat, receiving concomitant medication with anticholinergic activity,
or being subject to dehydration.
Dysphagia
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 XR and other antipsychotic drugs should be used cautiously in patients
at risk for aspiration pneumonia.
Suicide
The possibility of a suicide attempt is inherent in schizophrenia, bipolar
disorder and depression; close supervision of high risk patients should accompany
drug therapy. Prescriptions for SEROQUEL XR should be written for the smallest
quantity of tablets consistent with good patient management in order to reduce
the risk of overdose.
In three, 6-week clinical studies in patients with schizophrenia (N=951) the
incidence of treatment emergent suicidal ideation or suicide attempt was 0.6%
(n=6) in SEROQUEL XR treated patients and 0.9% (n=3) in placebo-treated patients.
In an 8-week clinical study in patients with bipolar depression (N=137 for
SEROQUEL XR and 140 for placebo) the incidence of treatment emergent suicidal
ideation or suicide attempt was 0.7% (n=1) for SEROQUEL XR treated patients
and 1.4% (n=2) for placebo.
In a 3-week clinical study in patients with bipolar mania (N=311, 151 for SEROQUEL
XR and 160 for placebo) the incidence of treatment emergent suicidal ideation
or suicide attempt was 1.3% (n=2) for SEROQUEL XR compared to 3.8% (n=6) for
placebo.
In two, 6-week MDD adjunctive therapy trials (n=936, 627 on SEROQUEL XR and
309 on placebo) the incidence of treatment emergent suicidal ideation or suicide
attempt was 0.5% (n=3) in SEROQUEL XR treated patients and 0.6% (n=2) in placebo.
Use in Patients with Concomitant Illness
Clinical experience with SEROQUEL XR in patients with certain concomitant systemic
illnesses [see Pharmacokinetics] is limited.
SEROQUEL XR has not been evaluated or used to any appreciable extent in patients
with a recent history of myocardial infarction or unstable heart disease. Patients
with these diagnoses were excluded from premarketing clinical studies. Because
of the risk of orthostatic hypotension with SEROQUEL XR, caution should be observed
in cardiac patients [see WARNINGS AND PRECAUTIONS].
In clinical trials quetiapine was not associated with a persistent increase
in absolute QT intervals. However, 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].
Caution should be exercised when quetiapine is prescribed in patients with cardiovascular
disease or family history of QT prolongation. Also caution should be exercised
when quetiapine is prescribed with medicines known to cause electrolyte imbalance
or increase QT interval or with concomitant neuroleptics, especially for patients
with increased risk of QT prolongation, i.e., the elderly, patients with congenital
long QT syndrome, congestive heart failure, heart hypertrophy, hypokalemia,
or hypomagnesemia.
Withdrawal
Acute withdrawal symptoms, such as insomnia, nausea and vomiting have been
described after abrupt cessation of atypical antipsychotic drugs, including
quetiapine fumarate. 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.
Patient Counseling Information
Information for Patients
[see Medication Guide]
Prescribers or other health professionals should inform patients, their families,
and their caregivers about the benefits and risks associated with treatment
with SEROQUEL XR 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 XR.
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 XR.
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Patients and caregivers should be advised that elderly patients with dementia-related
psychoses 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].
Clinical Worsening and Suicide Risk
Patients, their families, and their caregivers should be encouraged to be alert
to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression,
and suicidal ideation, especially early during antidepressant treatment and
when the dose is adjusted up or down. Families and caregivers of patients should
be advised to look for the emergence of such symptoms on a day-to-day basis,
since changes may be abrupt. Such symptoms should be reported to the patient's
prescriber or health professional, especially if they are severe, abrupt in
onset, or were not part of the patient's presenting symptoms. Symptoms such
as these may be associated with an increased risk for suicidal thinking and
behavior and indicate a need for very close monitoring and possibly changes
in the medication [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].
Hyperglycemia and Diabetes Mellitus
Patients should be aware of the symptoms of hyperglycemia (high blood sugar)
and diabetes mellitus. Patients who are diagnosed with diabetes, those with
risk factors for diabetes, or those that develop these symptoms during treatment
should have their blood glucose monitored at the beginning of and periodically
during treatment [see WARNINGS AND PRECAUTIONS].
Hyperlipidemia
Patients should be advised that elevations in total cholesterol, LDL-cholesterol
and triglycerides and decreases in HDL-cholesterol may occur. Patients should
have their lipid profile monitored at the beginning of and periodically during
treatment [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
Blood pressure should be measured at the beginning of, and periodically during,
treatment [see WARNINGS AND PRECAUTIONS].
Leukopenia/Neutropenia
Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia
should be advised that they should have their CBC monitored while taking SEROQUEL
XR [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.
Patients should limit consumption of alcohol during treatment with quetiapine
[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 overthe-counter drugs
[see WARNINGS AND PRECAUTIONS].
Pregnancy and Nursing
Patients should be advised to notify their physician if they become pregnant
or intend to become pregnant during therapy. Patients should be advised not
to breast feed if they are taking quetiapine [see Use In Specific Populations].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine
was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/kg
and to rats by gavage at doses of 25, 75, and 250 mg/kg for two years. These
doses are equivalent to 0.1, 0.5, 1.5, and 4.5 times the maximum human dose
for schizophrenia and bipolar mania (800 mg/day) on a mg/m² basis (mice)
or 0.3, 0.9, and 3.0 times the maximum human dose on a mg/m² basis (rats).
There were statistically significant increases in thyroid gland follicular adenomas
in male mice at doses of 250 and 750 mg/kg or 1.5 and 4.5 times the maximum
human dose on a mg/m² basis and in male rats at a dose of 250 mg/kg or
3.0 times the maximum human dose on a mg/m² basis. Mammary gland adenocarcinomas
were statistically significantly increased in female rats at all doses tested
(25, 75, and 250 mg/kg or 0.3, 0.9, and 3.0 times the maximum recommended human
dose on a mg/m² basis).
Thyroid follicular cell adenomas may have resulted from chronic stimulation
of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced
metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine,
and thyroxine clearance consistent with this mechanism were observed in subchronic
toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however,
the results of these studies were not definitive. The relevance of the increases
in thyroid follicular cell adenomas to human risk, through whatever mechanism,
is unknown.
Antipsychotic drugs have been shown to chronically elevate prolactin levels
in rodents. Serum measurements in a 1-year toxicity study showed that quetiapine
increased median serum prolactin levels a maximum of 32- and 13-fold in male
and female rats, respectively. Increases in mammary neoplasms have been found
in rodents after chronic administration of other antipsychotic drugs and are
considered to be prolactin-mediated. The relevance of this increased incidence
of prolactin-mediated mammary gland tumors in rats to human risk is unknown
[see WARNINGS AND PRECAUTIONS].
Mutagenesis
The mutagenic potential of quetiapine was tested in six in vitro bacterial
gene mutation assays and in an in vitro mammalian gene mutation assay
in Chinese Hamster Ovary cells. However, sufficiently high concentrations of
quetiapine may not have been used for all tester strains. Quetiapine did produce
a reproducible increase in mutations in one Salmonella typhimurium tester strain
in the presence of metabolic activation. No evidence of clastogenic potential
was obtained in an in vitro chromosomal aberration assay in cultured
human lymphocytes or in the in vivo micronucleus assay in rats.
Impairment of Fertility
Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral
doses of 50 and 150 mg/kg or 0.6 and 1.8 times the maximum human dose on a mg/m²
basis. Drug-related effects included increases in interval to mate and in the
number of matings required for successful impregnation. These effects continued
to be observed at 150 mg/kg even after a two-week period without treatment.
The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg,
or 0.3 times the maximum human dose on a mg/m² basis. Quetiapine adversely
affected mating and fertility in female Sprague-Dawley rats at an oral dose
of 50 mg/kg, or 0.6 times the maximum human dose on a mg/m² basis. Drug-related
effects included decreases in matings and in matings resulting in pregnancy,
and an increase in the interval to mate. An increase in irregular estrus cycles
was observed at doses of 10 and 50 mg/kg, or 0.1 and 0.6 times the maximum human
dose on a mg/m² basis. The no-effect dose in female rats was 1 mg/kg, or
0.01 times the maximum human dose on a mg/m² basis.
Use In Specific Populations
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of SEROQUEL XR use in pregnant
women. In limited published literature, there were no major malformations associated
with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity
occurred. Quetiapine should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
There are limited published data on the use of quetiapine for treatment of
schizophrenia and other psychiatric disorders during pregnancy. In a prospective
observational study, 21 women exposed to quetiapine and other psychoactive medications
during pregnancy delivered infants with no major malformations. Among 42 other
infants born to pregnant women who used quetiapine during pregnancy, there were
no major malformations reported (one study of 36 women, 6 case reports). Due
to the limited number of exposed pregnancies, these postmarketing data do not
reliably estimate the frequency or absence of adverse outcomes.
When pregnant rats and rabbits were exposed to quetiapine during organogenesis,
there was no increase in the incidence of major malformations in fetuses at
doses up to 2.4 times the maximum recommended human dose for schizophrenia (MRHD,
800 mg/day on a mg/m² basis); however, there was evidence of embryo-fetal
toxicity. In rats, delays in skeletal ossification occurred at 0.6 and 2.4 times
the MRHD and in rabbits at 1.2 and 2.4 times the MRHD. At 2.4 times the MRHD,
there was an increased incidence of carpal/tarsal flexure (minor soft tissue
anomaly) in rabbit fetuses and decreased fetal weights in both species. Maternal
toxicity (decreased body weights and/or death) occurred at 2.4 times the MRHD
in rats and at 0.6-2.4 times the MRHD (all doses) in rabbits.
In a peri/postnatal reproductive study in rats, no drug-related effects were
observed when pregnant dams were treated with quetiapine at doses 0.01, 0.12,
and 0.24 times the MRHD. However, in a preliminary peri/postnatal study, there
were increases in fetal and pup death, and decreases in mean litter weight at
3.0 times the MRHD.
Non-Teratogenic Effects
Neonates exposed to antipsychotic drugs (including SEROQUEL XR), during the
third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal
symptoms following delivery. There have been reports of agitation, hypertonia,
hypotonia, tremor, somnolence, respiratory distress and feeding disorder in
these neonates. These complications have varied in severity; while in some cases
symptoms have been self-limited, in other cases neonates have required intensive
care unit support and prolonged hospitalization.
SEROQUEL XR should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Labor and Delivery
The effect of SEROQUEL XR on labor and delivery in humans is unknown.
Nursing Mothers
SEROQUEL XR was excreted into human milk. Caution should be exercised when
SEROQUEL XR is administered to a nursing woman.
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
Safety and effectiveness of SEROQUEL XR have not been established in pediatric
patients and SEROQUEL XR is not approved for patients under the age of 18 years
[see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
In general, the adverse reactions observed in children and adolescents during
the clinical trials with SEROQUEL 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%).
Geriatric Use
Sixty-eight patients in clinical studies with SEROQUEL XR were 65 years of
age or over. In general, there was no indication of any different tolerability
of SEROQUEL XR in the elderly compared to younger adults. Nevertheless, the
presence of factors that might decrease pharmacokinetic clearance, increase
the pharmacodynamic response to SEROQUEL XR, 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 quetiapine was reduced by 30% to 50% in elderly patients
when compared to younger patients [see DOSAGE AND ADMINISTRATION and
Pharmacokinetics].
Renal Impairment
Clinical experience with SEROQUEL XR in patients with renal impairment [see
CLINICAL PHARMACOLOGY] is limited.
Hepatic Impairment
Since quetiapine is extensively metabolized by the liver, higher plasma levels
are expected in the hepatically impaired population, and dosage adjustment may
be needed [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 6/24/2011
This monograph has been modified to include the generic and brand name in many instances.