tre
`prescriber’s letter
`tre
`trc a pharmacist’s letter
`October 2018 ~ Resource #341007
`
`trc
`
`nurse’s letter
`
`~ThisClinical Resource gives subscribers
`additional insight related to the Recommendations published in
`2 pharmacytechnician's letter
`
`*
`
`Comparisonof Atypical Antipsychotics
`
`Second generation or “atypical” antipsychotics have a lower propensity than the first generation agents to cause extrapyramidal side effects and
`tardive dyskinesia, but are by no means devoid ofthese adverse effects.* Clozapine maybe the mosteffective atypical for schizophrenia, butits use is
`limited due to the risk of agranulocytosis.'*'* All carry “black box” wamings 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, cariprazine, and risperidone.**>°'>
`Hyperprolactinemia, associated with sexual dysfunction, gynecomastia, and irregular periods, seems most common with risperidone and
`paliperidone.**'? 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 IM
`antipsychotic injections under their supervision using CPT code 96372, and add the medication code.
`
`NOTE: *Usual or target daily ADULT dosage range maynotinclude initial 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 12.5 mg should be divided.
`
`Sedation**4
`CYP450
`QT
`FDA-ApprovedIndication(s) for
`Generic
`Metabolic Adverse Effects*!24.710-15.16
`
`
`
`(Brand)/ Prolonging’|Metabolism*ADULTSand Usualor Target Adult
`
`Cost” Weight|Diabetes|DyslipidemiaDaily Dosage Range (mg/day)**
`
`Gain
`Risk
`Low
`Low
`
`Low
`
`Yes
`
`
`
`
`
`
`
`
`
`
`Schizophrenia: 10-15 mg
`Aripiprazole
`,
`.
`.
`.
`(Abilify,
`See
`BipolarI disorder (manic or mixed
`generics)
`
`episodes and maintenance): 15 mg footnotes e|Specific dosing
`(monotherapyor with lithium or
`10 mgtablet
`and h.
`maybe advised
`~$45
`valproate)
`for CY P450
`oie
`es .
`interactions.
`Major depression(adjunct): 5-10 mg
`
`CYP2D6,
`CYP3A4
`
`Low
`
`Gralsalugen
`andorally
`disintegrating
`tabs available.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`More...
`
`LATUDA04357628
`
`1
`
`Exhibit 2091
`Slayback v. Sumitomo
`IPR2020-01053
`
`1
`
`Exhibit 2091
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`(Clinical Resource #341007: Page 2 of 11)
`
`
`
`400 mg
`$2,166.41
`
`
`
`
`
`
`
`Low
`
`Yes
`
`
`
`
`
`
`
`
`
`Sedation**5
`CYP450
`QT
`FDA-ApprovedIndication(s) for
`Generic
`Metabolic Adverse Effects*!7471"-1516
`
`(Brand)/ Prolonging’|Metabolism*ADULTSand Usual or Target Adult
`
`
`Cost? Weight|Diabetes|DyslipidemiaDaily Dosage Range (mg/day)**
`
`
`
`Gain
`Risk
`Low
`Low
`
`Schizophrenia: 400 mg IM (gluteal or
`Aripiprazole
`deltoid) once monthly. Continueoral
`(Abilify
`See
`agentfor 14 daysafterfirst dose, then
`Maintena
`
`
`long-acting footnotes e|Specific dosingstop.
`injection)
`Reduce dose if CYP2D6 poor metabolizer.
`and h,
`thaybe advised
`Avoid with CYP3A4inducers for more than
`for CYP450
`14 days.
`interactions.
`°Missed dose: If >6 weekselapse sincelast
`dose (>5 weeksif 2" or 3" dose is missed),
`restart oral aripiprazole x 14 days with the next dose.
`Aripiprazole
`Schizophrenia: 441 mg IM (gluteal or
`Low
`Low
`Low
`Yes
`CYP2D6,
`Low
`lauroxil
`deltoid), 662 mg (gluteal), or 882 mg
`CYP3A4
`See
`(gluteal) once monthly: 882 mg (gluteal)
`
`Aristada long-|once every 6 weeks; or 1,064 mg every footnotes e|Specific dosing
`acting
`2 months (gluteal). Continue
`and h.
`maybe advised
`injection
`corresponding oral aripiprazole dose for
`for CYP450
`662 mg
`21 daysafterfirst dose, then stop.
`interactions.
`$1,833.55
`Alternatively, load with Aristada Initio
`675 mg IM plus oral aripiprazole
`Aristada Initio|30 mg x 1. Can start Aristada on same
`(for loading)
`dayor up to 10 dayslater.
`675 mg x 1
`.
`$1,869.56
`Missed dose: If >6 to <7 weeks (441 mg). >8
`to <12 weeks (662 mg and 882 mg), or >10 to
`<12 weeks (1.064 mg)since last dose, restart
`oral aripiprazole x 7 days with next dose, or
`give with Aristada Initio x1.
`If>7 weeks (441 mg) or >12 weeks (662 mg.
`882 mg, and 1,064 mg)since last dose, restart
`oral aripiprazole x 21 days with next dose, or
`give with Aristada Initio 675 mg x 1 plus oral
`aripiprazole 30 mg x 1.
`
`
`
`CYP2D6,
`CYP3A4
`
`Low
`
`More. ..
`
`
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`LATUDA04357629
`
`2
`
`

`

`
`
`(Clinical Resource #341007: Page 3 of 11)
`
`Asenapine Low to|LowSchizophrenia: 10 mg (acute), 10-20 mg Low Yes CYPIA2, Lowto
`
`
`
`Sedation**5
`CYP450
`QT
`FDA-ApprovedIndication(s) for
`Generic
`Metabolic Adverse Effects*!7471"-1516
`
`(Brand)/ Prolonging’|Metabolism*ADULTSand Usual or Target Adult
`
`
`Cost? Weight|Diabetes|DyslipidemiaDaily Dosage Range (mg/day)**
`
`
`
`Gain
`Risk
`
`
`
`
`
`(Saphris)
`(after one week)
`moderate
`CYP3A4
`Moderate
`See footnote|(minor),
`10 mg
`Bipolar I disorder (manic or mixed
`d.
`CYP2D6
`sublingual
`episodes): 10-20 mg (monotherapyor
`(minor)
`tablet
`with lithium or valproate)
`$1,200.81
`
`©
`
`(Weak CYP2D6
`inhibitor.)
`Specific dosing
`maybe advised
`for CYP450
`interactions.
`
`
`For sublingual use. Avoid food/drink
`for 10 min afterward.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Brexpiprazole|Schizophrenia: 2-4 mg Moderate|Lowto Lowto No CYP2D6, Low
`
`
`
`
`(Rexulti) moderate|moderate CYP3A4
`Major depressive disorder(adjunct to
`,
`.
`antidepressants): 2 mg
`Specific dosing
`maybe advised
`for CYP450
`interactions.
`
`Reduce dose if CYP2D6 poor
`metabolizer.
`
`2 mgtablet
`$1,109.42
`
`Cariprazine
`(Vraylar)
`
`Schizophrenia: 1.5-6 mg
`
`Low
`
`Low
`
`CYP2D6,
`CYP3A4
`.
`.
`BipolarI disorder (manic or mixed
`
`3mg capsule|episodes): 3-6 mg Specific dosing
`$1,200.81
`maybe advised
`for CYP450
`interactions.
`
`Low
`
`No
`
`Lowto
`moderate
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`More...
`
`LATUDA04357630
`
`Avoid with
`CYP3A4
`inducers.
`
`3
`
`

`

`
`
`(Clinical Resource #341007: Page 4 of 11)
`
`NOTE: initial dose is 12.5 mg once or
`twice daily (for both indications).
`
`lloperidone Moderate|LowSchizophrenia: 12-24 mg Low Yes CYP3A4, Low
`
`
`
`
`
`Oral
`suspension
`and generic
`orally
`disintegrating
`tablet
`available.
`
`
`
`(Fanapt)
`CYP2D6
`
`Sedation**5
`CYP450
`QT
`FDA-ApprovedIndication(s) for
`Generic
`Metabolic Adverse Effects*!7471"-1516
`
`(Brand)/ Prolonging’|Metabolism*ADULTSand Usual or Target Adult
`
`
`Cost? Weight|Diabetes|DyslipidemiaDaily Dosage Range (mg/day)**
`
`
`
`Gain
`Risk
`High
`CYPIA2,
`Yes
`High
`High
`High
`Schizophrenia (treatment-resistant):
`Clozapine!
`
`(Clozaril, etc,|300-450 mg CYP3A4.
`generics) See footnote|CYP2D6
`
`Reducing suicidal behaviorin
`h.
`300 mg tablet|schizophrenia & schizoaffective disorder: Specific dosing
`
`~$190
`300-450 mg
`maybe advised
`for CYP450
`interactions.
`
`
`
`
`
`
`
`
`
`
`
`
`
`12 mgtablet
`$1,341.06
`
`See footnote
`g.
`
`Specific dosing
`maybe advised
`for CYP450
`interactions.
`
`
`
`
`
`
`
`
`
`
`
`Lurasidone Contraindicated|LowtoSchizophrenia: 40-160 mg Low Low Low No!”
`
`(Landa)
`with strong
`Moderate
`Bipolar I depression (monotherapyor See footnote|CYP3A4
`
`40 mgtablet
`with lithium or valproate): 20-120 mg
`c..
`inhibitors or
`$1,223.40
`inducers.
`Specific dose
`decrease may be
`advised with
`moderate
`inhibitors.
`
`¢
`
`Take with food (at least 350 keal).
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`More...
`
`LATUDA04357631
`
`4
`
`

`

`
`
`(Clinical Resource #341007: Page 5 of 11)
`
`Sedation**5
`CYP450
`QT
`FDA-ApprovedIndication(s) for
`Generic
`Metabolic Adverse Effects*!7471"-1516
`
`
`
`(Brand)/ Prolonging’|Metabolism*ADULTSand Usual or Target Adult
`
`Cost? Weight|Diabetes|DyslipidemiaDaily Dosage Range (mg/day)**
`
`Gain
`Risk
`High
`High
`
`High
`
`Yes
`
`See
`footnotes é
`andh.
`
`CYPIA2,
`CYP2D6
`
`Moderate
`
`Olanzapine
`(Zyprexa,
`generics)
`
`10 mgtablet
`<$30
`a.
`Injection:
`$43.92/10 mg
`
`Schizophrenia: 10 mg
`.
`.
`.
`.
`Bipolar I disorder (manic or mixed
`episodes and maintenance): 5-20 mg
`(monotherapyor with lithium or
`valproate)
`Bipolar depression, with fluoxetine:
`5-125 me
`:
`Depression (treatment-resistant), with
`fluoxetine: 5-20 mg
`
`:
`Generic orally
`disintegrating|Injection:
`tablet
`Zyprexa IntraMuscular, agitation
`available.
`associated with psychosisor bipolar I
`mania: 10 mg (lower dose
`[5 mg, 7.5 mg] may be given). May
`repeat dose in two hours. A third dose
`maybe given no soonerthan four hours
`after the second dose.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Olanzapine Schizophrenia: Establish tolerability and|High High High Yes CYPIA2, Moderate
`
`
`
`
`
`pamoate
`target dose with oral olanzapinefirst.
`CYP2D6
`.
`See
`(Zyprexa
`Patients can be switched directlyto
`Rare risk of
`
`Relprevv long-|Zyprexa Relprevv with or without footnotes e post-
`
`acting
`tapering.'’ Zyprexa Relprevyis initiated
`and h.
`injection
`injection)
`with an 8-week loading regimen, and is
`delirium/
`dosed every 2 or 4 weeks IM (gluteal).
`sedation
`Available only through a restricted
`syndrome.
`distribution program requiring
`Monitorfor
`prescriber,facility, patient, and pharmacy
`atleast 3
`enrollment.
`hours post-
`Missed dose: see footnotei.
`dose.
`More...
`
`300 mg
`$842.40
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`LATUDA04357632
`
`5
`
`

`

`
`
`(Clinical Resource #341007: Page 6 of 11)
`
`Sedation**5
`CYP450
`QT
`FDA-ApprovedIndication(s) for
`Generic
`Metabolic Adverse Effects*!7471"-1516
`
`(Brand)/ Prolonging’|Metabolism*ADULTSand Usual or Target Adult
`
`
`Cost? Weight|Diabetes|DyslipidemiaDaily Dosage Range (mg/day)**
`
`
`
`Gain
`Risk
`
`
`
`Unvega,
`moderate
`(minor),
`
`generics) See footnote|CYP3A4Schizoaffective disorder: 3-12 mg
`
`(monotherapyor adjunct to mood
`d.
`(minor)
`stabilizers or antidepressants)
`
`Paliperidone Lowto|LowSchizophrenia: 3-12 mg Low Yes CYP2D6 Low
`
`
`
`
`
`6 mg
`extended-
`release tablet
`$734
`
`
`
`Paliperidone Schizophrenia orschizoaffective disorder:|Low to|Low Low Yes CYP2D6 Low
`
`
`
`
`palmitate IM monthlyafter 2 doses one week apart.|moderate (minor),
`Establish tolerability with oral See footnote|CYP3A4
`
`paliperidone or risperidone before use.
`(nvega
`d
`(minor)
`Sustenna long-|Taperoral agent with first dose.
`acting
`Whenswitching from a long-acting
`Avoid CYP3A4
`injection)
`injectable, start in place of the next
`and/or P-
`117 mg
`scheduled dose. Missed maintenance
`glycoprotein
`$1,250.82
`dose: resume regular monthly dosing if
`inducers, if
`up to 2 weeks late. Details on handling
`possible.
`other missed dosing scenarios are
`provided in the product labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Paliperidone Lowto|LowSchizophrenia, after adequate treatment Low Yes CYP2D6 Low
`
`
`
`
`
`
`
`
`
`palmitate
`with Jnvega Sustenna for at least
`moderate
`(minor),
`IM every 3 months. Dose4 months: See footnote|CYP3A4
`
`
`
`(Unvega Trinza|depends on previous /nvega Sustenna d. (minor)
`
`long-acting
`dose. Can give up to 2 weeks early or up
`injection)
`to one month late. Details on handling
`410 mg
`missed doses are provided in the product
`$1,250.82
`labeling.
`
`Avoid CYP3A4
`and/or P-
`glycoprotein
`inducers, if
`possible.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`More...
`
`LATUDA04357633
`
`6
`
`

`

`
`
`(Clinical Resource #341007: Page 7 of 11)
`
`Risperidone Moderate|Moderate|LowSchizophrenia: 4-8 mg Yes CYP2D6, Low
`
`
`
`Sedation**5
`CYP450
`QT
`FDA-ApprovedIndication(s) for
`Generic
`Metabolic Adverse Effects*!7471"-1516
`
`(Brand)/ Prolonging’|Metabolism*ADULTSand Usual or Target Adult
`
`
`Cost? Weight|Diabetes|DyslipidemiaDaily Dosage Range (mg/day)**
`
`
`
`Gain
`Risk
`
`
`
`Quetiapine Moderate|Moderate|ModerateSchizophrenia: 150-750 mg Yes CYP3A4 Moderate
`
`
`(Seroquel,
`:
`it
`ri
`
`
`generics) See footnote|Specific dosingBipoke eens ome .
`Bipolar mania or bipolar I maintenance
`a.
`maybe advised
`
`400 mg tablet|(monotherapy[acute] or as an adjunctto forCYP450
`<$40
`lithium or valproate [acute.
`interactions.
`maintenance]); 400-800 mg
`
`
`Quetiapine Moderate|Moderate|ModerateSchizophrenia: 400-800 mg Yes CYP3A4 Moderate
`
`
`
`
`(Seroque!XR.|Bipolar depression (acute): : .
`
`generics) See footnote|Specific dosing300 mg
`
`
`.
`:
`.
`.
`d.
`maybe advised
`400 mg
`Bipolar | manic or mixed episode
`for CYP450
`extended-
`(monotherapy[acute] or as an adjunctto
`interactions.
`release tablet
`lithium or valproate [acute,
`$<40)
`maintenance |): 400-800 mg
`Major depressive disorder (adjunct to
`antidepressants): 150-300 mg
`®
`Take without food or with a light
`meal (about 300 kcal).
`
`
`
`
`(Risperdal,
`CYP3A4
`generics)
`(minor)!+
`
`
`
`
`
`
`
`
`
`
`
`
`Bipolar I disorder (acute manic or mixed
`episodes; monotherapyoras an adjunct to
`lithium or valproate): 1-6 mg
`
`4 mg tablet
`<$20
`
`Generic oral
`solution and
`orally
`disintegrating
`tablet available.
`
`See
`footnotes ¢
`and h.
`
`Specific dosing
`maybe advised
`for CYP450
`interactions.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`LATUDA04357634
`
`More...
`
`7
`
`

`

`
`
`(Clinical Resource #341007: Page 8 of 11)
`
`Sedation**5
`CYP450
`QT
`FDA-ApprovedIndication(s) for
`Generic
`Metabolic Adverse Effects*!7471"-1516
`
`(Brand)/ Prolonging’|Metabolism*ADULTSand Usual or Target Adult
`
`
`Cost? Weight|Diabetes|DyslipidemiaDaily Dosage Range (mg/day)**
`
`
`
`Gain
`Risk
`
`
`Risperidone Schizophrenia: 90-120 mg once monthly|Moderate|Moderate|Low Yes CYP2D6, Low
`
`
`
`(Perseris long-|(subcutaneousin the abdomen). Establish CYP3A4
`acting
`tolerability with oral risperidone before
`See
`(minor)"*
`injection)
`starting. Perseris 90 mg monthly equals
`footnotes ¢
`~3 mg oral risperidone once daily;
`and h,
`Perseris 120 mg equals ~4 mgoral
`risperidone oncedaily.
`
`90 mg
`$1,710
`
`Specific dosing
`maybe advised
`for CYP450
`interactions.
`
`Missed dose: restart as soonaspossible.
`
`
`
`
`
`
`
`
`
`
`
`
`Risperidone Schizophrenia: 25 mg IM every 2 weeks|Moderate|Moderate|Low Yes CYP2D6, Low
`
`
`
`
`
`
`(Risperdal
`CYP3A4
`Consta long-|Bipolar I maintenance (monotherapyor as See (minor)"*
`
`
`acting
`an adjunct
`to lithium or valproate):
`footnotes ¢
`injection)
`25 mg IM every 2 weeks
`and h.
`
`25 mg
`$906.92
`
`* Continue oral agent for 3 weeks after
`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
`passedsincelast injection, give injection
`alone. If >6 weeks have passed since last
`injection, give injection, plus oral agent
`for 3 weeks.'°
`
`Specific dosing
`maybe advised
`for CYP450
`interactions.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`LATUDA04357635
`
`More...
`
`8
`
`

`

`
`
`(Clinical Resource #341007: Page 9 of 11)
`
`Sedation**5
`CYP450
`QT
`FDA-ApprovedIndication(s) for
`Generic
`Metabolic Adverse Effects*!7471"-1516
`
`
`
`(Brand)/ Prolonging’|Metabolism*ADULTSand Usual or Target Adult
`
`Cost? Weight|Diabetes|DyslipidemiaDaily Dosage Range (mg/day)**
`
`Gain
`Risk
`Low
`Low
`
`Schizophrenia: 40-160 mg
`
`
`
`
`
`
`
`
`
`
`
`CYP3A4,
`Ziprasidone
`CYPIA2
`(Geodon,
`
`generics) See footnote|(minor)Bipolar | acute manic or mixed episodes:
`
`maintenance [adjunctto lithium or
`g.
`80 mg capsule|valproate|): 80-160 mg
`$~85
`
`Low
`
`Yes
`
`Moderate
`
`e
`
`Take with food.
`
`Injection
`$49.68/20 mg|Injection: agitation associated with
`schizophrenia: 10 mg IM q 2 hrs or
`20 mg q4hrs. Max 40 mg/day.
`
`Per U.S. product information: Abilify (February 2017), Abilify Maintena (March 2018), Aristada (January 2018), Aristada Initio (June
`2018), Saphris (February 2017), Rexulti (February 2018), Vravlar (November 2017), Clozaril (September 2015), Fanapt (January 2016),
`Latuda (March 2018), Zyprexa and Zyprexa IntraMuscular (January 2018), Zyprexa Relprevv (February 2018), Invega (July 2018). Jnvega
`Sustenna (July 2018), Invega Trinza (July 2018), Serogue/ (February 2017), Seroquel XR (February 2017), Risperdal (July 2018), Risperdal
`Consta (July 2018), Perseris (July 2018), Geodon (February 2017).
`Wholesale acquisition cost (U.S.) per month (unless otherwise specified), for generic if available, of dose specified. Medication pricing by
`Elsevier, accessed September 2018.
`Per FDA-approved product labeling and www.crediblemeds.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 historyof cardiac arrhythmias, or with medications that prolong the QT interval. Avoid in
`patients with risk factors for QT prolongation (¢.g., bradycardia, hypomagnesemia, hypokalemia, etc).
`Aripiprazole. olanzapine, and lurasidone may pose relatively lower torsades risk ys other antipsychotics based on product labeling and
`literature review. Risperidone may pose more moderate risk vs higher-risk atypical antipsychotics.
`In a QT study, lurasidone was associated
`with QT prolongation vs baseline at 120 mg and 600 mg daily.
`Clozapine is associated with severe neutropenia, scizures, and myocarditis, Hematological monitoring required. Clozapine is only available
`through the Clozapine REMSProgram. Prescribers and pharmacies mayobtain details at www.clozapinerems.com orbycalling the number
`in the manufacturer's product information.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
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`(Clinical Resource #341007: Page 10 of 11)
`
`g. Considerrelatively strong capacity to prolong QT interval when selecting an atypical agent. Avoid in patients with significant cardiovascular
`disease (e.g.. QT prolongation, cardiac arrhythmia, uncompensated heart failure, recent heart attack), or with drugs that prolong the QT
`interval. Use iloperidone with caution with drugs that inhibit its metabolism (¢.g., CYP2D6 and CYP3A4inhibitors), and in patients with
`reduced CYP2D6activity. Check baseline and periodic potassium and magnesium levels in patients at risk for electrolyte disturbance.
`h. Product
`labeling does not advise to avoid in long QT syndrome, but www.crediblemeds.org does (Accessed September
`|, 2018).
`(Olanzapine: also avoid in patients with low magnesiumor potassium, or with other QT-prolonging drugs).
`Zyprexa Relprevv, missed dose: no specific dosing guidance is available: use clinical judgment.
`In somestudies, up to 16 days (for every-2-
`week dosing) or 35 days (for every-4-week dosing) were allowed between doses.
`In practice, some patients can go >60 days between doses. The
`effective half-life of Zyprexa Relprevy is about 30 days.'’
`
`1.
`
`
`
`Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical
`judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national
`organizations.
`Information and internet links in this article were current as ofthe date ofpublication.
`
`Copyright © 2018 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`More...
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`(Clinical Resource #341007: Page 11 of 11)
`
`Project Leader in preparation of this clinical
`resource (341007): Melanie Cupp. Pharm.D.
`BCPS
`
`References
`1.
`American
`Association;
`Diabetes
`American
`Psychiatric Association; American Association 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.
`
`New atypical
`L, Nobili A.
`Caccia S, Pasina
`antipsychotics for schizophrenia:
`iloperidone. Drug
`Des Devel Ther 2010;4:33-48.
`the
`Bishara D, Taylor D.
`Upcoming agents for
`treatment of schizophrenia: mechanism of action,
`efficacy and tolerability. Drugs 2008;68:2269-92.
`Potkin SG, 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.
`Clin Schizophr Relat Psychoses 2011;4:251-7.
`Leucht S, Cipriani A, Spineli L, et al. Comparative
`al.
`et
`Lieberman JA, Stroup TS, McEvoy JP,
`efficacy and tolerability of 15 antipsychotic drugs in
`Effectiveness of antipsychotic drugs in patients with
`schizophrenia: a multiple-treatments meta-analysis.
`chronic
`schizophrenia.
`N
`Engl
`J Med
`Lancet 2013;382:951-62.
`2005;353: 1209-23.
`Clinical Pharmacology powered by Clinical Key.
`Rummel-Kluge C, Komossa K, Schwarz S, et al.
`Tampa,
`FL:
`Elsevier:
`2018.
`Second-generation
`antipsychotic
`drugs
`and
`http:/Awww.clinicalkey.com. (Accessed September 3,
`extrapyramidal side effects: a systematic review and
`2018).
`meta-analysis
`of
`head-to-head
`comparisons.
`Risperdal Consta
`Information.
`Janssen Medical
`Schizophr Bull 2012;38: 167-77.
`(risperidone). Dosing-dosage and administration.
`McDonagh M, Peterson K, Carson S, et al. Drug
`https: //Awww.janssenmd.com/risperdal-
`
`class review: atypical antipsychotic drugs:_final
`consta/dosage-and-administration/general/risperdal-
`report update 3 [Internet]. Portland (OR): Oregon
`consta-dosing-dosage-and-
`Health & Science University; 2010 Jul.
`administration?disclaimer&tid=20300754 195b8d48c1
`Chwieduk CM, Keating GM. Paliperidone extended
`b8faS7.65082093, (Accessed September3, 2018).
`release:
`a review ofits use in the managementof
`Werner F, Covenas R. New developments in the
`schizophrenia. Drugs 2010;70:1295-317.
`management of schizophrenia and bipolar disorder:
`Correll CU.
`Antipsychotic use in children and
`potential use of cariprazine. Ther Clin Risk Manag
`adolescents: minimizing adverse effects to maximize
`2015;11:1657-61.
`outcomes.
`J Am Acad Child Adolesc Psychiatry
`Zyprexa Relprevv
`Information.
`Eli Lilly Medical
`2008;47:9-20.
`release
`injectable
`extended
`(olanzapine)
`for
`Paliperidone
`Fowler JA, Bettinger TL, Argo TR.
`acute
`and
`extended-release
`tablets
`for
`the
`suspension:
`dosing of and switching to or from
`zyprexa Relprevv.
`Last
`reviewed November 13.
`maintenance treatment of schizophrenia. Clin Ther
`2016.
`2008;30:231-48.
`sleep, sedation,
`Miller DD. Atypical antipsychotics:
`and efficacy.
`Prim Care Companion J Clin
`Psychiatry 2004:6(Suppl 2):3-7.
`
`10.
`
`ts
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`hs
`
`Cite this document as follows:
`Clinical Resource, Comparison of Atypical Antipsychotics.
`Letter/Prescriber’s Letter. October 2018.
`
`Pharmacist’s
`
`tre 2 pharmacist's letter
`
`Evidence and Recommendations You Can Trust...
`
`trc™ prescriber's letter
`
`Copyright © 2018 by Therapeutic Research Center
`
`trc® pharmacytechnician's letter
`
`trc *
`
`nurse's letter
`
`3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249
`
`Subscribers to the Leffer can get clinical resources,like this one,
`on any topic covered in any issue by going to
`pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~
`pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com
`
`11
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`
`
`Dementia
`behaviors
`
`Continued...
`
`Aripiprazole (Abilify,
`
`generics [U.S.[)
`Olanzapine (Zyprexa,
`generics )
`Risperidone (Risperdal.
`generics)
`
`e Small benefits on agitation in dementia. Risperidone and olanzapine have the best evidence of
`efficacy,’ Oral risperidone is Health Canada-approved for symptomatic control of inappropriate
`behaviorin severe Alzheimer’s dementia.*”
`Use about one-quarter to one-halfthe usual adult starting dose.°
`|» Risperidone has the best evidence for psychosis.”
`
`PHARMaCIST’S
`LETTER
`
`(4a
`
`PL Detail-Document#310701
`—This PL Detail-Document gives subscribers
`additional insight related to the Recommendationspublished in—
`PHARMACIST’S LETTER / PRESCRIBER’S LETTER
`July 2015
`
`PRESCRIBER'S ee
`LETTER <?
`
`Off-Label Use of Atypical Antipsychotics in Adults
`Sixty percentof atvpical prescriptions are for an off-label use, But don’t assumethat just anyatypical will work for a given indication; evidence does
`not support a class effect.’ Weight gain and metabolic effects are of concern with atypicals. especially olanzapine,'’ and very few of these off-label
`uses are backed bylarge, high-quality, randomized controlled trials. Consider other drug options with more data and fewer side effects first (e.g..
`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 Chart, Lab Monitoringfor Common Medications. Although these agents
`pose a lowerrisk of extrapyramidal side effects (c.g. agitation) and tardive dyskinesia than first-generation agents, they are not devoid of these side
`effects.'’ The following chart lists commonoff-label uses for atypicals with at least level B evidence, and therapeutic considerations. See our PL
`Chart, Comparison ofAtypical Antipsychotics (U.S. 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 agentis effective for studied indication. See
`a.
`
`Therapeutic Considerations columnfordetails.
`Use Off-Label Medication’|Therapeutic Considerations
`
`
`Depression, Risperidone (Risperdal,|® Whenapatient doesn’t respond to an antidepressant, see our PL Charts, Choosing and Switching
`treatment-
`generics)
`Antidepressants and Combining and Augmenting Antidepressants.
`resistant, adjunet Ziprasidone (Geodon,
`¢ One morepatient in nine will respond when an atypical is added to antidepressant therapy compared
`generics; Zeldox
`to placebo.”
`[Canada])
`© Abilify (aripiprazole), Seroque! XR (quetiapine), and Zyprexa (olanzapine, with fluoxetine
`[Symbyax]) are FDA-approved for adjunctive treatment oftreatment-resistant major depressive
`disorder.’* In Canada, Abilify is approved as an adjunct, '* and Seroquel XR is approved as
`monotherapyfor treatment-resistant depression.’
`© Risperidone’s efficacy maybesimilarto aripiprazole or quetiapine,*'” but studyresults are
`inconsistent.”
`20,21,38
`¢ Ziprasidone maybe effective.
`
`More...
`
`Copyright © 2015 by Therapeutic Research Center
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com
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`(PL Detail-Document #310701: Page 2 of 5)
`
`Insomnia
`
`Quetiapine (Seroquel,
`gencrics)
`
`
`
`
`
`
`
`
`Use Off-Label Medication*|Therapeutic Considerations
`
`Dementia,
`Quetiapine (Seroquel)
`e Reserve foragitation ordistress with psychosis (delusions, hallucinations, paranoia), or for
`continued
`treatment-refractory agitation or aggression, in patients who are a danger to themselves or
`others,°”**
`e Increased risk of metabolic syndrome. Increased risk of stroke and mortality in elderly dementia
`patients.°*> There is one additional death for about every 50 to 100 dementia patients treated for
`8-12 weeks.*®? Discuss risks/benefits with patient/family.°
`* Tryto taper and discontinue the drug everythree to six months.°
`Use caution in patients with cerebrovascular disease or hypovolemia.®
`e Patients with Parkinson’s dementia and Lewy body dementia are extra-sensitive to antipsychotic
`
`extrapyramidal effects. Low-dose quetiapineis the antipsychotic of choice.*
` Quetiapine appears ineffective for primary insomnia.*””*
`® Quetiapine has been abused/misusedforits sedating and anxiolytic effects."”
`¢ Quetiapine and olanzapine have beenusedfor treatment of insomnia secondaryto specific causes
`(e.g., depression, drug withdrawal, Parkinson’s disease, fibromyalgia). Data are extremely
`limited.***
`Avoid for primary insomnia.** See our PL Charts, Comparison ofInsomnia Treatments (US.
`
`subscribers; Canadian subscribers), for insomnia treatment options.
`¢ Roleis for augmentation of antidepressants to reduce hyperarousal and re-experiencing.'!
`Aripiprazole (Abilify,
`Post-traumatic
`
`stress disorder,|generics [U.S.]) * Risperidone andolanzapine have the best evidence.***7”
`adjunct Risperidone (Risperdal,|» Notall studies have been favorable,'*!°?”
`
`
`generics)
`Olanzapine(Zyprexa,
`generics)
`Quetiapine (Seroquel,
`
`generics)
`e Roleis as adjunct to SSRI in treatment-resistant OCD.”
`Aripiprazole (Abilify,
`Obsessive-
`12-14,26,27
`e Risperidone and aripiprazole havethe best evidenceof efficacy.”'*”°
`generics [U.S.])
`compulsive
`disorder, adjunct|Risperidone (Risperdal,|« Olanzapine,paliperidone, and quetiapineare notconsistently better than placebo.
`
`generics)
`Olanzapine (Zyprexa,
`generics)
`Paliperidone (/nvega)
`Quetiapine (Seroquel,
`generics)
` PHARMACISTS
`LETTER|
`
`;
`3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
`Copyright © 2015 by Therapeutic Research Center
`www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com
`
`More...
`
`PRESCRIBER’S ee
`l ETiVER
`|
`
`LATUDA04357640
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`(PL Detail-Document #310701: Page 3 of 5)
`
`
`Use
`Off-Label Medication" Therapeutic Considerations
`Generalized
`Quetiapine (Seroquel,
`e SSRIs and SNRIsare first-line.”’ Second-line agents include buspirone or pregabalin.””*
`
`anxiety disorder
`generics)
`* Quetiapine has best evidence of efficacy.»'*?””*
`Risperidone (Risperdal,
`e Ziprasidoneis notbetter than placebo.'"”’
`generics)
`Olanzapine (Zyprexa,
`enerics)
`Aripiprazole (Abilify,
`
`generics [U.S.]
`Ziprasidone (Geodon,
`Zeldox |Canada)) SL=
`Risperidone (Risperdal,|« Aripiprazole and risperidone are FDA-approvedforirritability associated with autismin pediatrics
`generics)
`(up to age 17 vears).*””
`Olanzapine (Zyprexa,
`e Adults have been included in somerisperidone studies.”
`generics)
`© Olanzapine and quetiapine have been studied in an open-label fashion in adults.”!
`Quetiapine (Seroquel,
`generics)
`Olanzapine (Zyprexa,
`generics)
`Quetiapine (Seroquel,
`
`generics)
`Risperidone (Risperdal,
`generics)
`
`e Reserve for patients who are severelyagitated or distressed. *°
`Olanzapine maybeless effective in patients over 75 years of age.”
`© Sce our PL Chart, Preventing