HIGHLIGHTS OF PRESCRIBING INFORMATION
`¢=Neuroleptic Malignant Syndrome (NMS); Manage with immediate
`‘These highlights do not include all the information needed to use
`discontinuation and close monitoring (5.4)
`SEROQUELsafely and effectively. See full prescribing information for
`© Metabolic Changes: Atypical antipsychotics have beenassociated with
`SEROQUEL.
`metabolic changes. These metabolic changes include hyperglycemia,
`SEROQUEL®(quetiapine fumarate) tablets, for oral use
`dyslipidemia, and weight gain (5.5)
`Tnitial U.S. Approval: 1997
`«
`Hyperglycemia and Diabetes Mellitus: Monitor patients for
`WARNING: INCREASED MORTALITYIN ELDERLYPATIENTS
`symptoms ofhyperglycemia including polydipsia, polyuria,
`polyphagia, and weakness. Monitor glucose regularly in paticnts
`WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL
`with diabetes or at risk for diabetes
`THOUGHTS AND BEHAVIORS
`Seefullprescribing informationfor complete haxed warning.
`¢—Dyslipidemia: Undesirable alterations have been observed in
`Increased Mortality in Elderly Patients with Dementia-Related
`patients treated with atypical antipsychotics. Appropriate clinical
`Psychosis
`monitoring is recommended, including fasting blood lipid testing
`«
`Elderly patients with dementia-related psychosis treated with
`at the beginning of, and periodically, during treatment
`antipsychotic drugs are at an increased risk of death. SEROQUEL
`Weight Gain: Gain in body weight has been observed; clinical
`is not approved for elderly patients with dementia-related
`monitoring of weight is recommended
`psychosis (5.1)
`Suicidal Thoughts and Behaviors
`Tardive Dyskinesia: Discontinueif clinically appropriate (5.6)
`¢
`thoughts and behavior in children,
`e
`Increased risk of suicidal
`¢ Hypotension: Use with cautionin patients with known cardiovascular or
`adolescents and young adults taking antidepressants (5.2)
`cerebrovascular disease (5.7)
`Monitor for worsening and emergence of suicidal thoughts and
`Increased BloodPressure in Children and Adolescents: Monitor blood
`behaviors (5.2)
`pressure at the beginning of, and periodically during treatmentin children
`and adolescents (5.9)
`Leukopenia, Neutropenia andAgranulocytosis: Monitor complete blood
`count frequently during the first few months of treatment in patients with
`ones INDICATIONS AND USAGE
`4 pre-existing lowwhite cell count or a history of leukopenia/neutropenia
`SEROQUELis an atypical antipsychotic indicated for the treatment of:
`and discontinue SEROQUELatthefirst sign of'a decline in WBC in
`®
`Schizophrenia (1.1)
`absence ofother causative factors (5.10)
`e
`Bipolar ] disorder manic episodes (1.2)
`* Cataracts: Lens changes have been observedin patients during long-term
`e
`Bipolar disorder, depressive episodes (1.2)
`quetiapine treatment. Lens examination is recommended when starting
`treatment and at 6-month intervals during chronic treatment (5.11)
`——------------—- DOSAGE AND ADMINISTRATION
`e
`SEROQUELcan be taken with or without food (2.1
`ADVERSE REACTIONS
`
`Indication
`Initial Dose
`Recommended
`Maximum
`¢—Most common adverse reactions (incidence >5and twice placebo):
`Dose
`Dose
`
`Adults: somnolence, dry mouth, dizziness, constipation, asthenia,
`abdominalpain, postural hypotension, pharyngitis, weigh! gain,
`Schizophrenia - 150-750 mg/day|750 mg/day25 mg twice
`
`
`lethargy, ALT increased, dyspepsia (6.1)
`Adults (2.2)
`daily
`.
`Children and Adolescents; somnolence, dizziness, fatigue, increased
`appetite, nausea, vomiting, dry mouth, tachycardia, weight increased
`Schizophrenia -
`
`Schiz 400-800 mg/day|800 mg/dayi 25 mg twice
`
`
`(6.1)
`Adolescents (13-17
`daily
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`years) (2.2)
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`Bipolar Mania-i
`Adults
`DRUG INTERACTIONS
`Monotherapy or as an
`@=Concomitant use ofstrong CYP3A4 inhibitors: Reduce quetiapine dose
`adjunctto lithium or
`divalproex (2.2)
`to one sixth when coadministered with strong CYP3A4inhibitors (¢.g.,
`ketoconazole, ritonavir) (2.5, 7.1, 12.3)
`Bipolar Mania -
`Children and
`Concomitant use ofstrong CYP3A4 inducers: Increase quetiapine dose
`Adolescents (10 to 17
`up to 5 fold whenused in combination with a chronic treatment (more
`~— Monothorapy
`than 7-14 days) of potent CYP3A4inducers (¢.g., phenytoin, rifampin,
`
`300 mg/day
`300 mg/day
`50 mg once
`os Depression -
`St. John’s wort) (2.6, 7.1, 12.3)
`¢=Discontinuation ofstrong CYP3A4 inducers: Reduce quetiapine dose
`Adults (2.2)
`by5 fold within 7-14 days ofdiscontinuation ofCYP3A4inducers (2.6,
`Geriatric Use: Consider a lower starting dose (50 mg/day), slower
`Z1 23)
`titration and careful monitoring during theinitial dosing period in the
`elderly (23, 8.5)
`e Hepatic Impairment: Lowerstarting dose (25 mg/day) and slower
`titration may be needed (2.4, 8.7, 12.3)
`
`
`daily at bedtime
`
`300 ma/day
`
`_
`
`—--------------—-—-- RECENT MAJOR CHANGES-—-------—-------------
`Wamings and Precautions, Falls (5.8)
`02/2017
`
`50 mg twice
`daily
`
`400 800
`me/day
`
`¢
`
`¢
`
`©
`
`©
`
`——-----—-—-----— DOSAGE FORMS AND STRENGTHS
`Tablets: 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg (3)
`CONTRAINDICATIONS
`Known hypersensitivity to SEROQUELor any components in the
`formulation. (4)
`
`
`WARNINGS AND PRECAUTIONS ——-—-—-------—--
`e Cerebrovascular Adverse Reactions: Increased incidence of
`cerebrovascular adverse events(¢.g., stroke, transient ischemic attack) has
`been seen in elderly patients with dementia-related psychoses treated with
`atypical antipsychotic drugs (5.3)
`
`Reference ID: 4060088
`
`o—-------—- USE IN SPECIFIC POPULATIONS
`¢
`Pregnancy: Limited human data. Based on animal data, may cause fetal
`harm. Quetiapine should be used only if the potential benefit justifies the
`potential risk (8.1)
`© Nursing Mothers: Discontinue drug or nursing, taking into consideration
`importance ofdrug to mother’s health (8.3)
`
`See 17 for PATIENT COUNSELING INFORMATIONand Medication
`Guide
`
`Revised: 02/2017
`
`Exhibit 2049
`Exhibit 2049
`Slayback v. Sumitomo
`Slayback v. Sumitomo
`IPR2020-01053
`IPR2020-01053
`
`

`

`FULL PRESCRIBING INFORMATION; CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Schizophrenia
`1.2 Bipolar Disorder
`1,3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar
`I Disorder
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Administration Instructions
`2.2 Recommended Dosing
`2.3 Dose Modifications in ElderlyPatients
`2.4 Dose Modifications in Hepatically Impaired Patients
`2.5 Dose Modifications when used with CYP3A4 Inhibitors
`2.6 Dose Modifications when used with CYP3A4 Inducers
`2.7 Re-initiation ofTreatment in Patients Previously Discontinued
`2.8 Switching from Antipsychotics
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Increased Mortality in Elderly Patients with Dementia-Related
`Psychosis
`5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults
`5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly
`Patients with Dementia-Related Psychosis
`5.4 Neuroleptic Malignant Syndrome (NMS)
`5.5 Metabolic Changes
`5.6 Tardive Dyskinesia
`5.7 Hypotension
`5.8 Falls
`5.9 Increases in Blood Pressure (Children and Adolescents)
`5.10 Leukopenia, Neutropenia and Agranulocytosis
`5.11 Cataracts
`5.12 QT Prolongation
`5.13 Seizures
`5.14 Hypothyroidism
`5.15 Hyperprolactinemia
`5.16 Potential for Cognitive and Motor Impairment
`5.17 Body Temperature Regulation
`
`5.18 Dysphagia
`5.19 Discontinuation Syndrome
`6 ADVERSE REACTIONS
`6.1 Clinical Study Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Effect ofOther Drugs on Quetiapine
`7.2 Effect of Quetiapine on Other Drugs
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Laborand Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`10 OVERDOSAGE
`10.1 Human Expericnee
`10.2 ManagementofOverdosage
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment ofFertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Schizophrenia
`14.2 Bipolar Disorder
`16 HOWSUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`“Sections or subsections omitted from the full prescribing informationare notlisted.
`
`Reference ID: 4060088
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED
`PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS
`
`Increased Mortality in Elderly Patients with Dementia-Related Psychosis
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increasedrisk of
`death [see Warnings and Precautions (5.1)|. SEROQUELis not approvedfor the treatment of patients with
`dementia-related psychosis [see Warnings and Precautions (5.1)|.
`
`(8.4)].
`
`Suicidal Thoughts and Behaviors
`Antidepressants increased the risk of suicidal thoughts and behaviorin children, adolescents, and young adults
`in short-term studies. These studies did not show an increasein the risk of suicidal thoughts and behavior with
`antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged
`65 and older [see Warnings and Precautions (5.2)|.
`In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for
`emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation
`and communication with the prescriber [see Warnings and Precautions (5.2)].
`
`SEROQUELis not approved for use in pediatric patients under ten years of age [see Use in Specific Populations
`
`1 INDICATIONS AND USAGE
`
`1.1 Schizophrenia
`
`SEROQUELisindicated for the treatment of schizophrenia. The efficacy of SEROQUELin schizophrenia was
`established in three 6-weektrials in adults and one 6-weektrial in adolescents (13-17 years). The effectiveness of
`SEROQUEL for the maintenance treatment of schizophrenia has not been systematically cvaluated in controlled clinical
`trials [see Clinical Studies (14.1).
`
`1.2 Bipolar Disorder
`
`SEROQUELisindicated for the acute treatment of manic episodes associated with bipolar I disorder. both as
`monotherapyand as an adjunct to lithium or divalproex. Efficacy was established in two 12-week monotherapytrials in
`adults, in one 3-week adjunctive trial in adults, and in one 3-week monotherapy trial in pediatric patients (10-17 years)
`|see Clinical Stuclies (14.2)).
`
`SEROQUELis indicated as monotherapyfor the acute treatment of depressive episodes associated with bipolar disorder.
`Efficacy was established in two 8-week monotherapytrials in adult patients with bipolar | andbipolarII disorder [see
`Clinical Studies (1 4.2)|.
`
`SEROQUELis indicated for the maintenance treatment of bipolarI disorder, as an adjunct to lithiumor divalproex.
`Efficacy was established in two maintenance trials in adults. The effectiveness of SEROQUEL as monotherapyfor the
`maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [see Clinical
`Studies (14.2).
`
`Reference ID: 4060088
`
`

`

`1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder
`
`Pediatric schizophrenia and bipolarI disorder are serious mental disorders, however, diagnosis can be challenging. For
`pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients mayhave variable patterns
`of periodicity of manic or mixed symptoms. It is recommendedthat medication therapyfor pediatric schizophrenia and
`bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration
`given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar
`I disorder is indicated as part of a total treatment program that often includes psychological, educational and social
`interventions.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Important Administration Instructions
`
`SEROQUEL can be taken with or without food.
`
`2.2 Recommended Dosing
`
`The recommended initial dose,titration, dose range and maximum SEROQUELdose for cach approved indication is
`displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary. depending upon
`the clinical response andtolerability ofthe patient [see Clinical Studies (14.1 and 14.2).
`
`Table 1: Recommended Dosing for SEROQUEL
`
`Initial Dose and Titration|Recommended Dose|Maximum Dose
`
`150-750 mg/day
`
`750 mg/day
`
`Schizophrenia - Adults
`
`Day |: 25 mg twicedaily.
`Increase in increments of 25
`mg-50 mg divided two or
`three times on Days 2 and 3
`to range of 30000 mg by
`Day4.
`Further adjustments can be
`madein increments of 25-50
`mg twice a day, in intervals
`of not less than 2 days.
`
`
`
`
`
`
`
`Schizophrenia - Adolescents|Day |: 25 mg twice daily. 400-800 mg/day 800 mg/day
`
`
`(13-17 years)
`Day2: Twice daily dosing
`totaling 100 mg.
`Day3: Twice daily dosing
`totaling 200 mg.
`Day4: Twice daily dosing
`totaling 300 mg.
`Day5: Twice daily dosing
`totaling 400 mg.
`Further adjustments should
`be in increments no greater
`than 100 mg/day within the
`recommended dose range of
`400-800 mg/day.
`Based on response and
`tolerability, may be
`administered three times
`
`Reference ID: 4060088
`
`

`

` Day1: Twice daily dosing
`
` 800 mg/day
`
`600 mg/day
`
`300 mg/day
`
`800 mg/day
`
`
`
`400-800 mg/day
`
`400-600 mg/day
`
`300 mg/day
`
`400-800 mg/day
`
`400-800 mg/day
`N/A’
`800 mg/day
`Schizophrenia -
`Maintenance
`
`
`Bipolar Mania - Adults
`Monotherapyor as an
`adjunct to lithium or
`divalproex
`
`Bipolar Mania - Children
`and Adolescents (10 to 17
`years),
`Monotherapy
`
`totaling 100 mg.
`Day2: Twice daily dosing
`totaling 200 mg.
`Day3: Twice daily dosing
`totaling 300 mg.
`Day4: Twice daily dosing
`totaling 400 mg.
`Further dosage adjustments
`up to 800 mg/day by Day 6
`should be in increments of
`no greater than 200 mg/day.
`
`Day1: 25 mg twice daily.
`Day2: Twice daily dosing
`totaling 100 mg.
`Day3: Twice daily dosing
`totaling 200 mg.
`Day4: Twice daily dosing
`totaling 300 mg.
`Day5: Twice daily dosing
`totaling 400 mg.
`Further adjustments should
`be in increments no greater
`than 100 mg/daywithinthe
`recommended dose range of
`400-600 mg/day.
`Based on response and
`tolerability, may be
`administered three times
`daily.
`
`Bipolar Depression - Adults
`
`Administer once dailyat
`bedtime.
`
`Day1: 50 mg
`Day2: 100 mg
`Day3: 200 mg
`Day4: 300 mg
`
`Administer twice daily
`totaling 400-800 mg/dayas
`adjunct to lithium or
`divalproex. Generally, in
`the maintenance phase,
`patients continued on the
`same dose on which they
`
`Bipolar | Disorder
`Maintenance Therapy-
`Adults
`
`Reference ID: 4060088
`
`

`

`1. N/A Not applicable
`
`we abe
`
`___—
`
`Maintenance Treatment for Schizophrenia and Bipolar I Disorder
`Maintenance Treatment — Patients should be periodically reassessed to determine the need for maintenance treatment
`and the appropriate dose for such treatment [see Clinical Studies (1 4.2)].
`
`2.3 Dose Modifications in Elderly Patients
`
`Consideration should be given to a slower rate of dose titration and a lowertarget dose in the elderly and in patients who
`are debilitated or who have a predisposition to hypotensive reactions [see Clinical Pharmacology (12.3)|. When indicated,
`dose escalation should be performed with caution in thesepatients.
`
`Elderly patients should be started on SEROQUEL 50 mg/dayand the dose canbe increased in increments of 50 mg/day
`depending on the clinical response andtolerability of the individual patient.
`
`2.4 Dose Modifications in Hepatically Impaired Patients
`
`Patients with hepatic impairment should be started on 25 mg/day. The dose should be increased daily in increments of 25
`mg/day- 50 mg/dayto an effective dose. depending on the clinical response andtolerability of the patient.
`
`2.5 Dose Modifications when used with CYP3A4 Inhibitors
`
`SEROQUELdose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4inhibitor
`(e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4inhibitor is discontinued, the
`dose of SEROQUELshould be increased by6 fold [see Clinical Pharmacology (12.3) and Drug Interactions (7_1)|.
`
`2.6 Dose Modifications when used with CYP3A4 Inducers
`
`SEROQUELdose should be increased up to 5-fold of the original dose when used in combination with a chronic
`treatment(¢.g., greater than 7-14 days) of a potent CYP3A4inducer(e.g.. phenytoin, carbamazepine, rifampin, avasimibe,
`St. John’s wort etc.). The dose should betitrated based on the clinical response and tolerability of the individual patient.
`When the CYP3A4induceris discontinued, the dose of SEROQUELshould be reduced to the original level within 7-14
`days [see Clinical Pharmacology (12.3) and Drug Interactions (7_1)].
`
`2.7 Re-initiation of Treatment in Patients Previously Discontinued
`
`Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting
`therapyof patients who have been off SEROQUELfor more than one weck,the initial dosing schedule should be
`followed. Whenrestarting patients who have been off SEROQUELforless than one week, gradual dose escalation may
`not be required and the maintenance dose maybe re-initiated.
`
`2.8 Switching from Antipsychotics
`
`There are no systematically collected data to specifically address switching patients with schizophrenia from
`antipsychotics to SEROQUEL,or concerning concomitant administration with antipsychotics. While immediate
`discontinuation of the previous antipsychotic treatment maybe acceptable for some patients with schizophrenia, more
`gradual discontinuation maybe most appropriate for others. In all cases, the period of overlapping antipsychotic
`administration should be minimized. When switching patients with schizophrenia from depot antipsychotics, if medically
`appropriate, initiate SEROQUELtherapyin place of the next scheduled injection. The need for continuing existing EPS
`medication should be re-evaluated periodically.
`
`Reference ID: 4060088
`
`

`

`3 DOSAGE FORMS AND STRENGTHS
`
`e
`
`e
`
`e¢
`
`e
`
`e¢
`
`e
`
`25 mg tablets are peach. round, biconvex, film coated tablets, identified with 'SEROQUEL'and *25° onone side and
`plainon the otherside,
`50 mgtablets are white, round, biconvex,film coatedtablets, identified with 'SEROQUEL'and *50° on one side and
`plain on the other side
`100 mgtablets are yellow, round, biconvex, film coated tablets, identified with 'SEROQUEL'and *100° on one side
`and plain on the other side
`200 mgtablets are white, round, biconvex, film coated tablets, identified with “SEROQUEL and *200° on one side
`and plain on the other side
`300 mgtablets are white. capsule-shaped, biconvex, film coated tablets, intagliated with “SEROQUEL’ on oneside
`and *300° onthe other side
`
`400 mgtablets are yellow, capsule-shaped. biconvex, film coated tablets, intagliated with “SEROQUEL’ ononeside
`and *400° on the other side
`
`4 CONTRAINDICATIONS
`
`Hypersensitivity to quetiapine or to any excipients in the SEROQUELformulation. Anaphylactic reactions have been
`reported in patients treated with SEROQUEL
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
`
`Elderlypatients with dementia-related psychosis treated with antipsychotic drugsare at an increased risk ofdeath.
`Analysis of 17 placebo-controlledtrials (modal duration of 10 weeks), largelyin 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%,
`comparedto a rate of about 2.6%in the placebo group. Althoughthe causes of death were varied, most ofthe deaths
`appearedto be cither cardiovascular (c.g., heart failure, sudden death)orinfectious (¢.g., pneumonia) in nature.
`Observational studies suggestthat, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic
`drugs mayincrease mortality. The extent to which the findings of increased mortality in observational studies maybe
`attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear, SEROQUELis not
`approvedfor the treatment of patients with dementia-related psychosis [see Boxed Warning].
`
`5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults
`
`Patients with major depressive disorder (MDD), both adult and pediatric. may experience worsening oftheir depression
`and/or the emergence ofsuicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
`are taking antidepressant medications, and this risk maypersist until significant remission occurs. Suicide is a knownrisk
`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 mayhavea role in irducing worsening of
`depression and the emergence of suicidality in certain patients during the early phases oftreatment. Pooled analyses of
`short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showedthat 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)andother psychiatric disorders, Short-term studies did not showanincreasein the risk of
`suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants
`compared to placcbo in adults aged 65 and older.
`
`Reference ID: 4060088
`
`

`

`The pooled analyses of placcbo-controlled trials in children and adolescents with MDD,obsessive-compulsive disorder
`(OCD), or other psychiatric disorders includeda total of 24 short-termtrials of 9 antidepressant drugs in over 4400
`patients. The pooled analyses of placebo-controlled trials in adults with MDDorother 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 variationin risk of suicidality among drugs, but a tendency toward anincrease in the younger patients for
`almostall drugs studied. There were differences in absolute risk of suicidality across the different indications, with the
`highest incidence in MDD.Therisk differences (drug vs. placebo). however, were relatively stable within age strata and
`across indications. These risk differences (drug-placebo difference in the numberofcases ofsuicidality 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
`
`<18
`
`18-24
`
`25-64
`
`>65
`
`Drug-Placebo Difference in
`Numberof Cases of Suicidality
`per 1000 Patients Treated
`
`Increases Compared to Placebo
`
`14 additional cases
`
`5 additional cases
`
`Decreases Comparedto Placebo
`
`| fewer case
`
`6 fewer cases
`
`
`
`
`
`Nosuicides occurred in anyofthe pediatric trials. There were suicidesin the adult trials. but the number was not
`sufficient to reach any conclusion about drug effect on suicide.
`
`It is unknown whetherthe suicidality risk extends to longer-term use,i.c., beyond several months. However,there is
`substantial evidence from placebo-controlled maintenancetrials in adults with depression that the use of antidepressants
`can delaythe 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, anxicty, agitation. panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity.
`akathisia (psychomotorrestlessness), 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 psyc atric and
`nonpsychiatric, Although a causal link between the emergence of such symptomsand either the worsening of depression
`and/or the emergence ofsuicidal impulses has not been established, there is concern that such symptoms mayrepresent
`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 symptomsthat might be
`precursors to worsening depressionorsuicidality, especially if these symptoms are severe. abrupt in onset, or were not
`part ofthe 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
`
`3
`
`Reference ID: 4060088
`
`

`

`emergenceof agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well
`as the emergenceof suicidality, and to report such symptoms immediately to healthcare providers. Such
`monitoring should include daily observation by families and caregivers. Prescriptions for SEROQUELshould 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 maybetheinitial presentation ofbipolar disorder.
`It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant
`alone mayincreasethe likelihood of precipitation of a mixed/manic episodeinpatients at risk for bipolar disorder.
`Whether anyof the symptomsdescribed above represent such a conversion is unknown. However,prior to initiating
`treatment with an antidepressant, including SEROQUEL.patients with depressive symptoms should be adequately
`screened to determine if theyare at risk for bipolar disorder: such screening should include a detailed psychiatric history,
`including a familyhistory of suicide, bipolar disorder, and depression.
`
`5.3 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
`higherincidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including
`fatalities compared to placebo-treated subjects. SEROQUELis not approved for the treatment of patients with dementia-
`related psychosis [see also Boxed Warning avd Warnings and Precautions (5.1)\.
`
`5.4 Neuroleptic Malignant Syndrome (NMS)
`
`A potentiallyfatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS)has been reported
`in association with administration ofantipsychotic drugs, including SEROQUEL. Rare cases of NMShave been reported
`with SEROQUEL. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered menta! status, and evidence
`of autonomicinstability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysthythmia). Additional
`signs mayinclude elevated creatinine 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 medicalillness (e.g., pneumonia, systemic infection,
`etc.) and untreated or inadequatelytreated extrapyramidal signs and symptoms (EPS). Other important considerations in
`the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primarycentral nervous
`system (CNS) pathology.
`
`|) immediate discontinuation of antipsychotic drugs and other drugs not
`The management of NMSshould include:
`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 NMShavebeenreported
`
`5.5 Metabolic Changes
`
`Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus,
`dyslipidemia, and body weight gain. While al! 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 ofthe metabolic
`parameters of weight. blood glucose, and lipids was observedin clinical studies. Changesin these metabolic profiles
`should be managedas clinically appropriate.
`
`Reference ID: 4060088
`
`

`

`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. Assessmentofthe relationship between
`atypical antipsychotic use and glucose abnormalities is complicated bythe possibility of an increased background risk of
`diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the gencral
`population. Given these confounders, the relationship betweenatypical! 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. Anypatient treated with atypical antipsychotics should be
`monitored for symptomsof hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who
`develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergofasting 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 2126 mg/dL in Short-Term ($12 weeks)
`Placebo-Controlled Studies’
`
`Laboratory
`Category Change
`Treatment Arm
`N
`|
`Patients
`Analyte
`(At Least Once)
`n(%)
`from Baseline
`
`
`
`
`asting
`Glucose
`
`Normal to High
`(<100 mg/dL to
`
`Borderline to High
`(> 100 mg/dL and
`<126 mg/dL to
`
`1.
`
`Includes SEROQUEL and SEROQUEL XRdata.
`
`Quetiapine
`
`2907
`
`71 (24%)
`
`Quetiapine
`
`572
`
`67 (11.7%)
`
`279
`
`33 (11.8%)
`
`In a 24-weektrial (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 theincidence of a fasting treatment-emergent blood glucose level 2 126 mg/dL
`was 2.6%. The mean changein fasting glucose from baseline was 3.2 mg/dL and mean change in 2-10ur glucose from
`bascline was -|!.8 mg/dL for quetiapine.
`
`In 2 long-term placebo-controlled randomized withdrawalclinical trials for bipolar I disorder maintenance, mean
`exposure of 213 days for SEROQUEL (646patients) and 152 days for placcbo (680 patients), the mean change in glucose
`from baseline was +5.0 mg/dL for SEROQUELand —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 maynot
`have beenprecluded fromcalorie intake from fluids during fasting period) was 18.0 per 100 patient years for SEROQUEL
`(10.7% ofpatients: n=556) and 9.5 for placebo per 100 patient years (4.6%of patients: n=581).
`
`Reference ID: 4060088
`
`10
`
`10
`
`

`

`Children and Adolescenis:
`In a placebo-controlled SEROQUEL monother