HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`SEROQUEL XR safely and effectively. See full prescribing information
`for SEROQUEL XR.
`SEROQUEL XR (quetiapine fumarate) Extended-Release Tablets
`
`Initial U.S. Approval: 1997
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA See full prescribing information for complete boxed
`
`warning.
`
`Antipsychotic drugs are associated with an increased risk of death.
`
`ƒ
`(5.1)
`
`ƒ Quetiapine is not approved for elderly patients with Dementia-
`
`Related Psychoses. (5.1)
`
`
`
`ƒ
`
`
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See
`
`full prescribing information for complete boxed warning.
`
`Increased risk of suicidal thinking and behavior in children,
`
`
`adolescents and young adults taking antidepressants for major
`
`depressive disorder and other psychiatric disorders. (5.2)
`
`
`
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`Indications and Usage, Schizophrenia (1.1), 12/2009
`Indications and Usage, Bipolar Disorder (1.2), 12/2009
`Indications and Usage, Major Depressive Disorder (MDD), Adjunctive
`
`Treatment with Antidepressants (1.3), 12/2009
`Dosage and Administration, Schizophrenia (2.1), 12/2009
`
`Dosage and Administration, Bipolar Disorder (2.2), 12/2009
`
`Dosage and Administration, Major Depressive Disorder (MDD), Adjunctive
`
`Treatment with Antidepressants (2.3), 12/2009
`Warnings and Precautions, Hyperglycemia (5.4), 12/2009
`Warnings and Precautions, Hyperlipidemia (5.5), 12/2009
`Warnings and Precautions, Weight Gain (5.6), 12/2009
`Warnings and Precautions, Increases in Blood Pressure (Children and
`Adolescents) (5.9), 12/2009
`Warnings and Precautions, Hypothyroidism (5.13), 01/2009
`
`Warnings and Precautions, Hyperprolactinemia (5.14), 01/2009
`Warnings and Precautions, Potential for Cognitive and Motor Impairment
`(5.16), 12/2009
`Warnings and Precautions, Suicide (5.20), 12/2009
` ------ - -------------INDICATIONS AND USAGE---------------------------------
`SEROQUEL XR is an atypical antipsychotic indicated for the:
`Treatment of schizophrenia (1.1)
`
`
`Adults: Efficacy was established with SEROQUEL XR in one 6­
`•
`week and one maintenance trial in patients with schizophrenia as
`well as in three 6-week trials with SEROQUEL in patients with
`schizophrenia (14.1)
`
`Acute treatment of manic or mixed episodes associated with bipolar I
`
`
`disorder, both as monotherapy and as an adjunct to lithium or divalproex (1.2)
`
`
`Adults: Efficacy was established with SEROQUEL XR in one 3­
`
`•
`week trial in patients with manic or mixed episodes associated
`
`with bipolar I disorder as well as two 12-week monotherapy trials
`
`and one 3-week adjunctive trial with SEROQUEL in patients with
`
`manic episodes associated with bipolar I disorder (14.2)
`
`Acute treatment of depressive episodes associated with bipolar I disorder (1.2)
`
`Adults: Efficacy was established with SEROQUEL XR in one 8­
`•
`week trial in patients with bipolar I or II disorder as well as two 8­
`week trials with SEROQUEL in patients with bipolar I or II
`disorder (14.2)
`
`Maintenance treatment of bipolar I disorder as an adjunct to lithium or
`divalproex (1.2)
`
`Adults: Efficacy was established with SEROQUEL in two
`•
`maintenance trials in patients with bipolar I disorder (14.2)
`
`
`Adjunctive treatment of major depressive disorder (MDD) (1.3)
`
`Adults: Efficacy as an adjunct to antidepressants was established
`•
`in two 6-week trials in patients with MDD who had an inadequate
`response to an antidepressant alone (14.3)
`
`
`
`
`
`---------DOSAGE AND ADMINISTRATION------------------------------------
`SEROQUEL XR Tablets should be swallowed whole and not split, chewed or
`crushed. SEROQUEL XR should be taken without food or with a light meal
`(approx. 300 calories). SERQOUEL XR should be administered once daily,
`preferably in the evening.
`
`Indication
`
`Dosing Instructions*
`
`Recommended
`Dose / Dose
`Range
`
`
`Schizophrenia-(2.1)
`
`Schizophrenia
`Maintenance
`(Monotherapy) (2.1)
`
`Bipolar Mania-
`Acute monotherapy or
`
`
`as an adjunct to lithium
`
`or divalproex (2.2)
`
`Depressive Episodes
`Associated with Bipolar
`Disorder (2.2)
`
`
`Day 1: 300 mg/day
`
`Dose increases can be made
`at intervals as short as 1 day
`and in increments of up to
`
`300 mg/day.
`400 mg/day to 800 mg/day
`
`
`Day 1: 300 mg.
`
`Day 2: 600 mg.
`
`Day 3: between 400 mg and
`800 mg
`
`Day 1: 50 mg
`
`Day 2: 100 mg
`
`Day 3: 200 mg
`
`Day 4: 300 mg
`
`400 mg/day to 800 mg/day
`
`
`Day 1 and 2: 50 mg
`
`Day 3 and 4: 150 mg
`
`
`
`
`400-800 mg/day
`
`400-800 mg/day
`
`
`
`400– 800 mg/day
`
`300 mg/day
`
`
`400-800 mg/day
`
`
`150-300 mg/day
`
`
`
`Bipolar I Disorder-
`
`Maintenance Treatment
`as an adjunct to lithium
`
`or divalproex (2.2)
`
`Major Depressive
`Disorder, Adjunctive
`Therapy with
`Antidepressants (2.3)
`*After initial dosing, adjustments can be made upwards or downwards, if necessary,
`within the dose range depending upon the clinical response and tolerance of the
`patient.
`
`----------------DOSAGE FORMS AND STRENGTHS--------------------------
`Extended-Release Tablets: 50 mg, 150 mg, 200 mg, 300 mg, and 400 mg
`
`
`
`--------------------CONTRAINDICATIONS----------------------------------------
`None
`------------------------WARNINGS AND PRECAUTIONS----------------------
`Increased Mortality in Elderly Patients with Dementia-Related Psychoses:
`
`•
`Antipsychotic drugs, including quetiapine, are associated with an increased risk
`of death; causes of death are variable. (5.1)
`Suicidality and Antidepressant Drugs: Increased the risk of suicidal thinking
`and behavior in children, adolescents and young adults taking antidepressants
`for major depressive disorder and other psychiatric disorders. (5.2)
`
`
`Neuroleptic Malignant Syndrome (NMS): Manage with
`
`discontinuation and close monitoring. (5.3)
`
`Hyperglycemia and Diabetes Mellitus (DM): Ketoacidosis, hyperosmolar
`
`coma and death have been reported in patients treated with atypical
`including quetiapine. Any patient
`antipsychotics,
`treated with atypical
`
`antipsychotics should be monitored for symptoms of hyperglycemia including
`polydipsia, polyuria, polyphagia, and weakness..When starting treatment,
`
`patients with diabetes or risk factors for diabetes should undergo blood glucose
`testing before and during treatment. (5.4)
`
`Hyperlipidemia: Undesirable alterations in lipids have been observed.
`
`Increases in total cholesterol, LDL-cholesterol and triglycerides and decreases
`
`in HDL-cholesterol have been reported in clinical trials. Appropriate clinical
`monitoring is recommended, including fasting blood lipid testing at the
`beginning of, and periodically, during treatment. (5.5)
`
`• Weight Gain: Patients should receive regular monitoring of weight. (5.6)
`
`
`
`Tardive Dyskinesia: Discontinue if clinically appropriate. (5.7)
`
`•
`Orthostatic Hypotension: Associated dizziness, tachycardia and syncope may
`
`•
`occur especially during the initial dose titration period. Use in caution in
`patients with known cardiovascular or cerebrovascular disease. (5.8)
`
`Increased Blood Pressure in Children and Adolescents: Blood pressure
`
`
`should be measured at the beginning of, and periodically during treatment in
`children and adolescents. SEROQUEL XR has not been evaluated in pediatric
`
`patients. (5.9)
`
` Leukopenia, Neutropenia and Agranulocytosis: have been reported with
`
`
`
`
`atypical antipsychotics including SEROQUEL XR. Patients with a pre-existing
`low white cell count (WBC) or a history of leukopenia/neutropenia should have
`complete blood count (CBC) monitored frequently during the first few months
`
`
`of treatment and should discontinue SEROQUEL XR at the first sign of a
`
`
`
`decline in WBC in absence of other causative factors. (5.10)
`Cataracts: Lens changes have been observed in patients during long-term
`
`quetiapine treatment. Lens examination is recommended when starting
`
`
`treatment and at 6-month intervals during chronic treatment. (5.11)
`Suicide: The possibility of a suicide attempt is inherent in schizophrenia and
`
`bipolar disorder, and close supervision of high risk patients should accompany
`drug therapy. (5.20)
`
`
`See Full Prescribing
`PRECAUTIONS.
`-------------------------- ADVERSE REACTIONS------------------------------
`
`
`•
`
`
`
`
`•
`
`
`•
`
`•
`
`
`
`
`•
`
`•
`
`
`
`
`•
`
`
`•
`
`•
`
`
`
`immediate
`
`
`
`
`
`Information
`
`for additional WARNINGS and
`
`
`
`Exhibit 2034
`Slayback v. Sumitomo
`IPR2020-01053
`
`1
`
`

`

`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`SEE 17 FOR PATIENT COUNSELING INFORMATION AND MEDICATION
`GUIDE
`
`
`REVISED X
`
`Levodopa and Dopamine Agents: Quetiapine may antagonize the effect of
`
`
`these drugs. (7)
`
`---------------------------USE IN SPECIFIC POPULATIONS-------------------
`• Geriatric Use: Consider a lower starting dose (50 mg/day), slower titration,
`
`
`and careful monitoring during the initial dosing period in the elderly. (2.3 and
`8.5)
`
`• Hepatic Impairment: Lower starting dose (50 mg/day) and slower titration
`
`may be needed. (2.3, 8.7, 12.3)
`
`
`Pregnancy: Limited human data. Based on animal data, may cause fetal harm.
`
`
`
`(8.1)
`Nursing Mothers: Caution should be exercised when administered to a nursing
`
`
`woman. (8.3)
`Pediatric Use: Safety and effectiveness have not been established. (8.4)
`
`
`Most common adverse reactions (incidence ≥5% and twice placebo)
`
`in decreasing frequency are: somnolence, dry mouth, , constipation,
`
`
`dizziness, increased appetite, dyspepsia, weight gain, fatigue, dysarthria,
`
`and nasal congestion. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`-----------------------------DRUG INTERACTIONS------------------------
`P450 3A Inhibitors: May decrease the clearance of quetiapine. Lower
`
`
`•
`doses of quetiapine may be required. (7.1)
`
`
`• Hepatic Enzyme Inducers: May increase the clearance of quetiapine.
`
`
`
`Higher doses of quetiapine may be required with phenytoin or other
`
`
`inducers. (7.1)
`Centrally Acting Drugs: Caution should be used when quetiapine is
`used in combination with other CNS acting drugs. (7)
`
`Antihypertensive Agents: Quetiapine may add to the hypotensive
`
`effects of these agents. (7)
`_______________________________________________________________________________________________________________________
`[FULL PRESCRIBING INFORMATION: CONTENTS*
`PEDIATRIC USE
`8.4
`
`
`SUICIDALITY AND ANTIDEPRESSANT DRUGS; WARNING:
`
`
`8.5
`GERIATRIC USE
`
`INCREASED MORTALITY IN ELDERLY PATIENTS WITH
`8.6
` RENAL IMPAIRMENT
`DEMENTIA-RELATED PSYCHOSIS;
`8.7
` HEPATIC IMPAIRMENT
`
`9
`DRUG ABUSE AND DEPENDENCE
`
`
`
`1
`9.1
`CONTROLLED SUBSTANCE
`
`
`
`9.2
`ABUSE
`1.1
`
`OVERDOSAGE
`10
`1.2
`
`
`10.1 HUMAN EXPERIENCE
`1.3
`
`
`10.2 MANAGEMENT OF OVERDOSAGE
`
`
`11
`DESCRIPTION
`
`
`12
`CLINICAL PHARMACOLOGY
`
`
`12.1 MECHANISM OF ACTION
`
`
`12.2 PHARMACODYNAMICS
`
`
`12.3 PHARMACOKINETICS
`
`
`NONCLINICAL TOXICOLOGY
`13
`
`
`13.1 CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF
`
`FERTILITY
`
`
`13.2 ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
`
`
`CLINICAL STUDIES
`14
`
`
`14.1 SCHIZOPHRENIA
`
` BIPOLAR DISORDER
`14.2
`
`14.3 MAJOR DEPRESSIVE DISORDER
`
`15
`REFERENCES
`
`
`16
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`17.1
`INFORMATION FOR PATIENTS
`
`17.2 MEDICATION GUIDE
`
`
`* SECTIONS OR SUBSECTIONS OMITTED FROM THE FULL
`PRESCRIBING INFORMATION ARE NOT LISTED.
`
`
`2.7
`
`3
`
`4
`
`5
`
`5.1
`
`5.2
`5.3
`
`5.4
`
`5.5
`5.6
`5.7
`
`5.8
`
`5.9
`
`2
`
`2.1
`2.2
`
`2.3
`
`2.4
`
`2.5
`
`
`2.6
`
`
`INDICATIONS AND USAGE
` SCHIZOPHRENIA
`BIPOLAR DISORDER
`
`MAJOR DEPRESSIVE DISORDER, ADJUNCTIVE THERAPY
`
`
`
`WITH ANTIDEPRESSANTS
`DOSAGE AND ADMINISTRATION
`
`
`SCHIZOPHRENIA
`
`BIPOLAR DISORDER
`MAJOR DEPRESSIVE DISORDER, ADJUNCTIVE THERAPY
`
`WITH ANTIDEPRESSANTS
`DOSING IN SPECIAL POPULATIONS
`
`RE-INITIATION OF TREATMENT IN PATIENTS
`PREVIOUSLY DISCONTINUED
`
`SWITCHING PATIENTS FROM SEROQUEL TABLETS TO
`
`
`SEROQUEL XR TABLETS
`
`SWITCHING FROM ANTIPSYCHOTICS
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`INCREASED MORTALITY IN ELDERLY PATIENTS WITH
`DEMENTIA-RELATED PSYCHOSIS
`CLINICAL WORSENING AND SUICIDE RISK
`NEUROLEPTIC MALIGNANT SYNDROME (NMS)
`
`HYPERGLYCEMIA AND DIABETES MELLITUS
` HYPERLIPIDEMIA
`WEIGHT GAIN
`TARDIVE DYSKINESIA
`
`ORTHOSTATIC HYPOTENSION
`
`INCREASES IN BLOOD PRESSURE (CHILDREN AND
`
`ADOLESCENTS)
`
`
`LEUKOPENIA, NEUTROPENIA AND AGRANULOCYTOSIS
`5.10
`5.11 CATARACTS
`
`
`5.12 SEIZURES
`
`
`5.13 HYPOTHYROIDISM
`
`
`5.14 HYPERPROLACTINEMIA
`
`5.15 TRANSAMINASE ELEVATIONS
`
`
`5.16 POTENTIAL FOR COGNITIVE AND MOTOR IMPAIRMENT
`
`
`5.17 PRIAPISM
`
`
`5.18 BODY TEMPERATURE REGULATION
`
`
`5.19 DYSPHAGIA
`
`
`5.20 SUICIDE
`
`
`5.21 USE IN PATIENTS WITH CONCOMITANT ILLNESS
`
`5.22 WITHDRAWAL
`
`
`ADVERSE REACTIONS
`6
`
`
`6.1
`CLINICAL STUDIES EXPERIENCE
`
`6.2
`VITAL SIGNS AND LABORATORY VALUES
`6.3
`POST MARKETING EXPERIENCE
`
`
`7
`DRUG INTERACTIONS
`
`
`
`7.1
`THE EFFECT OF OTHER DRUGS ON QUETIAPINE
`
`
`7.2
`EFFECT OF QUETIAPINE ON OTHER DRUGS
`
`
`8
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`PREGNANCY
`
`
`8.2
`LABOR AND DELIVERY
`
`
`8.3
`NURSING MOTHERS
`
`
`
`2
`
`

`

`
`
`1
`1.1
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: 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. Analyses of seventeen 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 Warnings and Precautions (5.1)].
`
`
`SUICIDALITY AND ANTIDEPRESSANT DRUGS
`Antidepressants increased the risk compared to placebo of suicidal thinking and
`behavior (suicidality) in children, adolescents, and young adults in short-term
`studies of major depressive disorder (MDD) and other psychiatric disorders.
`
`Anyone considering the use of SEROQUEL XR or any other antidepressant in a
`child, adolescent, or young adult must balance this risk with the clinical need.
`
`Short-term studies did not show an increase in the risk of suicidality with
`antidepressants compared to placebo in adults beyond age 24; there was a
`reduction in risk with antidepressants compared to placebo in adults aged 65
`and older. Depression and certain other psychiatric disorders are themselves
`associated with increases in the risk of suicide. Patients of all ages who are
`started on antidepressant therapy should be monitored appropriately and
`observed closely for clinical worsening, suicidality, or unusual changes in
`behavior. Families and caregivers should be advised of the need for close
`observation and communication with the prescriber. SEROQUEL XR is not
`
` approved for use in pediatric patients [see Warnings and Precautions (5.2)].
`
`
`
`
`
`INDICATIONS AND USAGE
` Schizophrenia
`SEROQUEL XR is indicated for the treatment of schizophrenia. The
`efficacy of SEROQUEL XR in schizophrenia was established in one 6­
`week and one maintenance trial in adults with schizophrenia as well by
`
`
`
` 3
`
`

`

`
`
`extrapolation from three 6-week trials in adults with schizophrenia
`treated with SEROQUEL [see Clinical Studies (14.1)].
`
`
`1.2 Bipolar Disorder
`
`SEROQUEL XR is indicated for the acute treatment of manic or mixed
`episodes associated with bipolar I disorder, both as monotherapy and as
`an adjunct to lithium or divalproex. The efficacy of SEROQUEL XR
`in manic or mixed episodes of bipolar I disorder was established in one
`3-week trial in adults with manic or mixed episodes associated with
`
`bipolar I disorder as well by extrapolation from two 12-week
`monotherapy and one 3-week adjunctive trial in adults with manic
`
`episodes associated with bipolar I disorder treated with SEROQUEL
`[see Clinical Studies (14.2)].
`
`SEROQUEL XR is indicated for the acute treatment of depressive
`episodes associated with bipolar disorder. The efficacy of SEROQUEL
`XR was established in one 8-week trial in adults with bipolar I or II
`
`disorder as well as extrapolation from two 8-week trials in adults with
`
`bipolar I or II disorder treated with SEROQUEL [see Clinical Studies
`(14.2)].
`
`SEROQUEL XR is indicated for the maintenance treatment of bipolar I
`disorder, as an adjunct to lithium or divalproex. Efficacy was
`extrapolated from two maintenance trials in adults with bipolar I
`
`disorder treated with SEROQUEL. The effectiveness of monotherapy
`for the maintenance treatment of bipolar disorder has not been
`systematically evaluated in controlled clinical trials [see Clinical
`
`Studies (14.2)].
`
`
`
`1.3 Adjunctive Treatment of Major Depressive Disorder (MDD)
`
`SEROQUEL XR is indicated for use as adjunctive therapy to
`antidepressants for the treatment of MDD. The efficacy of SEROQUEL
`XR as adjunctive therapy to antidepressants in MDD was established in
`
`two 6-week trials in adults with MDD who had an inadequate response
`to antidepressant treatment [see Clinical Studies (14.3)].
`
`
`DOSAGE AND ADMINISTRATION
`SEROQUEL XR tablets should be swallowed whole and not
`split, chewed or crushed.
`
`
`It is recommended that SEROQUEL XR be taken without food or with
`a light meal (approximately 300 calories) [see Clinical Pharmacology
`(12.3)].
`
`2
`
`
`
`4
`
`
`
`

`

`
`
`
`
`
`2.1 Schizophrenia
`
`
`
`Dose Selection—SEROQUEL XR should be administered once daily,
`preferably in the evening. The recommended initial dose is 300 mg/day.
`Patients should be titrated within a dose range of 400 mg/day – 800
`mg/day depending on the response and tolerance of the individual
`
`patient [see Clinical Studies (14.1)]. Dose increases can be made at
`
`
`intervals as short as 1 day and in increments of up to 300 mg/day. The
`safety of doses above 800 mg/day has not been evaluated in clinical
`
`trials.
`
`Maintenance Treatment—A maintenance trial in adult patients with
`
`schizophrenia treated with SEROQUEL XR has shown this drug to be
`effective in delaying time to relapse in patients who were stabilized on
`
`SEROQUEL XR at doses of 400 mg/day to 800 mg/day for 16 weeks.
`Patients should be periodically reassessed to determine the need for
`maintenance treatment and the appropriate dose for such treatment [see
`
`Clinical Studies (14.1)].
`
`
`2.2 Bipolar Disorder
`
`
`Bipolar Mania
`
`Usual Dose for Acute Monotherapy or Adjunct Therapy (with
`lithium or divalproex)
`
`Dose Selection—When used as monotherapy or adjunct therapy (with
`lithium or divalproex), SEROQUEL XR should be administered once
`daily in the evening starting with 300 mg on Day 1 and 600 mg on Day
`2. SEROQUEL XR can be adjusted between 400 mg and 800 mg
`
`beginning on Day 3 depending on the response and tolerance of the
`individual patient.
`
`
`Day
`SEROQUEL XR
`
`Recommended Dosing Schedule
`Day 1
`Day 2
`Day 3
`300 mg
`600 mg
`400 mg to 800 mg
`
`
`
`
`
`
` Depressive Episodes Associated with Bipolar Disorder
`
`Usual Dose—SEROQUEL XR should be administered once daily in
`the evening to reach 300 mg/day by Day 4.
`
`
`
`
`Recommended Dosing Schedule
`Day
`Day 1 Day 2
`Day 3
`Day 4
`SEROQUEL XR 50 mg 100 mg
`200 mg
`300 mg
`
`
`
`
`
`
`
`
`5
`
`
`
`

`

`
`
`Maintenance Treatment for Bipolar I Disorder
`Maintenance Treatment—Maintenance of efficacy in bipolar I disorder
`was demonstrated with SEROQUEL (administered twice daily totaling
`400 mg/day to 800 mg/day) as adjunct therapy to lithium or divalproex.
`Generally, in the maintenance phase, patients continued on the same
`
`dose on which they were stabilized during the stabilization phase.
`
`Patients should be periodically reassessed to determine the need for
`maintenance treatment and the appropriate dose for such treatment [see
`
`Clinical Studies (14.2)].
`
`
`2.3 Major Depressive Disorder, Adjunctive Therapy with
`Antidepressants
`
`Dose Selection—SEROQUEL XR in a dose range of 150 mg/day to
`300 mg/day was demonstrated to be effective as adjunctive therapy to
`antidepressants. Begin with 50 mg once daily in the evening. On Day 3,
`the dose can be increased to 150 mg once daily in the evening. There
`
`the
`were dose-dependent
`increases
`in adverse
`reactions
`in
`
`recommended dose range of 150 mg/day to 300 mg/day. Doses above
`300 mg/day were not studied [see Clinical Studies (14.3)].
`
`2.4 Dosing in Special Populations
`Consideration should be given to a slower rate of dose titration and a
`lower target dose in the elderly and in patients who are debilitated or
`
`who have a predisposition to hypotensive reactions [see Use in Specific
`
`
`Populations (8.5, 8.7) and Clinical Pharmacology (12)]. When
`
`indicated, dose escalation should be performed with caution in these
`patients.
`
`
`
`
`
`
`
`
`
`Elderly patients should be started on SEROQUEL XR 50 mg/day and
`the dose can be increased in increments of 50 mg/day depending on the
`response and tolerance of the individual patient.
`
`Patients with hepatic impairment should be started on SEROQUEL XR
`50 mg/day. The dose can be increased daily in increments of 50 mg/day
`to an effective dose, depending on the clinical response and tolerance of
`the patient.
`
`The elimination of quetiapine was enhanced in the presence of
`
`phenytoin. Higher maintenance doses of quetiapine may be required
`when it is coadministered with phenytoin and other enzyme inducers
`
`such as carbamazepine and phenobarbital [see Drug Interactions (7.1)].
`
`
`
`
`6
`
`
`
`

`

`
`
`2.5 Re-initiation of Treatment in Patients Previously
`
`Discontinued
`Although there are no data to specifically address reinitiation of
`treatment, it is recommended that when restarting therapy of patients
`who have been off SEROQUEL XR for more than one week, the initial
`dosing schedule should be followed. When restarting patients who
`have been off SEROQUEL XR for less than one week, gradual dose
`escalation may not be required and the maintenance dose may be
`
`reinitiated.
`
`
`2.6
`
`
`2.7
`
`3
`
`4
`
`5
`
`
`
` Switching Patients from SEROQUEL Tablets to SEROQUEL
`XR Tablets
`Patients who are currently being treated with SEROQUEL (immediate
`release formulation) may be switched to SEROQUEL XR at the
`equivalent total daily dose taken once daily. Individual dosage
`
`adjustments may be necessary.
`
` Switching from Antipsychotics
`There are no systematically collected data to specifically address
`
`switching patients from other antipsychotics to SEROQUEL XR, or
`
`concerning concomitant administration with other antipsychotics.
`While
`immediate discontinuation of
`the previous antipsychotic
`treatment may be acceptable for some patients, more gradual
`discontinuation may be most appropriate for others. In all cases, the
`period of overlapping antipsychotic administration should be
`minimized. When switching patients from depot antipsychotics, if
`medically appropriate, initiate SEROQUEL XR therapy in place of the
`next
`scheduled
`injection. The need
`for continuing existing
`extrapyramidal
`syndrome medication
`should be
`re-evaluated
`periodically.
`
`DOSAGE FORMS AND STRENGTHS
`50 mg extended-release tablets
`
`150 mg extended-release tablets
`
`200 mg extended-release tablets
`
`300 mg extended-release tablets
`
`
`400 mg extended-release tablets
`
`
` CONTRAINDICATIONS
`None
`
`WARNINGS AND PRECAUTIONS
`
`
`7
`
`
`
`

`

`
`
`5.1
`
`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].
`
`
`5.2 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.
`
`
`
`
`8
`
`
`

`

`
`
`
`
`Age Range
`
`
`
`<18
`18-24
`
`
`25-64
`≥65
`
` Table 1
`
`Drug-Placebo Difference in
`Number of Cases of
`Suicidality per 1000 Patients
`Treated
`Increases Compared to
`Placebo
`14 additional cases
`5 additional cases
`Decreases Compared to
`Placebo
`
`1 fewer case
`
`6 fewer cases
`
`
`
`
`No suicides occurred in any of the pediatric trials. There were suicides
`
`in the adult trials, but the number was not sufficient to reach any
`conclusion about drug effect on suicide.
`
`It is unknown whether the suicidality risk extends to longer-term use,
`i.e., beyond several months. However, there is substantial evidence
`from placebo-controlled maintenance trials in adults with depression
`that the use of antidepressants can delay the recurrence of depression.
`
`All patients being treated with antidepressants for any indication
`
`should be monitored appropriately and observed closely for clinical
`worsening, suicidality, and unusual changes in behavior, especially
`
`during the initial few months of a course of drug therapy, or at
`times of dose changes, either increases or decreases.
`
`
`The following symptoms, anxiety, agitation, panic attacks, insomnia,
`irritability,
`hostility,
`aggressiveness,
`impulsivity,
`akathisia
`(psychomotor restlessness), hypomania, and mania, have been reported
`in adult and pediatric patients being treated with antidepressants for
`major depressive disorder as well as for other indications, both
`psychiatric and nonpsychiatric. Although a causal link between the
`emergence of such symptoms and either the worsening of depression
`
`and/or the emergence of suicidal impulses has not been established,
`there is concern that such symptoms may represent precursors to
`emerging suicidality.
`
`Consideration should be given to changing the therapeutic regimen,
`including possibly discontinuing the medication, in patients whose
`
`depression is persistently worse, or who are experiencing emergent
`suicidality or symptoms that might be precursors to worsening
`
`9
`
`
`
`

`

`
`
`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.
`
`5.3 Neuroleptic Malignant Syndrome (NMS)
`
`A potentially fatal symptom complex sometimes referred to as
`in
`Neuroleptic Malignant Syndrome (NMS) has been reported
`
`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.
`
`this syndrome
`The diagnostic evaluation of patients with
`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
`
`central
`considerations
`in
`the differential diagnosis
`include
`
`
`
`10
`
`
`
`

`

`
`
`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.
`
`
`5.4 Hyperglycemia and Diabetes Mellitus
`Hyperglycemia,
`in some cases extreme and assoc