SEROquel XR

• Seroquel^®
• Seroquel^® XR

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Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• side effects

The recommended dose range of Seroquel XR for the treatment of schizophrenia in adults and adolescents is 400-800mg/day.

The recommended dose range of Seroquel XR for the treatment of Bipolar I disorder (manic or mixed) in adults is 400-800mg/day.

The recommended dose range of Seroquel XR for the treatment of Bipolar I disorder (manic) in children and adolescents is 400-600 mg/day.

The recommended dose of Seroquel XR for bipolar depression is 300 mg/day.

The recommended dose range of Seroquel XR in combination with other medications to treat Major Depressive Disorder in adults is 150-300 mg/day.

 

This section provides information on the proper use of a number of products that contain quetiapine. It may not be specific to Seroquel XR. Please read with care.

Take this medicine exactly as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Quetiapine tablets may be taken with or without food on a full or empty stomach. However, if your doctor tells you to take it a certain way, take it as directed.

Swallow the extended-release tablets whole. Do not break, crush, or chew it. It is best to take this medicine without food or with a light meal (approximately 300 calories).

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (extended-release tablets):
  • For treatment of depression with bipolar disorder:
    • Adults—At first, 50 milligrams (mg) once a day in the evening. Your doctor may adjust your dose as needed. However, the dose is usually not more than 300 mg per day.
    • Children—Use and dose must be determined by the doctor.
  • For treatment of mania with bipolar disorder:
    • Adults—At first, 300 milligrams (mg) once a day in the evening. Your doctor may adjust your dose as needed. However, the dose is usually not more than 800 mg per day.
    • Children 10 to 17 years—At first, 50 mg once a day in the evening. Your doctor may adjust your dose as needed. However, the dose is usually not more than 600 mg per day.
    • Children younger than 10 years—Use and dose must be determined by the doctor.
  • For treatment of major depressive disorder (MDD):
    • Adults—At first, 50 milligrams (mg) once a day in the evening. Your doctor may adjust your dose as needed. However, the dose is usually not more than 300 mg per day.
    • Children—Use and dose must be determined by the doctor.
  • For treatment of schizophrenia:
    • Adults—At first, 300 milligrams (mg) once a day in the evening. Your doctor may adjust your dose as needed. However, the dose is usually not more than 800 mg per day.
    • Children 13 to 17 years—At first, 50 mg once a day in the evening. Your doctor may adjust your dose as needed. However, the dose is usually not more than 800 mg per day.
    • Children younger than 13 years—Use and dose must be determined by the doctor.
• For oral dosage form (tablets):
  • For treatment of depression with bipolar disorder:
    • Adults—At first, 50 milligrams (mg) once a day at bedtime. Your doctor may adjust your dose as needed. However, the dose is usually not more than 300 mg per day.
    • Children—Use and dose must be determined by the doctor.
  • For treatment of mania with bipolar disorder:
    • Adults—At first, 50 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 800 mg per day.
    • Children 10 to 17 years—At first, 25 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 600 mg per day.
    • Children younger than 10 years—Use and dose must be determined by the doctor.
  • For treatment of schizophrenia:
    • Adults—At first, 25 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 750 mg per day.
    • Children 13 to 17 years—At first, 25 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 800 mg per day.
    • Children younger than 13 years—Use and dose must be determined by the doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness.
• Headache.
• Feeling nervous and excitable.
• Hard stools (constipation).
• Dry mouth.
• Feeling sleepy.
• Weight gain.
• Upset stomach or throwing up.
• Feeling tired or weak.
• Belly pain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Seroquel XR is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

Suicidal Thoughts and Behaviors in Adolescents and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

Table 2: Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated

Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
	Increases Compared to Placebo
<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, including Seroquel XR, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. Seroquel XR is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

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 (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies. Changes in these metabolic profiles should be managed as clinically appropriate.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Adults:

Table 3: Fasting Glucose-Proportion of Patients Shifting to ≥ 126 mg/dL in Short-Term (≤ 12 weeks) Placebo-Controlled Studies*

* Includes SEROQUEL and Seroquel XR data.
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 <126 mg/dL to ≥126 mg/dL)	Quetiapine	572	67 (11.7%)
		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 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 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 4 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 4: 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	Seroquel XR   150 mg	280	19 (7%)
	Seroquel XR   300 mg	269	32 (12%)
	Placebo	277	17 (6%)

Children and Adolescents: Safety and effectiveness of Seroquel XR is supported from studies of SEROQUEL in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.2)]. 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.

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.

Dyslipidemia

Adults:

Table 5 shows the percentage of patients with changes in cholesterol and triglycerides from baseline by indication in clinical trials with Seroquel XR.

Table 5: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication

* 6 weeks duration † 8 weeks duration ‡ 3 weeks duration
Laboratory Analyte	Indication	Treatment Arm	N	Patients   n (%)
Total Cholesterol ≥240 mg/dL	Schizophrenia*	Seroquel XR	718	67 (9%)
		Placebo	232	21 (9%)
	Bipolar Depression†	Seroquel XR	85	6 (7%)
		Placebo	106	3 (3%)
	Bipolar Mania‡	Seroquel XR	128	9 (7%)
		Placebo	134	5 (4%)
	Major Depressive Disorder (Adjunct Therapy)*	Seroquel XR	420	67 (16%)
		Placebo	213	15 (7%)
Triglycerides ≥200 mg/dL	Schizophrenia*	Seroquel XR	659	118 (18%)
		Placebo	214	11 (5%)
	Bipolar Depression†	Seroquel XR	84	7 (8%)
		Placebo	93	7 (8%)
	Bipolar Mania‡	Seroquel XR	102	15 (15%)
		Placebo	125	8 (6%)
	Major Depressive Disorder (Adjunct Therapy) *	Seroquel XR	458	75 (16%)
		Placebo	223	18 (8%)
LDL-Cholesterol ≥ 160 mg/dL	Schizophrenia*	Seroquel XR	691	47 (7%)
		Placebo	227	17 (8%)
	Bipolar Depression†	Seroquel XR	86	3 (4%)
		Placebo	104	2 (2%)
	Bipolar Mania‡	Seroquel XR	125	5 (4%)
		Placebo	135	2 (2%)
	Major Depressive Disorder (Adjunct Therapy)*	Seroquel XR	457	51 (11%)
		Placebo	219	21 (10%)
HDL-Cholesterol ≤ 40 mg/dL	Schizophrenia*	Seroquel XR	600	87 (15%)
		Placebo	195	23 (12%)
	Bipolar Depression†	Seroquel XR	78	7 (9%)
		Placebo	83	6 (7%)
	Bipolar Mania‡	Seroquel XR	100	19 (19%)
		Placebo	115	15 (13%)
	Major Depressive Disorder (Adjunct Therapy)*	Seroquel XR	470	34 (7%)
		Placebo	230	19 (8%)

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 6 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 6: 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

* 6 weeks duration
Laboratory Analyte	Treatment Arm*	N	Patients n (%)
Cholesterol ≥ 240 mg/dL	Seroquel XR   150 mg	223	41 (18%)
	Seroquel XR   300 mg	197	26 (13%)
	Placebo	213	15 (7%)
Triglycerides ≥ 200 mg/dL	Seroquel XR   150 mg	232	36 (16%)
	Seroquel XR   300 mg	226	39 (17%)
	Placebo	223	18 (8%)
LDL-Cholesterol ≥ 160 mg/dL	Seroquel XR   150 mg	242	29 (12%)
	Seroquel XR   300 mg	215	22 (10%)
	Placebo	219	21 (10%)
HDL-Cholesterol ≤ 40 mg/dL	Seroquel XR   150 mg	238	14 (6%)
	Seroquel XR   300 mg	232	20 (9%)
	Placebo	230	19 (8%)

Children and Adolescents:

Safety and effectiveness of Seroquel XR is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)].

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 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.

Table 7 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 in adolescents (13–17 years) with schizophrenia and in children and adolescents (10–17 years) with bipolar mania.

Table 7: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication

* 13-17 years, 6 weeks duration † 10-17 years, 3 weeks duration
Laboratory Analyte	Indication	Treatment Arm	N	Patients   n (%)
Total Cholesterol ≥200 mg/dL	Schizophrenia*	SEROQUEL	107	13 (12%)
		Placebo	56	1 (2%)
	Bipolar Mania†	SEROQUEL	159	16 (10%)
		Placebo	66	2 (3%)
Triglycerides ≥150 mg/dL	Schizophrena*	SEROQUEL	103	17 (17%)
		Placebo	51	4 (8%)
	Bipolar Mania†	SEROQUEL	149	32 (22%)
		Placebo	60	8 (13%)
LDL-Cholesterol ≥ 130 mg/dL	Schizophrenia*	SEROQUEL	112	4 (4%)
		Placebo	60	1 (2%)
	Bipolar Mania†	SEROQUEL	169	13 (8%)
		Placebo	74	4 (5%)
HDL-Cholesterol ≤ 40 mg/dL	Schizophrenia*	SEROQUEL	104	16 (15%)
		Placebo	54	10 (19%)
	Bipolar Mania†	SEROQUEL	154	16 (10%)
		Placebo	61	4 (7%)

Weight Gain

Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.

Adults: Table 8 shows the percentage of adult patients with weight gain of ≥7% of body weight by indication.

Table 8: Percentage of Patients with Weight Gain ≥7% of Body Weight (Adults) by Indication

* 6 weeks duration † 3 weeks duration ‡ 8 weeks duration
Vital sign	Indication	Treatment Arm	N	Patients   n (%)
Weight Gain ≥7% of Body Weight	Schizophrenia*	Seroquel XR	907	90 (10%)
		Placebo	299	16 (5%)
	Bipolar Mania†	Seroquel XR	138	7 (5%)
		Placebo	150	0 (0%)
	Bipolar Depression‡	Seroquel XR	110	9 (8%)
		Placebo	125	1 (1%)
	Major Depressive Disorder (Adjunctive Therapy)*	Seroquel XR	616	32 (5%)
		Placebo	302	5 (2%)

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 9 shows the percentage of adult patients with weight gain of ≥7% of body weight for MDD by dose.

Table 9: 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	Seroquel XR   150 mg	309	10 (3%)
	Seroquel XR   300 mg	307	22 (7%)
	Placebo	302	5 (2%)

Children and Adolescents: Safety and effectiveness of Seroquel XR is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)]. 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.

Weight gain was greater in patients 10-12 years of age compared to patients 13-17 years of age. The percentage of patients 10-12 years of age with weight gain ≥7% at any time was 28% (7/25) for Seroquel XR vs. 0% (0/28) for placebo. The percentage of patients 13-17 years of age with weight gain ≥7% at any time was 10.4% (7/67) for Seroquel XR vs. 13.9% (10/72) for placebo.

Table 10 shows the percentage of children and adolescents with weight gain ≥7% of body weight in clinical trials with SEROQUEL in adolescents (13 – 17 years) with schizophrenia and in children and adolescents (10 – 17 years) with bipolar mania.

Table 10: Percentage of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents)

* 6 weeks duration † 3 weeks duration
Vital sign	Indication	Treatment Arm	N	Patients   n (%)
Weight Gain ≥7% of Body Weight	Schizophrenia*	SEROQUEL	111	23 (21%)
		Placebo	44	3 (7%)
	Bipolar Mania†	SEROQUEL	157	18 (12%)
		Placebo	68	0 (0%)

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.

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 ά1-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). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

5.8 Falls

A typical antipsychotic drugs, including Seroquel XR, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Increases in Blood Pressure (Children and Adolescents)

Safety and effectiveness of Seroquel XR is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)].

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.

In placebo-controlled trials in children and adolescents with schizophrenia (13-17 years old, 6-week duration) or bipolar mania (10-17 years old, 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.

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.

Cataracts

The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see Nonclinical Toxicology (13.2)]. 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.

QT Prolongation

In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine [see Overdosage (10.1)], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.

The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).

Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g., cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).

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. 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 Seroquel XR clinical trials across all indications 1.8% (24/1336) of patients on Seroquel XR versus 0.6% (3/530) on placebo experienced decreased free thyroxine (<0.8 LLN) and 1.6% (21/1346) on Seroquel XR versus 3.4% (18/534) on placebo experienced increased thyroid stimulating hormone (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 shifts in thyroid hormones and TSH were1: decrease in 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 11 shows the incidence of these shifts in short term placebo-controlled clinical trials.

Table 11: Incidence of Shifts in Thyroid Hormone Levels and TSH in Short Term Placebo-Controlled Clinical Trials*†

* Based on shifts from normal baseline to potentially clinically important value at any time 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 † Includes SEROQUEL and Seroquel XR data.
Total T4		Free T4		Total T3		Free T3		TSH
Quetiapine	Placebo	Quetiapine	Placebo	Quetiapine	Placebo	Quetiapine	Placebo	Quetiapine	Placebo
3.4% (37/1097)	0.6% (4/651)	0.7% (52/7218)	0.1% (4/3668)	0.5%   (2/369)	0.0%   (0/113)	0.2% (11/5673)	0.0% (1/2679)	3.2%   (240/7587)	2.7%   (105/3912)

In short-term placebo-controlled monotherapy trials, the incidence of reciprocal shifts in T3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0 % (1/3007) for placebo.

Children and Adolescents: Safety and effectiveness of Seroquel XR is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)].

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 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.

1

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 is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)]. 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 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 Nonclinical Toxicology (13.1)].

Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction 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).

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, e.g., 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.

Discontinuation Syndrome

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 reactions (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 dose reduction is advised.

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 (MRHD) of 800 mg/day based on mg/m2 body surface area (mice) or 0.3, 1, and 3 times the MRHD based on mg/m2 body surface area (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses 1.5 and 4.5 times the MRHD on mg/m2 body surface area and in male rats at a dose of 3 times the MRHD on mg/m2 body surface area. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (0.3, 1, and 3 times the MRHD on mg/m2 body surface area).

Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown.

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-year toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32- and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown [see Warnings and Precautions (5.15)].

Mutagenesis

The mutagenic potential of quetiapine was tested in the in vitro Ames bacterial gene mutation assay and in the in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. The clastogenic potential of quetiapine was tested in the in vitro chromosomal aberration assay in cultured human lymphocytes and in the in vivo bone marrow micronucleus assay in rats up to 500 mg/kg which is 6 times the maximum recommended human dose on mg/m2 body surface area. Based on weight of evidence quetiapine was not mutagenic or clastogenic in these tests.

Impairment of Fertility

Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the maximum human dose (MRHD) of 800 mg/day on mg/m2 body surface area. Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 3 times the MRHD even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg, or 0.3 times the MRHD dose on mg/m2 body surface area. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose approximately 1 times the MRHD of 800 mg/day on mg/m2 body surface area. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/kg, or approximately 0.1 and 1 times the MRHD of 800 mg/day on mg/m2 body surface area. The no-effect dose in female rats was 1 mg/kg, or 0.01 times the MRHD of 800 mg/day on mg/m2 body surface area.

Animal Toxicology and/or Pharmacology

Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study. Doses were 10 to 250 mg/kg in rats and 75 to 750 mg/kg in mice; these doses are 0.1-3, and 0.1-4.5 times the maximum recommended human dose (MRHD) of 800 mg/day on mg/m2 body surface area, respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.

In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the MRHD of 800 mg/day on mg/m2 body surface area. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta 8 cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the MRHD of 800 mg/day on mg/m2 body surface area.

NDC 310-0284-60

60 tablets

Seroquel XR®

quetiapine fumarate

extended-release tablets

400 mg* Once Daily

Rx only

AstraZeneca Pharmaceuticals LP

Wilmington, DE 19850

Product of Belgium

AstraZeneca

Applies to quetiapine: oral tablet, oral tablet extended release

General

The most common adverse reactions reported in adults have included somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, weight gain, lethargy, increased ALT, and dyspepsia. In children and adolescents, the most common adverse reactions reported have included somnolence, dizziness, fatigue, increased appetite, nausea, vomiting, dry mouth, tachycardia, and increased weight.

Psychiatric

Very common (10% or more): Discontinuation syndrome (12.1%), agitation (up to 20%)
Common (1% to 10%): Anxiety, depression, irritability, hypersomnia, abnormal dreams, aggression, suicidal ideation and behavior
Uncommon (0.1% to 1%): Abnormal dreams, abnormal thinking, amnesia, psychosis, hallucinations, manic reaction, depersonalization, catatonic reaction
Rare (0.01% to 0.1%): Delirium, emotional lability, euphoria, somnambulism
Frequency not reported: Suicides, nightmares, drug withdrawal syndrome neonate, withdrawal symptoms[Ref]

Nervous system

Somnolence usually occurred during the first 2 weeks and resolved with continued therapy.[Ref]

Very common (10% or more): Somnolence (up to 57%), dizziness (up to 18%), headache (21%)
Common (1% to 10%): Hypertonia, incoordination, tremor, speech disorder, ataxia, lethargy, paresthesia, extrapyramidal disorder, balance disorder, hypoesthesia, restless leg syndrome, hypersomnia, tremor
Uncommon (0.1% to 1%): Seizures, akathisia, dyskinesia, tardive dyskinesia, involuntary movements, hyperkinesia, abnormal gait, myoclonus, bruxism, hemiplegia, taste perversion
Rare (less than 0.1%): Neuroleptic malignant syndrome, aphasia, buccoglossal syndrome, choreoathetosis, neuralgia, subdural hematoma
Postmarketing reports: Retrograde amnesia[Ref]

Hypersensitivity

Very rare (less than 0.01%): Anaphylactic reactions
Frequency not reported: Hypersensitivity

Gastrointestinal

Logistic regression analysis has shown a positive dose response for dyspepsia and abdominal pain.[Ref]

Very common (10% or more): Dry mouth (up to 44%),
Common (1% to 10%): Constipation, dyspepsia, vomiting, abdominal pain, gastroenteritis, gastroesophageal reflux disease, dysphagia
Uncommon (0.1% to 1%): Increased salivation, gingivitis, flatulence, hemorrhoids, stomatitis, mouth ulceration, tongue edema
Rare (0.01% to 0.1%): Glossitis, hematemesis, intestinal obstruction, melena
Frequency not reported: Pancreatitis[Ref]

Cardiovascular

Collective data gathered from 17 placebo-controlled clinical studies (n=5106) involving the use of atypical antipsychotic agents, including quetiapine (the active ingredient contained in Seroquel XR) for the treatment of behavioral disorders in the elderly patient with dementia showed a risk of death 1.6 to 1.7 times greater in the drug treated patient than in the placebo treated patient. The average length of duration for the trials was 10 weeks with the cause of death in the majority of cases, though not all, reported as either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Similar results (i.e., increased risk of mortality with atypical antipsychotics) were reported in another meta-analysis involving elderly dementia patients that consisted of 15 randomized, placebo-controlled trials (n=3353) of 10 to 12 weeks in duration. Quetiapine is not approved by the FDA for use in the treatment of behavioral disorders in elderly patients with dementia.

An increased risk of mortality, possibly due to heart failure or sudden death, has been reported with the use of atypical antipsychotic agents in the treatment of behavioral disorders in the elderly patient with dementia.

The results of a large retrospective cohort study appear to indicate that atypical antipsychotic agents (i.e., risperidone, olanzapine, clozapine, quetiapine) increase the risk of venous thromboembolism in elderly patients; however, these events seem to be rare.

Blood pressure elevations described as systolic elevations of 20 mmHg or greater and diastolic elevations of 10 mmHg or greater were observed in 15.2% and 40.6% of children and adolescents, respectively. One child with a history of hypertension experienced a hypertensive crisis.

QT intervals have not been systematically evaluated. During clinical trials, persistent increases in QT intervals were not identified; however there have been postmarketing reports of QT prolongation in patients who overdosed on this drug, in patients with concomitant illness, and in patients taking drugs that are known to cause electrolyte imbalance or QT interval prolongation.[Ref]

Very common (10% or more): Systolic (15.2%) and diastolic (40.6%) blood pressure elevations in pediatric patients
Common (1% to 10%): Syncope, tachycardia, postural hypotension, peripheral edema, hypotension, hypertension, palpitations
Uncommon (0.1% to 1%): Bundle branch block
Rare (0.01% to 0.1%): Angina pectoris, atrial fibrillation, AV bloc first degree, congestive heart failure, ST elevated, T wave flattening, ST abnormality, increased QRS duration, venous thromboembolism
Very rare (less than 0.01%): Hypertensive crisis
Frequency not reported: Cardiomyopathy, myocarditis, bradycardia, peripheral edema
Postmarketing reports: QT prolongation[Ref]

Endocrine

Common (1% to 10%): Shifts in thyroid hormones and TSH, hyperprolactinemia, altered hormone levels, hypothyroidism
Uncommon (0.1% to 1%): Hypothyroidism
Rare (0.01% to 0.1%): Gynecomastia, hyperthyroidism
Frequency not reported: Priapism
Postmarketing reports: Syndrome of inappropriate hormone secretion (SIADH)[Ref]

In adults, dose-related decreases in thyroid hormone levels have been observed. It appears that maximal reductions in total and free thyroxine (T4) occur in the first 6 weeks of treatment and are maintained without adaptation or progression during chronic therapy. Upon therapy discontinuation, these effects mostly return to baseline values. The mechanism by which this drug affects the thyroid axis is unclear.[Ref]

Metabolic

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. While these effects have been shown as a class effect, each agent has its own profile.

Hyperglycemia: Adults: In controlled clinical trials of 12 weeks or less, 2.4% of patients with normal (less than 100 mg/dL) fasting plasma glucose (FPG) had at least 1 FPG reading of 126 mg/dL or greater (vs. placebo 1.4%) during treatment. For patients with baseline borderline to high FPG (100 mg/dL or higher), 11.7% had at least 1 FPG reading of 126 mg/dL or greater (vs. placebo, 11.8%). In 2 longer-term trials, the mean change in blood glucose from baseline in patients treated with quetiapine (the active ingredient contained in Seroquel XR) (mean exposure 213 days; n=646) was 5 mg/dL (vs. placebo -0.05 mg/dL). Among patients with major depressive disorder receiving the extended-release formulation of this drug, a FBG greater than 126 mg/dL occurred in 7%, 12%, and 6% of those receiving 150 mg, 300 mg, or placebo.
Pediatrics: In a study of patients 10 to 17 years old with bipolar mania, the mean change in fasting glucose was 3.62 mg/dL (n=170). No patients with a baseline fasting glucose level lower than 126 mg/dL had a treatment-emergent blood glucose level greater than 126 mg/dL.

Dyslipidemia: Across indications, adult patients who experienced shifts in total cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol from baseline to clinically significant levels occurred in up to 18%, 22%, 6%, and 14% of patients receiving this drug compared with up to 7%, 16%, 5%, and 14% receiving placebo, respectively. For pediatric patients, the shifts were up to 12%, 22%, 8%, and 15% compared to up to 3%, 13%, 5%, and 19% for this drug and placebo, respectively.

Weight gain: Logistic regression analysis has shown a positive dose response for weight gain. Five to 10% of adult patients experienced a weight gain of 7% or greater (vs. up to 5% in placebo). Among children and adolescents, a weight gain of 7% or greater occurred in 7% to 21% of patients receiving this drug compared with up to 7% in placebo patients. Mean change in body weight was 1.7 to 2 kg in 3 to 6 week trials and 4.4 kg in 26 week trials. These results were not adjusted for normal growth.[Ref]

Very common (10% or more): Hyperglycemia, increases in serum triglycerides, hyperlipidemia,
Common (1% to 10%): Weight gain, increased appetite, thirst
Uncommon (0.1% to 1%): Weight loss, alkaline phosphatase increased, hyperglycemia, hypoglycemia
Rare (0.01% to 0.1%): Glycosuria, gout, hypokalemia, water intoxication, metabolic syndrome
Postmarketing reports: Hyponatremia[Ref]

Dermatologic

Common (1% to 10%): Rash, sweating, acne
Uncommon (0.1% to 1%): Photosensitivity reaction, pruritus, eczema, contact dermatitis, maculopapular rash, seborrhea, skin ulcer, ecchymosis
Rare (0.01% to 0.1%): Exfoliative dermatitis, psoriasis, skin discoloration
Frequency not reported: Erythema multiforme
Postmarketing reports: Steven-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)[Ref]

Respiratory

Common (1% to 10%): Pharyngitis, rhinitis, sinusitis, nasal congestion, cough, sinus congestion, epistaxis, upper respiratory tract infection
Uncommon (0.1% to 1%): Pneumonia, asthma
Rare (0.01% to 0.1%): Hiccup, hyperventilation
Frequency not reported: Dyspnea[Ref]

Other

Common (1% to 10%): Pain, asthenia, fever, balance disorder,
Frequency not reported: Hypothermia, vertigo[Ref]

Hematologic

Very common (10% or more): Decreased hemoglobin
Common (1% to 10%): Decreased neutrophil count, leucopenia
Uncommon (0.1% to 1%): Leukocytosis, anemia, eosinophilia, lymphadenopathy, decreased platelets
Rare (0.01% to 0.1%): Agranulocytosis
Frequency not reported: Leukopenia/neutropenia, eosinophilia[Ref]

Ocular

Common (1% to 10%): Amblyopia, blurred vision
Uncommon (0.1% to 1%): Conjunctivitis, abnormal vision, dry eyes, blepharitis, eye pain
Rare (0.01% to 0.1%): Glaucoma
Frequency not reported: Lens changes[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection
Uncommon (0.1% to 1%): Urinary retention, moniliasis, dysmenorrhea, vaginitis, urinary incontinence, metrorrhagia, dysuria, abnormal ejaculation,
Rare (0.01% to 0.1%): Nocturia, polyuria
Frequency not reported: Galactorrhea
Postmarketing reports: Nocturnal enuresis[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, twitching, arthralgia, dysarthria, extremity pain, muscle rigidity, musculoskeletal stiffness
Uncommon (0.1% to 1%): Pathological fracture, myasthenia, leg cramps, bone pain
Frequency not reported: Elevations in serum creatine phosphokinase (not associated with NMS)
Postmarketing reports: Rhabdomyolysis[Ref]

Renal

Rare (0.01% to 0.1%): Acute renal failure[Ref]

Hepatic

Common (1% to 10%): Increased ALT, increased AST
Rare (0.01% to 0.1%): Jaundice, hepatitis
Frequency not reported: Gamma GT elevations[Ref]

Immunologic

Common (1% to 10%): Infection, tooth abscess
Frequency not reported: Influenza

Some side effects of Seroquel XR may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.