- This Clinic“! Resource gives subscribers
`additional insight related to {he Recoriiinemimions published in
`
`It
`
`pharmacists letter
`
`1:
`
`trC
`
`tl'C
`prescriber‘s letter
`trc
`October 2018 ~ Resource #341007
`
`1:
`
`pharmacy tetlililcinn‘slctler
`
`trC
`
`“UFSE‘S letter
`
`Comparison of Atypical Antipsychotics
`
`Second generation or "atypical" antipsycliotics have a lower propensity than the first generation agents to cause extrapyramidal side effects and
`tardivc dyskinesia. but are by no means devoid of these adverse effects.4 Clozapine maybe the most effective atypical for schizophrenia. but its use is
`limited due to the risk ofagranulocytosisll'” All ean’y "black box‘= warnings regarding mortality risk in dementia-related psychosis, and suicidality
`if indicated for depression. Atypicals pose varying risks of QT prolongation, drug interactions. and metabolic adverse effects. Extrapyramidal side
`effects are low with quetiapine, brexpiprazole. and olanzapine, and high with lurasidone. paliperidone. eariprazine. and IisperidOIie.“-"“9"3
`Hyperprolactinemia. associated with sexual dysfunction. gyneeomastia. and irregular periods. seems most common with risperidone and
`paliperidonc.”"” These factors. plus cost and dosing frequency. are all considerations in choice of agent The chart below compares atypicals in
`regard to adult indications and dosing, metabolic side effects, sedation, QT prolongation, CYP metabolism. and cost. Prescribers can bill for [M
`antipsyehotic injections under their supervision using CPT code 96372. and add the medication code.
`
`NOTE: *Usual or target daily ADULT dosage range may not include initiai and maximum doses. Use lowest effective dose. Dosing in Special
`populations (e.g.. renal
`impairment) is not
`included. Maximum doses of oral aripiprazole. brexpiprazole, cariprazine,
`lurasidone,
`olanzapine, paliperidone, quetiapine XR, and risperidone are approved for once-daily administration. Divide asenapine, iloperidone,
`quetiapine IR (except for bipolar depression), and ziprasidone twice daily. Clozapine doses above [2.5 mg should be divided.
`
`Metabolic Adverse Effects"~'3r‘47""'l3““
`
`
`Weight Diabetes Dyslipidemia
`Gain
`Risk
`Low
`Low
`
`Low
`
`Generic
`ran
`B
`d]
`Costh
`
`FDA—Approved lndicationts) for
`u t
`an
`sua or ar at
`ADULTS
`clU
`] TgAdl
`Daily Dosage Range (mgfday)*"
`
`IO-IS mg
`Schizophrenia:
`.
`_
`_
`.
`Bipolar l disorder (manic or mixed
`episodes and maintenance): 15 mg
`(monotlierapy or with lithium or
`valproatc)
`
`Major depression (adjunct): 5-10 mg
`
`Aripiprazole
`(Abilijflit.
`generics)
`
`10 mg tablet
`4345
`
`Oral solution
`and orally
`disintegrating
`tabs available.
`
`QT
`m on in
`l’lg’gc
`
`CYP450
`eta o ism
`M bl'“
`
`Sedation”-'-‘
`
`Yes
`
`See
`footnotes 0
`and 11,
`
`CYP2D6,
`CYP3A4
`
`Low
`
`Specific dosing
`may be advised
`for CYP450
`
`interactions.
`
`
`
`
`
`
`
`
`
`
`Copyrig1t © 2015 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 20947272240 ~ Fax: 2094722249
`pharmacist therapeutleresearchcom ~ preseribertherapeutiereseareheom ~ pharmaeytechtherapeulicresearehcom ~ nursesletter.therapeutaeresearchcem
`
`injure, .
`
`.
`
`LATUDA04357625
`
`1
`
`Exhibit 2091
`Slayback v. Sumitomo
`|PR2020-01053
`
`1
`
`Exhibit 2091
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`
`
`(Clinical Resource #341007: Page 2 of t 1)
`
`Metabolic Adrerse Effects"“'2'*'7"""““
`
`
`Sedation“"~“
`
`CYP450
`QT
`FDA—Approved lndication(s) for
`Generic
`(Brand)!
`ADULTS and Usual or Target Adult
`Prolongingt
`Metabolism“
`Cost”
`Daily Dosage Range (mg/clay)”
`Weight Diabetes Dyslipidemia
`
`Gain
`Risk
`Low
`Low
`
`Aripiprazole
`(AM/if}:
`Marmara
`long-acting
`thocuon)
`
`400 mg
`$2,166.41
`
`Arismn'a long-
`acting
`injection
`662 mg
`$1,833,55
`
`Aristada 1mm:
`(For loading)
`675 mg x 1
`$1,869.56
`
`
`
`
`
`Yes
`
`See
`footnotes 0
`and 11’
`
`See
`footnotes 6
`and It.
`
`
`
`CYPZDS,
`CYP3A4
`
`Specific dosing
`may be “df'md
`for C9430
`Interactions.
`
`Specific dosing
`may be advised
`for CYP450
`interactions.
`
`
`
`Low
`
`
`
`
`
`Schizophrenia: 400 mg 1M (gluteal or
`deltoid) once monthly, Continue oral
`agent for 14 days after first dose. then
`stop.
`Roducc dose 11' CYPZDé poor molabolimr.
`Amid with CYP3A4 inducers for more than
`I 4 daVs.
`'Missed tlose: If >6 weeks elapse since last
`dose (>5 weeks if 2"" or 3'd dose is missed).
`restart oral aripipmmlc x 14 days with the next dose,
`Aripiprazolc
`Schizophrenia: 44l mg IM (gluical or
`Low
`Low
`Low
`Yes
`CYP2D6,
`Low
`lauroxil
`doltoid), 662 mg {gluteal‘}. or 882 mg
`CYP3A4
`(gluteal) once monthly: 882 mg (gluteal)
`once every 6 weeks: or 1,064 mg every
`2 months (glutcal). Continue
`corresponding oral aripiprazole dose for
`21 days after first dose, then stop.
`Altematively, load with Artstoda Inirio
`675 mg TM plus oral aripiprazolc
`30 mg x 1. Can start Aristoda on same
`day or up to 10 days later.
`_
`Missed (lose: It >6 to £7 weds (4-11 mg). >8
`to 512 weeks (662 mg and 882 mg). or >10 to
`512 weeks (1.064 1ng}siucc last dose. restart
`oral aripipmzole x 7 days with next dose. or
`give wifltArismda Initio x1.
`lf>7 weeks (441 mg) or >12 weeks (662 mg,
`882 mg. and 1,064 mg) since last dose. restart
`oral aripiprnzolc x 2| days with next dose. or
`give \vithrlm'rada Im'tm 675 mg x 1 plus oral
`ariaigmzole 30 mg x l.
`
`
`
`
`
`Low
`
`
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 209-472-240 ~ Fax: 209-472-2249
`pharmacisl.therapeuticresearch.com ~ prescriberlherapeuticresearehsom -- pharrnacytech.therapeLtticreseareh.com ~ nurseslelterltherapeut‘tcreseamhcom
`
`lllore. .
`
`.
`
`LATUDA04357629
`
`2
`
`

`

`
`
`(CEinical Resource #341007: Page 3 of 11)
`
`Metabolic Adrerse Effects"“'2'*'7"""““
`
`
`Sedation“"~“
`
`Asenapine
`(Sophrfs)
`
`IO mg (acute). 10—20! mg
`Schizophrenia:
`(afier one week)
`
`Low
`
`Yes
`
`See footnote
`d1
`
`CYP1A2,
`CYP3A4
`(minor),
`CYP2D6
`(minor)
`
`Low to
`Moderate
`
`
`
`CYP450
`QT
`FDA—Approved lndication(s) for
`Generic
`(Brand)!
`ADULTS and Usual or Target Adult
`Prolongingt
`Metabolism“
`Cost”
`Daily Dosage Range (mg/clay)”
`Weight Diabetes Dysiipidemia
`
`Gain
`Risk
`bow to
`Low
`moderate
`
`
`
`
`
`
`
`
`
`
`10 mg
`sublingual
`tablet
`$12003]
`
`Bipolar I disorder (manic or mixed
`episodes): 10-20 mg (monothcrapy or
`with lithium or valproate)
`
`(Weak CYPZDE
`mh‘bm”
`Specific dosing
`may be advised
`for CYP450
`interactions.
`
`
`-
`
`For sublingual use. Avoid food/drink
`for 10 min afterward
`
`Brexpiprazole
`(Rexm’fl)
`
`2 mg tablet
`$1,109i42
`
`Cariprazinc
`(meiar)
`
`3 mg capsule
`$120031
`
`Schizophrenia: 24 mg
`
`Major depressive disorder (adjunct to
`antidepressants): 2 mg
`
`Reduce dose if CY P2D6 poor
`metabolizcr:
`
`Low to
`Moderate Low to
`moderate moderate
`
`No
`
`Schizophrenia: l.5-6 mg
`
`Low
`
`Low
`
`Low
`
`No
`
`Bipolar I disorder (manic or mixed
`episodes):
`3—6 mg
`
`Low
`
`Low to
`moderate
`
`CYP2D6,
`CYP3A4
`_
`.
`Spec1fic dosing
`may be advxsed
`for ”3’450
`interactions.
`
`CYP2D6,
`CYP3A4
`,
`.
`SPC‘HfiC dosing
`may be advnsed
`for CYP450
`interactions.
`
`Avoid with
`CYP3A4
`
`inducers.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 209-472-240 ~ Fax: 209-472-2249
`pharmacisl.therapeuticresearcheom ~ preseriberlherapeuticresearcheom -- pharrnacytech.therapeulicresearcheom ~ nursesletteLtherapeut‘lereseamheem
`
`illore. r
`
`.
`
`LATU DA04357630
`
`3
`
`

`

`
`
`(CEinical Resource #341007: Page 4 of 11)
`
`Metabolic Adrerse Effects"“'2'*'7"""““
`
`
`Sedation“"~“
`
`CYP450
`QT
`FDA—Approved lndication(s) for
`Generic
`(Brand)!
`ADULTS and Usual or Target Adult
`Prolongingt
`Metabolism“
`Cost”
`Daily Dosage Range (mg/clay)”
`Weight Diabetes Dysiipidemia
`
`Gain
`Risk
`High
`High
`
`Schizophrenia (treatment-resistant):
`300—150 mg
`
`Reducing suicidal behavior in
`schizophrenia & schizoafi‘cctivo disorder:
`300—150 mg
`
`initial dose is 12.5 mg once or
`NOTE:
`twice daily (for both indications).
`
`High
`
`High
`
`Yes
`
`CYP1A2,
`CYP3A4.
`See footnote CYP2D6
`h.
`
`Specific dosing
`may be advised
`for CYP450
`interactions,
`
`Clozapiner
`(Clozarr‘l, etc,
`generics)
`
`300 mg tablet
`~$190
`
`Oral
`suspension
`and generic
`orally
`disintegrating
`tablet
`available,
`[loperidone
`(I'kmrrpf)
`
`12 mg tablet
`$I,34l .06
`
`
`
`
`
`
`
`
`
`
`
`
`Schizophrenia;
`
`[2-24 mg
`
`Moderate Low
`
`Low
`
`Yes
`
`See footnote
`g.
`
`Low
`
`CYP3A4,
`CYP2D6
`
`Specific dosing
`may be advised
`for CYP450
`interactions.
`
`Lurasidone
`(Lmuda)
`
`40 mg tablet
`$1,223.40
`
`Schizophrenia: 40460 mg
`
`Low
`
`Low
`
`Low
`
`No”
`
`Bipolar E depression (monotlierapy or
`with lithium or valproate): 20-120 mg
`
`-
`
`Take with food (at least 350 kcat),
`
`Low to
`Moderate
`
`Contmindicated
`“ith strang
`See footnote CYP3A4
`6.
`inhibitors or
`inducers.
`Specific dose
`decrease may be
`advised with
`moderate
`
`inhibitors.
`illore. .
`.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 209-472-240 ~ Fax: 209-472-2249
`pharmacisl.therapeutieresearcheom ~ preseriberlherapeuticreseareheom -- pharrnacytech.therapeuticreseareh.com ~ nursesletteEitherapeut‘lcreseareheom
`
`LATU DA04357631
`
`4
`
`

`

`
`
`(CEinical Resource #341007: Page 5 of 11)
`
`CYP450
`QT
`FDA—Approved lndication(s) for
`Generic
`(Brand)!
`ADULTS and Usual or Target Adult
`Prolongingt
`Metabolisma
`Cust"
`Daily Dosage Range (mg/clay)”
`Weight Diabetes Dyslipidemia
`
`Gain
`Risk
`High
`High
`
`
`
`
`
`Olanzapine
`(threxa,
`generics)
`
`10 mg tablet
`($39
`7
`.
`.
`Injection.
`$43.92/IU mg
`
`.
`Generic orally
`disintegrating
`tablet
`available.
`
`l0 mg
`
`Schizophrenia:
`.
`‘
`_
`_
`Bipolar} disorder (manic or mixed
`episodes and maintenance): 5-20 mg
`(monotherapy or with lithium or
`valproate)
`Bipolar depression. with fluoxetinc:
`542 5 mg
`‘
`Depression (treatment-resistant). with
`flnoxetine: 5-20 mg
`
`Injection;
`Ziwrem InrmMuscufar. agitation
`associated with psychosis or bipolar I
`mania:
`l0 mg (lower dose
`[5 mg. 7.5 mg] may be given). May
`repeat close in two hours A third dose
`may be given no sooner than four hours
`after the second dose.
`
`Schizophrenia: Establish tolerability and
`Olanzapine
`target dose with oral olanzapine first.
`panioate
`Patients can be switched directly to
`(Zyprexa
`Relprew long- Ziwrem Relprevv with or without
`acting
`tapering.‘7 Zyprexa Reflurevv is initiated
`injection)
`with an 8-week loading regimen. and is
`dosed every 2 or4 weeks 1M (gluteal),
`Available only through a restricted
`distribution program requiring
`prescri her, facility. patient, and pharmacy
`enrollment.
`Missed (lose: see footnote i.
`
`300 mg
`$842.40
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 209-472-240 ~ Fax: 209-472-2249
`pharmacisl.therapeuticresearcheom ~ prescribertherapeutiereseareheom -- pharrnacytech.therapeuticreseareh.c0m ~ nurseslelteuherapeutiereseamimeom
`
`Sedation“"~“
`
`Moderate
`
`Metabolic Adverse Effects"“'2'*'7"""““
`
`
`
`
`
`
`High
`
`High
`
`High
`
`High
`
`
`
`CYP1A2,
`CYPZDG
`
`CYP | A2,
`CYPZDG
`
`Yes
`
`See
`footnotes e
`and 11,
`
`Yes
`
`See
`footnotes c
`and h.
`
`
`
`
`
`
`
`
`
`Moderate
`_
`Ram “51‘ 0f
`PQSI' _
`injection
`dehrnnmt
`sedation
`53'“d.r°‘““-
`Monitor for
`at 1955‘ 3
`hours 1705‘"
`d955-
`illore. .
`
`.
`
`LATU DA04357632
`
`5
`
`

`

`CYP450
`QT
`FDA—Approved lndication(s) for
`Generic
`(Brand)!
`ADULTS and Usual or Target Adult
`Prolongingt
`Metabolism“
`Cost”
`Daily Dosage Range (mg/day)”
`Weight Diabetes Dysiipidemia
`
`Gain
`Risk
`bow to
`Low
`moderate
`
`Paliperidone
`(Invega,
`genenes)
`
`Schizophrenia: 3-l2 mg
`
`Schizosffeetive disorder: 3-12 mg
`(monotherapy or adj unet to mood
`stabilizers or antidepressants)
`
`6 mg
`extended-
`relcase tablet
`$734
`Paliperidone
`palmitate
`
`Schizophrenia or sehizoaffeetive disorder:
`1M monthly after 2 doses one week apart.
`Establish tolerability with oral
`paliperidone or risperidene before use.
`(lnvega
`Susrerma long- Taper oral agent with first dose.
`acting
`When switching from a long—acting
`injection)
`injectable, start in plane of the next
`117 mg
`scheduled dose. Missed maintenance
`$125082
`dose: resume regular monthly dosing if
`up to 2 weeks later Details on handling
`other missed dosing scenarios are
`provided in the product labeling.
`
`Paliperidone
`palmitate
`
`(Invega Trinza
`long-acting
`injection)
`4I0 mg
`$l.250.82
`
`Schizophrenia, afier adequate treatment
`with Invega Susienm for at least
`4 months: 1M every 3 months. Dose
`depends on previous Invega Susrenna
`dose Can give up to 2 weeks early or up
`to one month late. Details on handling
`missed doses are provided in the product
`labeling.
`
`
`
`
`
`(CEinical Resource #341007: Page 6 of 11)
`
`Metabolic Adrerse Effects"“'2'*'7"""““
`
`
`Sedation“"~“
`
`Low
`
`Yes
`
`CYPZDS
`(minor),
`See footnote CYP3A4
`d.
`(minor)
`
`Low
`
`Low to
`moderate
`
`Low
`
`Low
`
`Yes
`
`CYP2D6
`(minor).
`See footnote CYP3A4
`d
`(minor)
`
`Avoid CYP3A4
`and/or P-
`glycoprotein
`inducers. if
`possible.
`
`Low to
`moderate
`
`Low
`
`Low
`
`Yes
`
`CYPZDG
`(minor),
`See footnote CYP3A4
`d.
`(minor)
`
`Low
`
`Low
`
`
`
`
`
`
`
`
`
`
`Avoid CYP3A4
`andlor P-
`glyeoprotein
`inducers. if
`possible.
`
`illore. i
`.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 209-472-240 ~ Fax: 209-472-2249
`pharmacisl.lherapeutieresearcheem ~ preseribertherapeutiereseareheom -- pharrnacyteehiherapeulicreseareheom ~ nursesletteLtherapeuticreseareheom
`
`LATU DA04357633
`
`6
`
`

`

`CYP450
`QT
`FDA—Approved lndication(s) for
`Generic
`(Brand)!
`ADULTS and Usual or Target Adult
`Prolongingt
`Metabolisma
`Cost”
`Daily Dosage Range (mg/day)”
`Weight Diabetes Dysiipidemia
`
`Gain
`Risk
`Moderate Moderate Moderate
`
`
`
`
`
`
`
`
`
`
`
`
`Schizophrenia: 150-750 mg
`-
`-
`.
`Bipolar depressmn: 300 mg _
`BlpOifiJ‘ mama or bipolar l mamtenance
`(monetherapy [acute] or as an adjunct to
`lithium or valproate [acute
`maintenanceD: 400-800 mg
`Schizophrenia: 400-800 mg
`Bipolar depression (acute):
`300 mg
`_
`_
`_
`_
`Bipolar} manic or mixed episode
`(monothcmpy [acute] 0" 35 an adjunct ‘0
`lithium or valproate [acute
`maintenance”: 400-800 mg
`Major depressive disorder (adjunct to
`antidepressants): 150-300 mg
`-
`Take without food or with a light
`meal (about 300 kcal),
`Schizophrenia: 4-8 mg
`
`Quetiapine
`(Seroquel,
`generics)
`
`400 mg tablet
`($40
`
`Quetiapine
`(5%?!” XR=
`generics)
`
`400 mg
`extended-
`release tablet
`$<40
`
`Risperidone
`(Risperdal,
`genetics)
`
`4 mg tablet
`<§20
`
`Generic oral
`solution and
`orally
`disintegrating
`tablet available.
`
`
`
`(Ciinieal Resource #341007: Page 7 of 11)
`
`Metabolic Adverse Effects"“'2'*'7"""““
`
`
`Sedation“"~“
`
`Yes
`
`CYP3A4
`
`Moderate
`
`See footnote
`.1
`
`Moderate Moderate Moderate
`
`Yes
`
`See footnote
`do
`
`Moderate Moderate Low
`
`Yes
`
`Specific dosing
`mm. be advised
`for'CYPLlSO
`interactions,
`
`CYP3A4
`i
`.
`Speeifie dosmg
`may be advised
`for CYP450
`interactions.
`
`Moderate
`
`Low
`
`CYPZDG,
`CYP3A4
`(minor)H
`
`Specific dosing
`may be advised
`for CYP450
`interactions
`
`Bipolar i disorder (acute manic or mixed
`episodes: monotherapy or as an adjunct to
`lithium or valproate): 1-6 mg
`
`See
`footnotes c
`and h.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 209-472-240 ~ Fax: 209-472-2249
`pharmacisl.therapeutieresearcheom ~ preseribertherapeuticreseareheom -- pharrnaeytechtherapeutiereseareheom ~ nursesletteritherapeutiereseareheem
`
`illore. i
`
`.
`
`LATU DA04357634
`
`7
`
`

`

`CYP450
`QT
`FDA—Approved lndication(s) for
`Generic
`(Brand)!
`ADULTS and Usual or Target Adult
`Prolongingt
`Metabolism“
`Cost”
`Daily Dosage Range (mg/day)”
`Weight Diabetes Dysiipidemia
`
`Gain
`Risk
`Schizophrenia: 90-120 mg once monthly Moderate Moderate Low
`(subcutaneous in the abdomen). Establish
`tolerability with oral risperidone before
`muting. Perseri‘s 90 mg monthly equals
`~3 mg oral rispcridone once daily:
`Person's 120 mg equals ~4 mg oral
`rispcridone once daily.
`
`Risperidone
`(Pers'eris long-
`acting
`injection)
`
`90 mg
`$1,710
`
`Yes
`
`See
`footnotes e
`and 11,
`
`Low
`
`CYPZDS,
`CYP3A4
`(minor)”
`
`Specific dosing
`may be advised
`for CYP450
`interactions.
`
`
`
`(CEinical Resource #341007: Page 8 of 11)
`
`Metabolic Adrerse Effects"“'2'*'7"""““
`
`
`Sedation“"~“
`
`
`
`
`
`
`
`
`
`
`
`
`Missed dose: restart as soon as possible.
`
`Rispendonc
`(Risperdo'l
`Comm long—
`acting
`injection)
`
`Schizophrenia: 25 mg IM every 2 weeks Moderate Moderate Low
`
`ch
`
`Bipolar l maintenance (monothcrapy or as
`an adjunct
`to lithium or valproate):
`25 mg lM every 2 weeks
`
`See
`footnotes 6
`and 11.
`
`25 mg
`$90692
`
`I Continue oral agent for 3 weeks afier
`first dose, then discontinue.
`
`Missed dose, and <4 consecutive doses
`received: Give injection, plus oral agent
`for 3 weeks.”
`Missed dose. and 4 or more consecutive
`doses received: If only 3-6 weeks have
`passed since last injection: give injection
`alone. lf>6 weeks have passed since last
`injection. give injection, plus oral agent
`for 3 nooks.”
`
`Low
`
`CYP2D6.
`CYP3A4
`(minor)H
`
`Specific dosing
`may be advised
`for CYP450
`interactions,
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 209-472-240 ~ Fax: 209-472-2249
`pharmacist.therapeutieresearchcom ~ prescribertherapeuticresearehcom -- pharrnacytechtherapeuticresearehcom ~ nursesletteLtherapeut‘lcresearchcom
`
`illore. .
`
`.
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`
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`

`
`
`(Clinical Resource #341007: Page 9 of 11)
`
`Metabolic Adrerse Effects"“'2'*'7"""““
`
`
`QT
`Prolongingt
`
`CYP450
`Metabolisma
`
`Sedation“"~“
`
`Weight Diabetes Dysiipidemia
`Gain
`Risk
`Low
`Low
`
`Low
`
`Yes
`
`See footnote
`g.
`
`CYP3A4,
`CYP 1A2
`(minor)
`
`Moderate
`
`
`
`
`
`
`
`
`
`
`
`Generic
`(Brand)!
`Cost”
`
`Zipmsidone
`(German.
`genencs)
`
`80 mg capsule
`$~85
`
`Injection
`$49,68/20 mg
`
`FDA—Approved lndication(s) for
`ADULTS and Usual or Target Adult
`Daily Dosage Range (mg/clay)”
`
`Schizophrenia: 40-160 mg
`
`Bipolar l acute manic or mixed episodes;
`maintenance [adjunct to lithium or
`valproatcl): 80-160 mg
`
`o
`
`Take with food.
`
`Injection: agitation associated “ith
`schizophrenia: 10 mg [M q 2 hrs or
`20 mg ‘14 hrs. Max 40 mg/dav.
`
`Per U.S. product information: Abu’gfj} (February 2017). Abilifi' Mainfena (March 2018). Aristotle (January 20l8). Aristada 1mm) (June
`2018), Scipio-1‘s (February 2017)= Remlri (February 2018) I’hryiar (November 2017), ('lozm'r'r' (September 2015). mept (January 2016).
`[made (March 2018). Zyprexa and Zyprexrr ImraMuscuinr (January 20l8), Zyprem Relprevv (February 2018), Invega (July 2018). [mega
`Smferma (July 2018), [nvego an'nza (July 20E8). S'emque! (February 2017). Semqrtel XR (February 2017) Rfsperdal (July 2018), Risperda/
`Com-m (July 2018), Ferrari's (July 2018). Gender: (February 2017).
`Wholesale acquisition cost (U.S.) per month (unless otherwise specified), for generic ifavailablc, of dose specified. Medication pricing by
`Elscvicr. accessed September 2018.
`Per FDA-approved product labeling and www.crcdiblemeds.org. A "yes“ in the QT column means, at minimum, QT prolongation has been
`reported in patients taking the medication. regardless of causality. Some of these medications have contraindications or recommendations to
`avoid use related to QT prolongation (see pertinent footnotes).
`Avoid use in patients with long QT syndrome. or history of cardiac arrhythmias. or with medications that prolong the QT interval. Avoid in
`patients with risk factors for QT prolongation (cg. bradycardia. hypomagncscmia, hypokalemia, etc).
`Aripiprazoie, olanzapine. and lurasidone may pose relatively lower torsadcs risk vs other antipsychotics based on product labeling and
`literature review. Risperidone may pose more moderate risk vs higher-risk atypical antipsychoties.
`In a QT study, lurasidone was associated
`with QT prolongation vs baseline at 120 mg and 600 mg daily.
`Clozapinc is associated with severe neutropenia. seizures, and myocarditis. Hematological monitoring required. Clomprnc is only available
`through the Clozapinc REMS Program. Prescribers and pharmacies may obtain details at www.clozapineremscom or by calling the number
`in the manufacturer’s product information.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 209-472-240 ~ Fax: 209-472-2249
`pharmacisl.therapeutieresearchcom ~ preseribertherapeuticreseareheom -- pharrnacytech.therapeulicresearehcom ~ nursesletteLtherapeuticresearehcom
`
`illore. .
`
`.
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`LATU DA04357638
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`

`(clinical Resource #341007: Page 1!) of 11)
`
`g. Consider relatively strong capacity to prolong QT interval when selecting an atypical agent. Avoid in patients with significant cardiovascular
`disease (cg. QT prolongation, cardiac arrhythmia. uncompensated heart failure. recent heart attack), or with drugs that prolong the QT
`interval. Use iloperidoite with cautiOn with drugs that inhibit its metabolism (cg. CYP2D6 and CYP3A4 inhibitors), and in patients with
`reduced CYP2D6 activity. Check baseline and periodic potassium and magnesium levels in patients at risk for electrolyte disturbance.
`11. Product
`labeling does not advise to avoid in long QT syndrome, but www.crediblemedsorg does (Accessed September
`I. 2018).
`(Olanzapine: aEso avoid in patients with low magnesium or potassium, or with other (QT-prolonging drugs),
`Zyprexa Refprew, missed dose: no specific dosing guidance is available; use clinical judgment.
`In some studies, up to 16 days (for every—2—
`week dosing) or 35 days (for every—4—week dosing) were allowed between doses.
`in practice, seine patients can go >60 days between doses. The
`effective half—life of varcxcr Retprew is about 30 days.'7
`
`i.
`
`
`
`Users of fins resource are cautioned to use their own profisstnrmt jutt‘gment and consult any other necessnrv or appropriate sources prior to making clinical
`judgments based on the content of this document. Our editors have researched the tit/(mutation with input fi'om experts, government agencies. amt nattwml
`argnmzatmus
`Infimnattnn and internal lurks m ”113’ article were current as fifth? date ufpubltcatfun.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 209-472-240 ~ Fax: 209-472-2249
`pharmacisl.therapeuticresearchcom ~ prescribertherapeuticresearehcom -- pharrnacytech.therapeuticresearch.com ~ nurseslettertherapeut‘tcreseatehcom
`
`More. .
`
`.
`
`LATUDA04357637
`
`10
`
`10
`
`

`

`(Clinical Resource #341007: Page 11 of 11)
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`New atypical
`L, Nobili A.
`Caccia S, Pasina
`antipsychotics for schizophrenia:
`iloperidorre Drug
`Des Deva! Thar 2010;4133—48.
`the
`Bishara D, Taylor D.
`Upcoming agents for
`treatment of schizophrenia; mechanism of action.
`efficacy and tolerability. Drugs 2008;68:2269—92.
`Potkin 86, Cohen M, Panagides J.
`Efficacy and
`tolerability of asenapine in acute schizophrenia:
`a
`placebo and risperidone~controlled trial.
`J Clin
`Psychiatry 2007;68:1492-500.
`a brief
`Citrome L. Lurasidone for schizophrenia:
`review of a new second—generation antipsychotic.
`Grin Schizophr Reiat Psychoses 2011;4:251—7.
`Leucht S, Cipriani A, Spineli L, et ai. Comparative
`efficacy and tolerability of 15 antipsychotic drugs in
`schizophrenia: a multiple-treatments meta-analysis.
`Lancet 2013;382:95162.
`Clinical Pharmacology powered by Clinical Key.
`Tampa,
`FL:
`Elsevier;
`2018.
`http:iMww.clinicalkey.com. (Accessed September 3.
`2018)
`Risperdai Consta
`information.
`Janssen Medical
`(risperidone).
`Dosing—dosage and administration.
`https:iiwvvw.janssenmd.comirisperdal-
`constaldosage-and-administrationigeneraL’risperclal-
`consta-ciosing-dosage-and-
`administraticn?disclaimer&tid=20300754195b8d48c1
`b8fa57.65082093. (Accessed September 3. 2018).
`Werner F. Covenas R. New developments in the
`management of schizophrenia and bipolar disorder:
`potential use of cariprazine. Ther Ciin Risk Manag
`2015;11:165761.
`Zyprexa Reiprew
`Information.
`Eli Lilly Medical
`release
`injectable
`extended
`(olanzapine)
`for
`suspension:
`dosing of and switching to or from
`Zyprexa Reiprew.
`Last
`reviewed November 13.
`2016.
`
`Project Leader in preparation of this clinical
`resource (341007): Melanie Camp. Pharm.D..
`BCPS
`
`References
`1.
`American
`Association;
`Diabetes
`American
`Psychiatric Association; American Assocration of
`Clinical
`Endocrinologists;
`North
`American
`Association for the Study of Obesity. Consensus
`deVelopment conference on antipsychotic drugs and
`obesity and diabetes. Diabetes Care 2004;27:596-
`601.
`
`al.
`et
`Lieberman JA. Stroup TS: McEvoy JP.
`Effectiveness of antipsychotlc drugs in patients with
`chronic
`schizophrenia
`N
`Engl
`J Med
`2005;353:1209-23.
`Rommel-Kluge C, Komossa K. Schwarz S‘ et al.
`Secondrgeneration
`antipsychotic
`drugs
`and
`extrapyramidal side effects: a systematic review and
`meta-analysis
`of
`head-to-head
`comparisons.
`Schrzophr Bali 2012;33:167—77.
`McDonagh M. Peterson K, Carson S, et al. Drug
`class review:
`atypical antipsychotic drugs:
`final
`report update 3 [Internet]. Portland (OR): Oregon
`Health & Science University; 2010 Jul.
`Chwieduk CM. Keating GM. Paliperidone extended
`release:
`a review of its use in the management of
`schizophrenia. Drugs 2010;70:1295—317.
`Correll CU.
`Antipsychotic use in children and
`adolescents: minimizing adverse effects to maximize
`outcomes.
`J Am Acad Chiid Adolesc Psychiatry
`2008:4719—20.
`Paliperidone
`Fowler JA. Bettinger TL. Argo TR.
`acute
`and
`extended-release
`tablets
`for
`the
`maintenance treatment of schizophrenia. Clin Ther
`2008;30:231—48.
`sleep. sedation,
`Miller DD. Atypical antipsychotics:
`and efficacy.
`Prim Care Companion J Ciin
`Psychiatry 2004;6{Suppl 2):3-7.
`
`Clinical Resource, comparison of Atypical Amamrchorics.
`Cite this document as foibles:
`Letterfl’rescriber’s Letter. October 2018.
`
`Pharmacist ’s
`
`ll
`
`trc
`
`pharmacists letter
`
`Evidence and Recommendations You (“an Tmsr...
`
`trc” prescriber‘s letter
`
`Copyright © 2018 by Therapeutic Research Center
`
`trc" pharmacy technicians letter
`
`it
`
`tI'C
`
`nurse's letter
`
`3120 West March Lane. Stockton. CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249
`
`Subscribers to the Letter can get clinical resources. like this one.
`on any topic covered in any issue by going to
`pharmacisuherapeuticresearch.com ~ prescriber.therapeuticresearch.com ~
`pharmacylech.therapeuticresearchcom ~ nursesletter.therapeuticresearch.com
`
`11
`
`LATUDA04357638
`
`11
`
`

`

`mnmm -'
`Jigfl' fl EVE;
`
`PL Detail-Document #310701
`, This PL Detail-Doctrinal!gives subscribers
`additional insrghr related to the Recommendations published in -
`PHARMACIST’S LETTER / PRESCRIBER’S LETTER
`July 2015
`
`Passe-mom's
`igj—TE'E 75;,
`
`‘
`
`Off-Label Use of Atypical Antipsychotics in Adults
`Sixty percent of atypical prescriptions are for an off-label use. But don't assume that just any at3pical will work for a given indication; evidence does
`not support a class effect.7 Weight gain and metabolic effects are of concern with atypicals, especially olanzapine,l7 and very few of these off-label
`uses are backed by large. high—quality. randomized controlled trials. Consider other drug options with more data and few er side effects first (cg.
`antidepressants).
`If an atypical is used. suggested monitoring includes weight, glucose, and lipids. Monitoring for metabolic side effects is outlined
`in the product labeling. and in expert recommendations. Also see our PL Cheri, Lab Monitoring‘for Common Medications. Although these agents
`pose a lower risk of extrapyramidal side effects (eg. agitation) and tardive dyskiuesia than first-generation agentst they are not devoid of these side
`effects.17 The following chart lists common off-label uses for atypicals with at least level B evidence. and therapeutic considerations, See our PL
`(77an Comparison qunyJi'cnl Anri‘psjt‘norics (US subscribers: Canadian subscribers). for approved adult indications. side effects. and CYP
`interactions.
`
`Inclusion means medication has at least level B eVIdence. But inclusion does not mean agent is effective for studied indication, See
`at.
`
`Therapeutic Considerations column ‘or details.
`
`Off-Label Medication“ Therapeutic Considerations
`Use
`Depression.
`Rispcridone (Rispera‘nl.
`I When a patient doesn't respond to an antidepressant. see our PL Charts. Choosing and Switching
`treatment-
`generics)
`Antidepressants and Combining and Augmenting Amidcpresmms.
`resistant, adjunct Ziprasidone (Gannon.
`0 One more patient in nine will respond when an atypical is added to antidepressant therapy compared
`generics; Zeldox
`to placebo.”
`[Canada])
`I Abilifj/ (aripiprazole). Seroque/ XR (quetiapine), and Zyprexa (olanzapine. with fluoxetinc
`[.8111mbyax]) are FDA-approved for adj unctive treatment oftreatment-resistant major depressive
`disorder."3 In Canada. Abilify is approved as an adjunct.” and Semqnel XR is approved as
`monotherapy for treatment-resistant depression)
`I Risperidone‘s efficacy may be similar to aripiprazole or quetiapinef’ |"’but study results are
`inconsistent.22
`20.3 LES
`I Ziprasiclone may be effective.
`
`
`
`
`
`
`illore. .
`
`.
`
`LATU DA04357639
`
`Copyright © 2015 by Therapeutic Research Center
`3120 W. March Lane. Stockton. CA 95219 ~ Phone: 2094722240 ~ Fax: 2094722249
`www PharmacistsLettereom ~ www.PrescribersLetter com - www.PharmacyTechnieiarsLetter cam
`
`12
`
`Dementia
`behaviors
`
`Continued. .
`
`.
`
`Aripiprazolc (Abilifl).
`
`generics [UiS.I)
`Olanmpine (Zr/pram,
`generics )
`Rispcridone (Risperdm'.
`generics)
`
`I Small benefits on agitation in dementia. Risperidone and olanzapine have the best evidence of
`efficauau5 Oral risperidone is Health Canada-approved for symptomatic control of inappropriate
`behavior in severe Alzheimer’s dementia.37
`I Use about one-quarter to One-half the usual adult starting (1056.5
`I Risperidone has the best evidence for psychosis.i
`
`12
`
`

`

`(FL Detail-Document#310701: Page 2 015)
`
`Insomnia
`
`Quetiapine (Seroqiwl.
`generics)
`
`
`
`Use
`Off—Label Medication“ Therapeutic Considerations
`Dementia.
`Quetiapine (Semquei)
`I Reserve for agitation or distress with psychosis (delusions, hallucinations. paranoia), or for
`continued
`treatment-refractory agitation or aggression. in patients who are a danger to themselves or
`others.“ 7"“
`I Increased risk of metabolic syndrome. Increased risk of stroke and mortality in elderly dementia
`patientsfm There is one additional death for about every 50 to 100 dementia patients treated for
`8-12 weeksd'fm Discuss risks/benefits with patientlfamily.fi
`I Try to taper and discontinue the drug every three to six months.‘3
`I Use caution in patients with cerebrovaseular disease or hypovolcmia.6
`I Patients with Parkinsons dementia and Lewy body dementia are extra-sensitive to antipsyehotie
`
`extrapyramidal effects, Low~dose quetiapine is the antipsyehotic of choice.8
`I Quotiapinc appears ineffective for primary insot‘ril‘ii=1.j‘9'24
`I Quetiapine has been abused/misused for its sedating and anxiolytic effects.'0
`I Quetiapine and olanzapine have been used for treatment of insomnia secondary to specific causes
`(e.g., depression, drug withdrawal, PaIkinson’s disease, fibromyalgia). Data are extremely
`Limited-‘34
`I Avoid for primary insomnia.33 See our PL Charts. Comparison Qf'lmomm‘a Treatments (U.S.
`
`subscribers; Canadian subscribers), for insomnia treatment options.
`I Role is for augmentation of antidepressants to reduce layperarousal and re-experiencing.”
`I Risperidone and olanzapine have the best evidenee.5'2”7
`. Not all studies have been favorablels'm'37
`
`
`
`
`
`Post—traumatic
`SHOES diSOFdCf.
`adjunct
`
`Obsessive-
`COH'IPl-flSiVC
`disorder, adjunct
`
`I Role is as adjunct to SSRI in treatment-resistant 0CD.5
`I Rispcridone and aripiprazole have the best evidence ofet‘ficacy.“2 3"
`I Olanzapinc. paliperidone. and quetiapine are not consistently better than placebo.
`
`l 244.1617
`
`Aripiprazole (Abiiijfiv,
`generics lU-S-l)
`Risperidone (Risperci‘aL
`
`genetics)
`Olanzapine (Zyprexa.
`generics)
`Quctiapine (Seroqiiei,
`
`generics)
`Aripiprazole (Abifgfiz,
`generics lU-S-l)
`
`RiSPCFidOHC (Rfspem‘al,
`generics)
`Olanzapine (Zyprexa.
`genetics)
`Paliperidonc (Invegn)
`Quetiapine (Seroquei.
`
`generics)
`
`
`
`
`
`PM
`
`
`l
`[L152— tflfi":
`P .,_.._..._,
`‘2’“qu
`
`he
`R
`h earner: Th
`o
`en er
`OPWIQ
`erape ic eseare
`y
`i
`'
`t
`ut'
`3120W March Lane, Stockton, CA 95219 - Phone: 209-472-2240 ~ Fax: 209-472-2249
`wwaharmacislsLettereom ~ wwarescribersLettercorn ~ wwaharrnaeyTechniciansLettereom
`
`"HaremM
`[LE9 {El}?
`.
`as? .1
`
`LATU DA04357640
`
`13
`
`13
`
`

`

`(Ft. Detail-Document#310701: Page 3 01 5)
`
`
`
`Use
`Off—Label Medication“ Therapeutic Considerations
`Generalized
`Quetiapine (Seraquel,
`I SSRls and SNRls are first-line.27 Second-line agents include bnspirone or pregabalin.27‘“
`
`anxiety disorder
`generics)
`I Quetiapine has best evidence of eFfieacy.5"127'1*
`Risperidone (Risperci‘ai'.
`I Ziprasidone is not better than [:ilai:ebo.”'27
`generics)
`Olanzapine (Zyprexa,
`generics)
`Aripiprazole (Ability,
`
`generics [U.Sv]
`Ziprasidone (Geodan.
`Zelda): CanadaD —
`Risperidone (Risperciai',
`I Aripiprazolc and risperidone are FDA-approved for irritability associated with autism in pediatrics
`generics)
`(up to age 17 _\'ears).3'39
`Olanzapine (Zyprexa.
`- Adults have been included in some risperidene studies.”
`gCflCTiCS)
`0 Olanzapine and quotiapine have been studied in an open-label fashion in adults“
`Quctiapine (Seroquei,
`generics)
`Olanzapine (Zyprem‘
`generics)
`Quetiapine (SW01]“?l.
`
`generics)
`stperidone (Risperdai',
`generics)
`
`I Reserve for patients who are severely agitated or distressed.“3
`0 Olanzapine may be 1055 effective in patients over 75 years of age.35
`0 See our PL Chart, Preventing and treating Deiiriiim in Inpatients, for more infomlation.
`
` Autism
`
`
`
`
`
`Delirium in
`hospitalized
`patients
`(treatment)
`
`
`
`Users ofthis PI. Detail-Document are cautioned to use their own