HIGHLIGHTS OF PRESCRIBING INFORMATION
`'l‘liecc Highlights do not include all the Information needed to use
`SEROQUEL safeb' arni elfecttvdy. Sec I'll] preserttdng tnt'omiation tor
`SEROQUEL.
`SEROOUEL" (quetiaplne hnmrate) tablets. for oral use
`Initial ILS. AppmVid: I997
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATEI) PSYCHOSIS; and SUICIDAL
`TIIOUGIITS AND BEIIAVIORS
`Stefuflprcvcribbig informationfor complete hitter! wanting.
`Increased Mortality in Elder-Iv Patients with Dementia-Related
`Psychosis
`o
`Elderly patient: wflh dementia-related psyctiiicis treated with
`antipsydiotic drugs are at an hicrcascd risk of death. SEROOUEL
`is In approved for ddcrly patients with drntntta-relatcd
`memoir
`Suicidal IMsund Behaviors
`thoughts and bctnvior in children.
`0
`[Increased risk of suicidal
`adolescents and young adults taking antidepressants (Si)
`0 Monitor for womnirg and emergence of aulctdal them: and
`
`behavior-9(2)
`
`RECENT MAJOR CHANGES
`Warnings and I’rccautims. Ellis (5.8)
`
`02/2017
`
`————————— INDICATIONS AND USAGE
`SEROQUEL is an atypical antipsychotic indicated for the treatment of:
`-
`Schizophrenia Ll._l)
`-
`Bipolar l disorder manic episodes» (Lg)
`I
`Bipolar disorder. depressive episodes (£1
`—-—-—--—--——-—- DOSAGE AND ADMINISTRATION
`o
`SERI OL’ELcan be taken with or without food 2.]
`Maximum
`Indication
`Initial Dose
`Reumnieitdixl
`Dose
`
`
`SGIIILOPIII‘CIIIa -
`Adult: (Q1
`
`25 mg twice
`daily
`
`25 mg twice
`
`400-800 mg/day
`
`800 mg/day
`
`---
`
`150-750 mg/day
`
`Schizophrenia -
`Adolescents ( l3-l7
`3am) (2.2)
`Bipolar Militia -
`Adults
`Momthempy or ac an
`adjunct to lithium or
`dival m (Q)
`Bipolar Mania »
`Children and
`Adolescenis (It) to I?
`years), Monothorapy
`2“'I
`50 mg once
`Bipolar Depression -
`dailv at bedtime
`Adults (2,2)
`Gcn‘atric Urc: Considcra lower starting dose (50 tug/day) slowa‘
`titration and careful monitoring during the initial dosing periodin tlic
`eldeny(2_s, w
`- Hepatic Impairment. Lower starting dose (25 mg/day) and slmwr
`titration may be needed (a. L1. 1;!)
`
`50 mg twice
`daily
`
`4007 800
`mg'day
`
`800 mg/day
`
`'
`
`400-600 nig/day
`
`600 mg/day
`
`'
`
`'
`
`.
`
`300 mg/day
`
`300 mg’dav
`
`——-———— DOSAGE FORMS AND STRENGTHS
`Tablets: 25 mg, 50 mg. 100 mg, 200 mg, 300 mg. and 400 mg Q)
`-——-—-——-—-—-—— CONTRAINDICATIONS
`Known hypersensitiVity to SEROQUEI. or any components in the
`furmulatim. (1)
`
`
`o
`
`WARNINGS AND PRECAUTIONS ———-——-.____
`Cerebromsctrlar.-idver.re Reactmm‘ Increased incidence of
`ccrehrnvascular adverse events (etgn stroke, transient isclientic attack) has
`been seen in elderly patients with danontia-roloted psychoses treated with
`atypical antipsychotic drugs (5.3)
`
`Reference ID: 4060088
`
`0
`
`0
`
`- Neurolepuc Ada/13nd)” Smdrome (NMS): Manage with immediate
`discontinuation and close monitoring (53)
`I Metabolic Chunger: Atypical mtipawhotics have been associated with
`metabolic changes. These metabolic changes include hyperglycemia.
`dyslipidcmia. and weight gain L5_._5_1
`o
`Hyperglycemia and Diabetes Meltitus: Monitor patients for
`symptoms ofliypaglyccniia including polydipsia, polyuria.
`polyphagia. and “cams. Monitor glucose regularly in patients
`with diabetes or at risk for diabetes
`Ib'slipidemia: Undccirabte alterations have been observed in
`patients treated with atypical aitipswliotics. Appropriate clinical
`monitoring is recaumcnded. including fasting blood lipid testing
`at the beginning of. and periodically. (hiring treatment
`Weight Gain: (join in body weight has been observed; clinical
`monitoring of weight is recommended
`Tardr've [ZI’IIUUQXKL' Discontinue ifcliiiically appropriate m
`[I'VPUICIIJIUIL Use with caution in patients with known cardiovascular or
`ccrebrovoscular disease (fl)
`[nor-cared BloodPressure m Children and Adolescents: Monitu' blood
`pressure at the beg‘nning of. and periodically during treatment in children
`and adolescents (5.3)
`Lerrhllretrtu. Neutrapema urtilxlgrunulucytusts: Mmiltt cunpleb blood
`count fi'equently during the first few months of treatment in patients with
`a preexisting low white cell count or a history of lenkopeniu‘neutropenia
`and disamtintie SERmUEI. at the first Sign ofa decline in WBC in
`absmcc of other causative factors (5.10)
`o Calarm”; Lens changes have been observed in patients during Iong~tmn
`quetiapinc treatment. Lens examinatim is: reatrnnmded what starting
`treatment and at 6-month mtcrvals during chronic treatment (SJ 1]
`ADVERSE REACTIONS
`Mom cmmon cdvcrsc reactions (incidence 25% and twice placebo):
`Adultc somnolence. dry mouth. dizziness. constipation. asthenia.
`abdominal pain. postural hypotension. pharyngitis. “eight gain,
`lethargy. ALT increased. dyspepsia (6.1)
`Children and Adolescents: soninolence. dimness. fatigue. increased
`appetite. natuca. vomiting. drymouth. tachycardia. weight increased
`(6—1]
`To report SL'SPECI'ED ADVERSE REACTIONS, ooldact AatrnZencca
`at 1-800-236-9933 or FDA at I-KD-FIIA-Im orW
`
`-
`C
`
`0
`
`0
`
`-
`
`0
`
`a
`
`I
`
`-
`
`DRUG INTERACTIONS
`Concomitant use (ifs/mug ('t'Pfi/ll mlnbrmrs: Reduce thtiapine dose
`tonne sixth when cnadmiiiistered with strong CYP3A4 inhibitors (e.g..
`ketocoaazolc. ritonavir) (2.5. 7.1. 123)
`Concomrlanl use oj’alrong CYP3A4 inducers: Increase quetiapine dose
`up to 5 told when used in combination with a chronic treatment (more
`than 7-l 4 days) of potent CYP3A4 inducus (c.g., phenytoin. rifampiii.
`St. Jolui‘s non) (L6, 11. 13;)
`Disconflmmhon ofstrong Cl‘l’3rl4 inducers: Reduce quetiapine dose
`by 3 fold within 7-| 4 days ofdiuxlitinuation ofCYPfiA-t induwrs (E.
`u, IZJ)
`
`-
`
`USE IN SPECIFIC POPULATIONS
`Pregnancy: Limited human data. Based on animal data. may cause I‘ctal
`harm. Quetinpinc should be used only if the potential benefit iustifies the
`potential risk tle
`- Nimmg Mothers: Discoutiim drug or nursing, taking into consideration
`impedance ofdrug to mother's health (8:3)
`
`See I7 for PATIENT (‘OI'NSELING INFORMATION and Meditation
`(Mlle
`
`Revised: 02/20”
`
`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 Ill Treating Pediatric Schizophrenia and Bipolar
`I Disordcr
`2 DOSAGE AND ADMINISTRATION
`21 Important Administration Instructions
`2.2 Recommended Dosing
`2.3 Dos: Modifications in Elda'ly Patients
`2.4 Dose Modifications in I'Icpalicallv Impaired Patients
`2.5 Dose Modifications when used with CYP3A4 Inhibitm
`2.6 Dose Modifications when used with CYP3A4 Induccrs
`Z7 Ro-initiation ofTreatment in Patients Praiously Discontinued
`2.8 watchmg tiom (\nIIPSYChOIICS
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Incrcasod Mortality in Eldcrly Paticnts with Dcmcntia—Rdatcd
`Psychosis
`5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults
`5.3 Ccrobrovascular Adverse Rmctiuls, Including Stmkc. in Elderly
`Patients with [Menu-Related Psychosis
`5.4 Noumlcptic Malignant Syndromc (NMS)
`5.5 Metabolic Changes
`5.6 'I'ardive Dyskinesm
`5.7 Hypotcnsioa
`5.8 Falls
`5.9 Increases in Blood Pressure (Children and Adolescents)
`5.10 Inukopcnia. Neutmpcnia and Agranulooyiosis
`5.1 l Cataracts
`5.12 QT I‘rolongation
`5.13 Seizures
`5.14 Hypothyroidism
`5.15 Ilypcrpmlactincmia
`5.16 Potential for Cognitive and Motor Impairment
`5.17 Body Temperature Regulation
`
`5.18 Dysphagia
`5.19 Dimtfiauatioa Syndrome
`6 ADVERSE REACTIONS
`6.1 Clinical Study Experience
`6.2 Postinarkcting Experience
`7 DRUG INTERACTIONS
`7.1 Effect ofOther Drugs on Qictiapinc
`72 Effect onrctiapinc on Other Rugs
`8 USE IN SPECIFIC POPL'LATIONS
`8.1 Prognancy
`11.2 Labor and Delivery
`83 Nursing Mothors
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Rona] Impairment
`8.7 qutic Impaimicnt
`9 DRUG ABUSE AND DEPE NDENCE
`9.1 Controlled Stbstauw
`9.2 Abuse
`10 OVERDOSAGE
`10.1 Human Experimoc
`102 Management ofoverdosage
`11 DESCRIPTION
`12 CLINICAL PIIAK\IA(I)I.OG\'
`12.1 Mechanism ol‘Action
`122 Phamiaoodynamics
`123 Phannnookinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carciriogamis. Mutagcncsis. Impairment ril‘Fa’tility
`132 Animal Toxicology and/or Immunology
`14 CLINICAL STUDIES
`14.1 Schizoflirunia
`I42 Bipolar Disorder
`16 IIOW SUPPLIED/STORAGE AND HANDLING
`I7 PATIENT COUNSELING INFORMATION
`
`:Sootims or xuhscctions omittod firm the full prescribing infonnation are not listed.
`
`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 increased risk of
`death [see Warning and Precautions (5.12]. SEROQUEL is not approved for the treatment of patients with
`dementia-related psychosis [see Warnings and Precautions (5. Ill.
`
`(it-0|.
`
`Suicidal Thoughts and Behaviors
`Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults
`in short—term studies. These studies did not show an increase in 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”.
`
`SEROQUEL is not approved for use in pediatric patients under ten years of age [see Use in Specific Populations
`
`l INDICATIONS AND USAGE
`
`1.1 Schizophrenia
`
`SEROQU EL is indicated for the treatment of schizophrenia. The efficacy of SEROQUEL in schizophrenia was
`established in three 6-week trials in adults and one 6-week trial in adolescents ( l 3-l7 years). The echctiveness of
`SEROQU EL For the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical
`trials [sec Clinical Studies (14.12].
`
`1.2 Bipolar Disorder
`
`SEROQUEL is indicated for the acute treatment of manic episodes associated with bipolar I disorder. both as
`
`monotherapy and as an adjunct to lithium or divalproex. Efficacy was established in two 12-week monotherapy trials in
`adults, in one 3-week adj unctive trial in adults. and in one 3-week monotherapy trial in pediatric patients (IO-l7 years)
`[see ( ‘linical Studies (14. 21].
`
`SEROQUEL is indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder.
`Efficacy was established in two 8~wcek monothcrapy trials in adult patients with bipolar | and bipolar ll disorder [see
`("linica! Studies (I 4. 22 |.
`
`SEROQUEL is indicated For the maintenance treatment of bipolar l disorder, as an adjunct to lithium or divalproex.
`Efficacy was established in two maintenance trials in adults. The effectiveness of SEROQU EL as monotherapy for 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 l Disorder
`
`Pediatric schizophrenia and bipolar l disorder are serious mental disorders. however. diagnosis can be challenging. For
`pediatric schizophrenia. symptom profiles can be variable. and for bipolar l disorder. patients may have variable pattcms
`of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and
`bipolar I disorder be initiated only after a thorough diagnostic evaluation has been perfomted and careful consideration
`given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar
`l disorder is indicated as part of a total treatment program that often includes psychological. educational and social
`interventions.
`
`2 DOSAGE AND ADMTNISTRATION
`
`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 SEROQU EL dose for each approved indication is
`displayed in Table 1. After initial dosing. adjustments can be made upwards or downwards. if necessary. depending upon
`
`the clinical response and tolerability of the patient [see (‘linical Studies (fl and I 4.2)].
`
`Table 1: Recommended Dosing for SEROQUEL
`
`Initial Dose and Titration
`
`Recommended Dose Maximum Dose
`
`Schizophrenia - Adults
`
`150-750 mg/day
`
`750 mg/day
`
`Day I: 25 mg twice daily.
`Increase in increments 01°25
`
`mg-SO mg divided two or
`three times on Days 2 and 3
`to range of 300-400 mg by
`Day 4.
`
`Further adjustments can be
`made in increments of 25-50
`
`mg twice a day. in intervals
`of not less than 2 days,
`
`800 mg/day
`
`
`
`Schizophrenia - Adolescents Day I: 25 mg twice daily.
`“347 years)
`Day 2: Twice daily dosing
`totaling 100 mg.
`
`400-800 mg/day
`
`
`
`Day 3: Twice daily dosing
`totaling 200 mg.
`
`Day 4: Twice daily dosing
`totaling 300 mg.
`
`Day 5: 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
`
`

`

`N/A’
`400—800 mg/day
`800 tug/day
`Schizophrenia -
`
`Maintenance
`
`Bipolar Mania - Adults
`
`Monotherapy or as an
`adjunct to lithium or
`divalproex
`
`Bipolar Mania - Children
`and Adolescents (10 to 17
`years).
`
`Monotherapy
`
`Day I: Twice daily dosing
`totaling 100 mg.
`
`Day 2: Twice daily dosing
`totaling 200 mg.
`
`Day 3: Twice daily dosing
`totaling 300 mg.
`
`Day 4: 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.
`
`Day 1: 25 mg twice daily.
`
`400-600 mg/day
`
`Day 2: Twice daily dosing
`totaling 100 mg.
`
`Day 3: Twice daily dosing
`totaling 200 mg.
`
`Day 4: Twice daily dosing
`totaling 300 mg.
`
`Day 5: Twice daily dosing
`totaling 400 mg.
`
`Based on response and
`tolerability, may be
`administered three times
`
`daily.
`
` 800 mg/day
`
`600 mg/day
`
`300 mg/day
`
`800 mg/day
`
`
`
` 400-800 mg/day
`
`Further adjustments should
`be in increments no greater
`than 100 mg/day within the
`recommended dose range of
`400—600 mg/day.
`
`Bipolar Depression - Adults
`
`Administer once daily at
`bedtime.
`
`300 mg/day
`
`Day I: 50 mg
`
`Day 2: 100 mg
`
`Day 3: 200 mg
`
`Day 4: 300 mg
`
`Administer twice daily
`totaling 400-800 mg/day as
`adjunct to lithium or
`divalproex. Generally. in
`the maintenance phase,
`patients continued on the
`same dose on which they
`
`400-800 mg/day
`
`Bipolar l Disorder
`Maintenance Therapy -
`Adults
`
`Reference ID: 4060088
`
`

`

`— m...
`1. N/A Not applicable
`
`—
`
`Maintenance Treatment for Schizophrenia and Bipolar l 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 (14.21].
`
`2.3 Dose Modifications in Elderly Patients
`
`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 Clinical Pharmacology [[231] When indicated.
`dose escalation should be performed with caution in these patients.
`
`Elderly patients should be started on SEROQUEL 50 mg/day and the dose can be increased in increments of‘ 50 trig/day
`depending on the clinical response and tolerability of the individual patient.
`
`2.4 Dose Modifications in Hepatically Impaired Patients
`
`Patients with hepatic impairment should be started on 25 myday. The dose should be increased daily in increments of 25
`in day - 50 mg/day to an effective dose. depending on the clinical response and tolerability of the patient.
`
`2.5 Dose Modifications when used with CYP3A4 Inhibitors
`
`SEROQUEL dose should be reduced to one sixth of original dose when co-medieated with a potent CYP3A4 inhibitor
`
`(e g, ketoconazole, itraconazole, indinavir. ritonavir, nefazodone, etc). When the CYP3A4 inhibitor is discontinued. the
`dose of SEROQUEL should be increased by 6 Fold [see Clinical Pharmacologv (lug and Drug lnleraclions (7.1”.
`
`2.6 Dose Modifications when used with CYP3A4 lnducers
`
`SEROQUEL dose should be increased up to 5-fold of the original dose when used in combination with a chronic
`treatment (e.g.. greater than 7-14 days) of a potent CYP3A4 inducer (cg, phenytoin, carbamazepinc. rifamprn. avasimibe.
`St. John's wort etc.). The dose should be titrated based on the clinical response and tolembility of the individual patient.
`When the CYP3A4 inducer is discontinued, the dose of SEROQUEL should be reduced to the original level within 7-14
`
`days [see (‘linical Pharmacologv (12.32 and Drug Interactions (77. l 2].
`
`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
`therapy of patients who have been off SEROQUEL for more than one week, the initial dosing schedule should be
`followed. When restarting patients who have been off SEROQUEL for less than one week. gradual dose escalation may
`not be required and the maintenance dose may be re-initiated.
`
`2.8 Switching from Antipsychotics
`
`There are no systematically collected data to specifically address switching patients with schizophrenia from
`
`antipsyclrotics to SEROQUEL, or concenring concomitant administration with antipsychotics. While immediate
`discontinuation of the previous antipsychotie treatment may be acceptable for some patients with schizophrenia, more
`gradual discontinuation may be most appropriate for others. In all cases. the period of overlapping antipsychotie
`administration should be minimized. When switching patients with schizophrenia from depot antipsychotics, if medically
`
`appropriate, initiate SEROQUEL therapy in place of the next scheduled injection. The need for continuing existing EPS
`medication should be rc-evaluatcd periodically.
`
`Reference ID: 4060088
`
`

`

`3 DOSAGE FORMS AND STRENGTHS
`
`o
`
`0
`
`-
`
`o
`
`0
`
`0
`
`25 mg tablets are peach. round. biconvex, film coated tablets. identified with 'SEROQUEL' and ‘25' on one side and
`plain on the other side.
`
`50 mg tablets are white, round. biconvex. film coated tablets. identified with 'SEROQUEL' and '50' on one side and
`plain on the other side
`
`“)0 mg tablets are yellow, round, biconvex. film coated tablets. identified with 'SEROQUEL‘ and ‘100- on one side
`and plain on the other side
`
`200 mg tablets are white. round. biconves. film coated tablets. identified with 'SEROQUEL' and ‘200' on one side
`and plain on the other side
`
`300 mg tablets are white. capsule-shaped. biconvcx. film coated tablets. intagliated with ‘SEROQUEL' on one side
`and '300‘ on the other side
`
`400 mg tablets are yellow. capsule-shaped. biconvex. film coated tablets. intagliated with ‘SEROQUEL‘ on one side
`and '400’ on the other side
`
`4 CONTRAINDICATIONS
`
`Hypersensitivity to quetiapine or to any excipients in the SEROQUEL formulation. 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
`
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
`Analysis of l7 placebo-controlled trials (modal duration of IO weeks). largely in patients taking atspical 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 Ill-week controlled trial, the rate of death in dnrg-trcated patients was about 4.5%.
`compared to a rate of about 2.6% in the placebo group. Although the causes of death we re varied, most of the deaths
`appeared to be either cardiovascular (c.g.. heart failure. sudden death) or infectious (c.g.. pneumonia) in nature.
`Observational studies suggest that. similar to atypical antipsychotie drugs. treatment with conventional antipsychotic
`
`drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be
`attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. SEROQUEL is not
`approved for the treatment of patients with dementia-related psychosis [.vee 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 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 dcprcssron and certain other psychiatric disorders. and these disorders themselves are the strongest predictors of
`suicide. There has been a long-standing conccm. however. that antidepressants may haw a role in irducing worsening of
`
`depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of
`short-tenn placebo-controlled trials of antidepressant dnigs (SSRls 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.
`
`Reference ID: 4060088
`
`

`

`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-temi 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 l l 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 ofsurcidality 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 n'sk differences (drug-placebo difference in the number ofcases ofsuicidality per 1000 patients
`treated) are provided in Table 2.
`
`Table 2: Drug-Placebo Difference in Number of Cases of Suicidallty per 1000 Patients Treated
`
`
`
`Age Range
`
`< l 8
`
`18-24
`
`25-64
`
`263
`
`Drug-Placebo Difference in
`Number of Cases of Suicidality
`cr [000 Patients Treated
`
`Increases Compared to Placebo
`
`l4 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-tom use. i.e.. beyond several months. l-lowcwr. there is
`substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants
`can delay the recurrence ofdepressiou.
`
`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 psyctiatric and
`nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depressron
`and/or the emergence of suicidal impulses has not been established. there is concem 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
`
`8
`
`Reference ID: 4060088
`
`

`

`emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above. as well
`as the emergence of suicidality. and to report such symptoms immediately to healthcare providers. Such
`monitoring should include daily observation by families and caregivers. Prescriptions for SEROQUEL should be
`
`written for the smallest quantity of tablets consistent with good patient management. in order to reduce the risk of
`overdose.
`
`Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder.
`It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant
`alone may increase the likelihood of precipitation ofa mixed/manic episode in patients at risk For bipolar disorder.
`Whether any of the symptoms described above represent such a conversion IS unknown. However. prior to initiating
`treatment with an antidepressant. including SEROQUEL. patients with depressive symptoms should be adequately
`screened to determine if they are at risk for bipolar disorder: such screening should include a detailed psychiatric history.
`including a family history of suicide. bipolar disorder, 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
`higher incrdencc of cerebrovascular adverse reactions tccrcbrovascular accidents and transient ischemic attacks) including
`fatalities compared to placebotreated subjects. SEROQUEL is not approved for the treatment of patients with dementia-
`related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].
`
`5.4 Neuroleptic Malignant Syndrome (NMS)
`
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported
`in association with administration of antipsychotic drugs. including SEROQUEL. Rare cases of NMS have been reported
`with SEROQUEL Clinical manifestations of NMS are hyperpyrexia. muscle rigidity. altered mental status. and evidence
`of‘ autonomic instability (irregular pulse or blood pressure. tachycardia diaphorcsis. and cardiac dysrhythmia). Additional
`signs may include elevated creatinine phosphokinase. myoglobinuria (rhabdomyolysis) and acute renal Failure.
`
`The diagnostic evaluation of patients with this syndrome is complicated. ln aniving at a diagnosis. it is important to
`exclude cases where the clinical presentation includes both serious medical illness (cg. pneumonia. systemic infection.
`etc.) and untreated or inadequately treated cxtr’apyramidal signs and symptoms (EPS). Other important considerations in
`the difi'erential diagnosis include central anticholinergic toxicity. heat stroke. drug fever and primary central nervous
`system (CNS) pathology.
`
`The management of NMS should include: I) 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 oFdnig therapy
`should be carefully consrdcrcd. The patient should be carefully monitored since recurrences ofNMS have been reported
`
`5.5 Metabolic Changes
`
`Atypical antipsycliotrc drugs have been assocratcd with metabolic changes that include hyperglycemia/diabetes mellitus.
`dyslipidcmia. 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.
`
`Reference ID: 4060088
`
`

`

`Hyperglycemia and Diabetes Mellitus
`Hyperglycemia. in some cases extreme and associated with kctoacidosis 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 confoundcrs. the relationship between atypical antipsychotic use and hyperglycemia-rclatcd
`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 antipsyehotics. Precise risk
`estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsyehotics 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 (c.g.. obesity, family history of
`diabetes) who are starting treatment with atypical antipsychotics should tuidergo fasting blood glucose testing at the
`beginning oFtreatment and periodically during treatment. Any patient treated with atypical antipsyehotics 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 2126 mgIdL in Short-Term (512 weeks)
`Placebo-Controlled Studies’
`
`
`Laboratory
`Analyte
`
`Category Change
`(At Least Once)
`from Baseline
`
`Normal to High
`
`(<100 mg/dL to
`
`Treatment Arm
`
`N
`
`'
`
`Patients
`it (°/o)
`
`Quetiapine
`
`2907
`
`71 (2.4%)
`
`
`
`
`Borderline to High
`
`Quetiapine
`
`(2 100 mg/dL and
`<126 mg/dL to
`
`346
`
`572
`
`67 (1 1.7%)
`
`279
`
`33 11.891 )
`
`1.
`
`Includes SliROQUlil, and Sl-‘ROQlllil. XR data.
`
`l 15 patients treated with SEROQUEL) designed to evaluate glyccmic status with
`In a 24-week trial (active-controlled.
`oral glucose tolerance testing of all patients. at week 24 the incidence of a treatment-emergent post-glucose challenge
`glucose level 2 200 mg/dL was l 7% and the incidence ofa fasting treatment-emergent blood glucose level 2 126 mg/dL
`was 2 6%. The mean change in fasting glucose Front baseline was 3.2 mg/dL and mezui change in 2-‘tour glucose from
`baseline was -1.8 mg/dL for quctiapine.
`
`1n 2 long-term placebo-controlled randomized withdrawal clinical trials For bipolar l disorder maintenance. mean
`exposure of213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients), the mean change in glucose
`from baseline was +5 .0 mg/dL for SEROQUEL and #005 mg/dL for placebo. The exposure-adjusted rate of any
`increased blood glucose level (2 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not
`have been precluded front calorie intake front fluids during Fasting period) was 18.0 per 100 patient y