Psychopharmacology Update Kayode Giwa, PharmD, BCPP Clinical Pharmacy Specialist August 29 th, 2015

Psychopharmacology Update

Kayode Giwa, PharmD, BCPPClinical Pharmacy SpecialistAugust 29th , 2015

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Objectives

• Discuss the therapeutic efficacy, place in therapy, and some clinical pearls of the new drugs based on available clinical trials

• Overview of old drugs with new indications

• Overview a few “kind of new” medications

• A special new medication review

• Upcoming generic availability

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New Drugs

Generic Brand Description

Suvorexant Belsomra Orexin receptor antagonist

Naltrexone/bupropion

Contrave Chronic weight management agent

Brexpiprazole RexultiSerotonin-dopamine activity modulator

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Suvorexant (Belsomra®)

Manufactured by: Merck & CO., IncFDA Approval Date: August 2014

http://www.multivu.com/players/English/7412251-merck-belsomra-insomnia/http://www.belsomra.com/

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Belsomra ®(suvorexant) Package Insert. Whitehouse, NJ: Merck & CO 2014

Therapeutic Class

Orexin receptor antagonist

Indication

The treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance

Mechanism of

Action Antagonism of orexin receptors

http://behavenet.com/suvorexant

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What is orexin???

• Other name is hypocretin

• A neuropeptide secreted from hypothalamus– Wakefulness– Arousal– Promotes appetite– Energy expenditure

• Excites dopamine, norepinephrine, histamine

• Deficiency narcolepsy; often obesity


Pharmacol Rev 61:162–176, 2009

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Absorption• Tmax: 2 hours• Absolute bioavailability of 10 mg is

82%

Distribution • Protein binding: >99%

Metabolism • Through CYP pathways: CYP 3A4 {major}; 2C19 {minor}

Excretion• 23% recovered in urine, 66%

recovered in feces• t½: 12 hours

Pharmacokinetics


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Dosage & Administration

Initiate at 10 mg within 30 mins of going to bed (with at least 7 hrs before planned awakening)

Increase to 20 mg/day if well tolerated but not effective

Max dose of 20 mg/day

Contraindications

Patients with narcolepsy

Precautions

•CNS depression (driving)•Combination with other CNS depressants•Evaluate for co-morbid psych disorders•Abnormal thinking/behavior•Worsening of depression/suicidal ideation•Compromised respiratory function•Sleep paralysis, hypnagogic/hypnopompic hallucinations, cataplexy-like symptoms

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Drug Interactions

•CNS active agents (alcohol)•Inhibitors/inducers of CYP3A4

Adverse effects

•Headache (7%)•Somnolence (7%)•Dizziness (3%)•Abnormal dreams (2%)

Special populations

•Pregnancy category C•No adjustment needed in the elderly•No renal adjustment needed •No adjustment in mild-moderate hepatic impairment (not studied in severe hepatic impairment)•Higher concentrations in BMI >30 vs BMI <25

Cost•~ $10.50 per tablet (5 mg, 10 mg, 20 mg)•~ $315 (30 days supply)

Morris and Dickson Co. LLC; Vilazodone. Accessed 10 August 2015

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Trial DesignPatient

populationAdverse effects

P028

•Randomized, double-blind, placebo-controlled, parallel-group (3 months)

•Primary efficacy endpoint:sleep onset and sleep maintenance via self report and via polysomnography at 1 month and 3 months

775 patients aged 18-87 years

N= 291 Suvorexant 30-40 mg QHS (high dose)N= 193 Suvorexant 15-20 mg QHS (low dose)N= 291 Placebo (P)

Somnolence:

•High dose 10.7%•Low dose 5.1%•Placebo 3.4%

P029

•Randomized, double-blind, placebo-controlled, parallel-group (3 months)

•Primary efficacy endpoint:sleep onset and sleep maintenance via self report and via polysomnography at 1 month and 3 months

725 patients aged 18-87 years

N= 286 Suvorexant 30-40 mg QHS (high dose)N= 145 Suvorexant 15-20 mg QHS (low dose)N= 286 Placebo (P)

Somnolence:

•High dose 10.3%•Low dose 8.4%•Placebo 3.1%

Submission PM-2013-00325-1-1 Extract from the Clinical Evaluation Report for Rivuley/ Silumbra/Vispli/ Belsomra

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ResultsHigh dose vs.

PlaceboLow dose vs.

Placebo

P028

Sleep maintenance

sTST= 19.7 minssWASO= -6.9 minsWASO= -22 mins

sTST= 10.7 minssWASO= -2.4 minsWASO= -16.3 mins

Sleep onsetsTSO= -8.4 minsLPS= -9.4 mins

sTSO= -5.2 minsLPS= -7.3 mins

P029

Sleep maintenance

sTST= 25.1 minssWASO= -8.9minsWASO= -29.4 mins

sTST= 22.1 minssWASO= -7.7 minsWASO= -31.1 mins

Sleep onsetsTSO= -13.2 minsLPS= -3.6 mins

sTSO= -7.6 minsLPS= -0.3 mins



sTST:subjective totalsleep time

sWASO:subjective wake time after sleep onset

WASO:objective waketime after sleep onset

sTSO:subjective timeto sleep onset

LPS:objectivelatency topersistent sleep

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Suvorexant (Belsomra®)Objective Safety and efficacy of suvorexant in subjects with primary

insomnia

Design

•Randomized, double-blind, placebo-controlled, parallel-group (12 months)•Primary efficacy endpoints: safety, tolerability, total sleep time, time to sleep onset

Study Arms

484 patients•N= 322- Suvorexant 30-40 mg QHS •N= 162- Placebo

Results

After 12 months:•Subjective total sleep time 27.5 mins vs placebo•Subjective time to sleep onset -9.7 mins vs placebo

Adverse effects- Somnolence•Drug 13%•Placebo 3%

Conclusion

Suvorexant was safe and well tolerated for long term use


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Place in Therapy & Clinical Pearls

• Novel mechanism of action– May be disease modifying, not just sedate patients– MDD, weight loss on the horizon?

• Onset and duration of sleep improved, but no robust study on quality of sleep

• No evidence of dependence or withdrawal– Is Schedule IV controlled substance– “Similar” to Ambien at high doses by substance abusers

• Low doses are safe, but don’t work as well as high doses– Less efficacy than “Z” drugs (not compared)

• Half life is LONG for a new sleep aid ~ 12 hours

• Not much data, but worth trying in non-benzo pts with insurance


Ann Gen Psychiatry. 2012; 11: 15 BMJ 2012;345;e8343

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Naltrexone/bupropion (Contrave®)

Manufactured by: Takeda Pharmaceuticals America, Inc and Orexigen Therapeutics, Inc

FDA Approval Date: September 2014

http://www.takeda.us/responsibility/patient_assistance_program.aspx http://www.rxlist.com/contrave-drug.htm

+

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Contrave (naltrexone /bupropion) [package insert]. Deerfield, Il; La Jolla, CA: Takeda Pharmaceuticals America, Inc., Orexigen Therapeutics, Inc. 2014

Therapeutic Class

Chronic weight management

Indication

An adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: >30 kg/m2 or greater (obese) or < 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)

Mechanism of

Action

Naltrexone and bupropion have effects on two separate areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The exact neurochemical effects leading to weight loss are not fully understood.

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Absorption• Naltrexone- Tmax: 2 hours • Bupropion- Tmax: 3 hours• DO NOT take with high fat meal

Distribution • Protein binding:

• Naltrexone 21%• Bupropion 84%

Metabolism• Naltrexone- active metabolite 6-

beta-naltrexol• Bupropion- 3 active metabolites

• Metabolized by CYP 2B6• Inhibits CYP 2D6

Excretion • Naltrexone- T½: 5 hours• Bupropion- T½: 21 hours

Pharmacokinetics


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Dosage and administration

•Each tablet contains Naltrexone 8 mg and Bupropion 90 mg•Week 1 1 tablet QAM•Week 2 1 tablet BID•Week 3 2 tablets QAM + 1 tablet QPM•Week 4 and onward 2 tablets BID

•Maximum dose is Naltrexone 32 mg and Bupropion 360 mg

Contraindications

•Chronic HTN•MAOI use concurrently, or within 14 days of stopping MAOI•Seizure disorder•Bulimia nervosa•Chronic opioid use or opioid withdrawal•Pregnancy

Precautions

•Suicidal ideation•Serotonin Syndrome•Elevated blood pressure or heart rate•Pts receiving opioids•Seizures •Narrow-angle glaucoma•Hepatotoxicity•Activation of mania/hypomania•Hypoglycemia in pts on antidiabetic therapy

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Drug Interactions

•MAOIs•Opioid analgesics•Inhibitors/inducers of CYP 2B6•Drugs that lower seizure threshold•Dopaminergic drugs•Alcohol

Adverse effects

•24% discontinuation rate in clinical trials•Nausea (32.5%)•Constipation (19.2%)•Headache (17.6%)•Vomiting (10.7%)

Special populations

•Pregnancy category X•Caution needed in the elderly•Hepatic impairment- max dose of 1 tablet QAM•Moderate-severe renal impairment: max dose of 1 tablet BID; ESRD- not recommended

Cost•$1.99 per tablet •$239 for 30 days supply Morris and Dickson Co. LLC; Contrave. Accessed 11 August

2015.

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Trial DesignPatient

population Outcome/Conclusion

COR-I

Lancet.2010 Aug 21;376 (9741): 595-605.

56 week, randomized, double-blind, placebo-controlled, study.

•Primary endpoints:-percentage change in bodyweight

-proportion of patients with a decrease in bodyweight ≥5%

•Adults aged 18-65•N= 1742 (85% women)•BMI 30-45 or 27-45 with HTN and/or HLD

•Randomized to: -Contrave 32 mg (C32)-Contrave 16 mg (C16)Placebo (Pbo)

•Wt loss C32= -6.1 kg•Wt loss C16= -4.9 kg•Wt loss Pbo= -1.4 kg; p<0.00001

•Pts with ≥5% wt loss: C32= 48%, C16= 39%, placebo= 16%; p<0.00001

•Difference between drug and placebo seen as early as week 4•Wt loss sustained for 56 weeks

•Adverse effects: nausea (29.8% vs 5.3%), headache, constipation, dizziness

COR-BMOD

Obesity (Silver Spring). 2011 Jan;19(1):110-20.




•Adults aged 18-65•N= 1742 (~90% women)•BMI 30-45 or 27-45 with HTN and/or HLD

•Randomized to: -Contrave 32 mg + BMOD-Placebo + BMOD

•Wt loss C32= -9.3 kg•Wt loss Pbo= -5.1 kg; p<0.001

•Pts with ≥5% wt loss: C32= 66.4%, placebo= 42.5%; p<0.001


•Adverse effects: nausea (34% vs. 10.5%), headache, constipation, dizziness

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Trial DesignPatient

populationOutcome/

Conclusion

COR-DM

Diabetes Care. 2013 Dec;36(12):4022-9.




•Type 2 DM aged 18-70

•N= 505 (54% women)

•BMI 27-45 with: A1c 7-10% and FBS < 270

•Randomized to:-Contrave 32 mg (C32)-Placebo (Pbo)

•Wt loss C32= -6.1 kg•Wt loss = -1.4 kg; p<0.00001

•Pts with ≥5% wt loss: C32= 48%, C16= 39%, placebo= 16%; p<0.00001


•Adverse effects: nausea (43% vs 7.1%), headache, constipation, dizziness

Bupropion alone

Obes Res. 2002 Oct;10(10):1049-56

•26 week, randomized, double-blind, placebo-controlled study

•Primary endpoints: -percentage change in bodyweight


•N= 384

•BMI 30-44

•Randomized to:-Wellbutrin SR 400 mg/day-Placebo

•Wt loss Wellbutrin= -4.4 kg•Wt loss placebo= -1.7 kg; p<0.001

•Pts with ≥5% wt loss: -Wellbutrin= 50%-Placebo= 28%; p<0.001

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• “Novel” mechanism of action for weight loss

• Combination product shows significant improvement:– Wt loss– Waist circumference– Triglycerides– HDL– A1c

• Wt loss was sustained long term– Wellbutrin wt loss similar, but not long term in studies

Naltrexone/bupropion (Contrave®)Place in Therapy & Clinical

Pearls

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• Significant reports of nausea is a major concern– Considerably higher than either agent alone– Buproprion 300 mg13%; Bupropion 400 mg 18%– Naltrexone 50 mg 10%

• Cost of agents with goodrx.com coupons:– Contrave: $210/month– Bupropion: $26/month– Naltrexone: $38/month

• Good choice for:– Pt who can tolerate nausea– Have prescription insurance coverage– Complications from obesity

Naltrexone/bupropion (Contrave®)Place in Therapy & Clinical

Pearls

http://www.goodrx.com. Accessed 13 August 2015

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Brexpiprazole (Rexulti®)Manufactured by: Otsuka/Lundbeck Pharmaceutical

Co, LTDFDA Approval Date: July 2015

https://vimeo.com/133156164

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Brexpiprazole (Rexulti®)

http://forum.schizophrenia.com/t/fda-approves-otsuka-and-lundbeck-s-rexulti-brexpiprazole/27691/7

Therapeutic Class

Serotonin dopamine activity stabilizer (SDAM)

Indication

-Adjunctive Treatment for Adults with Major Depressive Disorder

-Treatment for Adults with Schizophrenia

Mechanism of Action

Unknown, but may be through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.

Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015

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Absorption• Tmax: 4 hours• Absolute bioavailability 95%• Can be given with or without food


Metabolism • Through CYP pathways: CYP 3A4 and 2D6

Excretion• 25% recovered in urine, 46%

recovered in feces• t½: 91 hours

Pharmacokinetics


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MDD•Start at 0.5 or 1 mg/day•Recommended dose is 2 mg/day•Max dose of 3 mg/day

Schizophrenia•Start at 1 mg/day•Recommended dose is 2-4 mg/day•Max dose of 4 mg/day

ContraindicationsHypersensitivity to suvorexant or to any of the other ingredients.

Precautions

•Suicidal thoughts in children, adolescents, young adults•CV ADRs in elderly pts with dementia related psychosis•Metabolic changes•Neuorleptic malignant syndrome•Hypotension and syncope•Seizures•Potential for cognitive impairment•Increased mortality in elderly patients with dementia-related psychosis

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Drug Interactions

•CYP 3A4 inhibitors: fluconazole, HIV protease inhibitors•CYP 3A4 inducers: Tegretol, Trileptal, Dilantin•CYP 2D6 inhibitors: Prozac, Paxil, Wellbutrin•CYP 2D6 inducers: Decadron?

Adverse effects

•3% discontinuation rate in clinical trials•Akathisia (9%)/(6%)•Weight gain (7%)/(4%)•Headache (7%)/(< 2%)•Somnolence (5%)/(2%)

Special populations

•Pregnancy category n/a???•Caution needed in the elderly … probably (no studies > 65 yo)•Hepatic impairment- reduce max dose (2 mg MDD, 3 mg schiz)•Moderate-severe renal impairment: (Crcl < 60 ml/min) reduce max dose (2 mg MDD, 3 mg schiz)•CYP 2D6 poor metabolizers: administer half the dose•See next slide for more dosage recommendations

Cost•$34.62 per tablet •$1038.50 for 30 days supply; “$15” manufacturer copay card

Morris and Dickson Co. LLC; Rexulti. Accessed 16 August 2015.

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm

https://www.rexulti.com/us/mdd/. Accessed 16 August 2015.

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Factors Adjusted DosageCYP2D6 Poor Metabolizers

CYP2D6 poor metabolizers Administer half of the usual dose

Administer half of the usual dose

Known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors

Administer a quarter of the usual dose

Patients Taking CYP2D6 Inhibitors and/or CYP3A4 Inhibitors

Strong CYP2D6 inhibitors Administer half of the usual dose

Strong CYP3A4 inhibitors Administer half of the usual dose

Strong/moderate CYP2D6 inhibitors with strong/moderate CYP3A4 inhibitors

Administer a quarter of the usual dose

Patients Taking CYP3A4 Inducers

Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks



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Trial DesignPatient

populationOutcome/Conclusion

Am J Psychiatry. 2015 Apr 16


•Primary endpoints:-Change in PANSS score

Pts were hospitalized for entire study duration

•Adults aged 18-65•N= 636

•Randomized to: -Drug 0.25 mg-Drug 2 mg-Drug 4 mg-Placebo

Change in PANSS vs placebo:•0.25 mg -2.9 (not significant)•2mg -8.72•4mg -7.64

Akathisia Weight gain •0.25 mg 0% 0.25 mg 0•2mg 4.4% 2mg 1.45 kg•4mg 7.2% 4mg 1.28 kg•Placebo 2.2% Placebo 0.42 kg

•Treatment doses were effective, and well tolerated

Schizophr Res. 2015 May;164(1-3):127-35


•Primary endpoints:-Change in PANSS score

Pts were hospitalized for entire study duration


•Randomized to: -Drug 1 mg-Drug 2 mg-Drug 4 mg-Placebo

Change in PANSS vs placebo:•1 mg -3.4 (not significant)•2mg -3.1 (not significant)•4mg -6.5

Akathisia Weight gain •1 mg 4.2% 1 mg 1.23 kg•2mg 4.8% 2mg 1.89 kg•4mg 6.5% 4mg 1.52 kg•Placebo 7.1% Placebo 0.35 kg

•Only highest dose was effective; low akathisia rate

Int J Clin Pract. 2015 Aug 6

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Trial DesignPatient


Thase et al. J Clin Psychiatry 201510.4088/JCP.14m09688


•Primary endpoints:-Change in MADRS score


•Randomized to: -Drug 2 mg-Placebo

Change in MADRS vs placebo:•2mg -3.1

Akathisia Weight gain •2mg 7.4% 2mg 1.64 kg•Placebo 1% Placebo 0.37 kg

•Effective treatment; high rate of akathisia

Thase et al. J Clin Psychiatry 201510.4088/JCP.14m09689


•Primary endpoints:-Change in MADRS score


•Randomized to: -Drug 1 mg-Drug 3 mg-Placebo

Change in MADRS vs placebo:•1 mg -1.3 (not significant)•3mg -2• Akathisia Weight gain •1 mg 4.4% 1 mg 1.4 kg•3 mg 13.5% 3 mg 1.4 kg•Placebo 2.4% Placebo n/a

•Only higher dose was effective; high akathisia rate


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Rexulti AbilifyAkathisia MDD 8.6% 25%

Akathisia schizophrenia 5.5% 8%

Weight increase MDD 6.7% 3%

Weight increase schizophrenia

4% n/a

Receptor affinityLower D2 antagonism

Higher 5HT1A/2 affinity

Additional dosage forms

Orally dissolving tablet; oral solutionShort acting injectionLong acting injection

Cost$895/month (coupon)

$29.83 per pill$440/month (coupon)

$14.67 per pill


Am I my brother’s keeper?

Int J Clin Pract. 2015 Aug 6 Abilify (aripiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2014

http://www.goodrx.com/abilify/price; http://www.goodrx.com/rexulty/price. Accessed 17 August 2015

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• Is this a new, better version of Abilify?• Less akathisia• Little somnolence

• Or just a new, more expensive version of Abilify?• No bipolar indications• No variety in dosage forms

• Being studied for new indications:• Agitation associated with Alzheimer’s disease• PTSD

• Cariprazine (another dopamine partial agonist) on the way soon




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New Indication

Generic Brand Description

Asenapine SaphrisBipolar mania in pediatrics pts (10-17 yo)

Paliperidone palmitate extended release

injectable suspension

Invega Sustenna

Schizoaffective disorder

Lisdexamfetamine

Vyvanse Binge eating disorder

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Manufactured by: Shire US, Inc

http://www.vyvanse.com/ http://geekandsundry.com/wp-content/uploads/2015/06/tumblr_n585jnSj0r1tagnkeo3_500.gif

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Lisdexamfetamine (Vyvanse®)

Vyvanse ®(lisdexamfetamine) Package Insert. Wayne, PA: Shire US, Inc. 2015


Initiate at 30 mg every morningIncrease by 20 mg weeklyEffective dose 50-70 mg/day

Max dose of 70 mg/day

Contraindications

•Current use of an MAOI or within 14 days of last dose of an MAOI

Precautions

•Potential for abuse or dependence•Serious CV reactions•Increase of BP and/or HR•Induce new or exacerbate manic or psychotic conditions•Peripheral vasculopathy (Raynaud’s Phenomenon)

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Vyvanse ®(lisdexamfetamine) Package Insert. Wayne, PA: Shire US, Inc. 2015

Drug Interactions

•Acidifying agents (Vitamin C)- inc drug metabolism•Alkalinizing agents (sodium bicarb)- dec drug metabolism•MAOIs

Adverse effects

•Dry mouth (36%)•Insomnia (20%)•Decreased appetite (8%)•Increased heart rate (7%)•Feel jittery (6%)

Special populations

•Pregnancy category C•No official adjustment needed in the elderly•Renal adjustment:-GFR 30-15 ml/min- max of 50 mg/day-GFR < 15 ml/min- max of 30 mg/day •Not studied in hepatic impairment

Cost•~ $9.11 per tablet•~ $273 (30 days supply)

Morris and Dickson Co. LLC; Vyvanse. Accessed 17 August 2015

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Why binge eating disorder?

• Most prevalent eating disorder– Lifetime prevalence 2.6%– More than anorexia and bulimia combined

• Not included as official diagnosis until DSM 5

• Traditional antidepressants, anti-anxiety meds not significantly effective


Int J Clin Pract. 2015 Apr;69(4):410-21

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• Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following:– eating, in a discrete period of time (for example, within any 2-hour

period), an amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances

– a sense of lack of control over eating during the episode (for example, a feeling that one cannot stop eating or control what or how much one is eating)

• The binge-eating episodes are associated with three (or more) of the following:– eating much more rapidly than normal– eating until feeling uncomfortably full – eating large amounts of food when not feeling physically hungry – eating alone because of feeling embarrassed by how much one

is eating– feeling disgusted with oneself, depressed, or very guilty afterwards

• Marked distress regarding binge eating is present.• The binge eating occurs, on average, at least once a week for three

months.• The binge eating is not associated with the recurrent use of inappropriate

compensatory behavior (for example, purging) and does not occur exclusively during the course Anorexia Nervosa, Bulimia Nervosa, or Avoidant/Restrictive Food Intake Disorder


DSM 5 Diagnostic Criteria

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing

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Trial DesignPatient

PopulationOutcome/Conclusion

NCT01718483

12 week, randomized, double-blind, parallel group, placebo-controlled, dose optimization study.

•Dose was titrate up to 70 mg, but reduced to 50 mg at week 3 if not well tolerated

•Primary endpoints:-change in baseline # of binge days per week

•Moderate to severe binge eating disorder

•Adults aged 18-55•N= 383 (86% female)

•Randomized to: -Drug 70 mg-Placebo Baseline binge days/week-Drug 4.78-Placebo 4.59

Change in # binge days/week vs placebo:•70 mg -3.87; p< 0.001•Placebo -2.51

Dry mouth- 39.58%Insomnia- 17.7%Headache- 13.5%Decreased appetite- 8.85%Irritability- 8.33%

NCT01718509

12 week, randomized, double-blind, parallel group, placebo-controlled, dose optimization study.

•Dose was titrate up to 70 mg, but reduced to 50 mg at week 3 if not well tolerated

•Primary endpoints:-change in baseline # of binge days per week

•Moderate to severe binge eating disorder

•Adults aged 18-55•N= 383 (85% female)

•Randomized to: -Drug 70 mg-Placebo Baseline binge days/week-Drug 4.66-Placebo 4.85

Change in # binge days/week vs placebo:•70 mg -3.92; p< 0.001•Placebo -2.26

Dry mouth- 33%Headache- 17.68%Insomnia- 10.5%Fatigue- 9.39%Nausea- 8.84%

Int J Clin Pract. 2015 Apr;69(4):410-21

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• Results were impressive … but• Is 12 weeks enough time to assess efficacy?• Side effect % high, but seemingly tolerable? (only 19 SE

dropouts )

• Exclusion criteria maybe not generalizable• No current psychotherapy• No history of suicide attempts

• Abuse/dependence risk• CII• Not for weight loss, but misuse is possible• Better study partner than coffee

• Probably a better option than topiramate




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Generic Brand Indication

Paliperidone palmitate extended release

injectable suspension

Invega Trinza Schizophrenia

Kind of New Drug #1

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Paliperidone (Invega Trinza™)

Absorption• Tmax: 30-33 days• Deltoid muscle ~ 11-12% > than

gluteal muscle


Metabolism • Through CYP pathways: 3A4 and 2D6 in vitro

Excretion • t½: 84-95 days deltoid; 118-139 gluteal

Pharmacokinetics

Invega Trinza (paliperidone palmitate) Package Insert. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2015

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Invega Trinza (paliperidone palmitate) Package Insert. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2015


Schizophrenia•Only after pt has been treated with monthly Invega Sustenna for at least 4 months•Administer every 3 months•Start when next Invega Sustenna dose is due•Dose is 3.5 x Invega Sustenna dose•Max dose of 819 mg Q3 months

If last dose of Invega Sustenna:78 mg 273 mg117mg 410 mg156 mg 546 mg234 mg 819 mg

If GFR 50-80 ml/min decrease dose for Invega Sustenna, then convert to TrinzaIf GFR < 50 do not useNot recommended in moderate/severe hepatic impairment

Missed Doses

•If dose is missed 3.5-4 months, give ASAP•If dose is missed 4-9 months, adhere to re-titration schedule•If dose is missed >9 months, reinitiate with Invega Sustenna for 4 months

•If converting to Invega Sustenna or pills, give Sustenna or start pills 3 months after date of last injection

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Trial DesignPatient


JAMA Psychiatry. 2015;72(8):830-839.

29 week, double-blind, placebo-controlled, relapse prevention study

-17 weeks receive monthly Invega Sustenna-12 weeks receive 3 month Trinza-Double blind Trinza vs placebo (open-ended time period)

•Primary endpoints:-Time to relapse

•Adults aged 18-70•N= 506305

•Randomized to: -Trinza (various doses)-Placebo

Time to relapse:•Trinza not determined (study ended early)•Placebo 395 days p< 0.001

Pts who relapsed•Trinza 9%•Placebo 29%

Relapse is:•Hospitalization •Inc in PANSS score by 25%•Self injury or violent behavior•HI or SI + aggressive behavior

Akathisia Weight gain •Trinza 4% Trinza 2.38 kg•Placebo 1% Placebo 0.55 kg

Headache•Trinza 9%•Placebo 4%

•Trinza was significantly more effective than placebo and well tolerated.

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• Results were very impressive …• Excluded substance abusers high relapse rate in

schizophrenia• Upcoming study between Invega Sustenna and Trinza is

NI • 395 days Trinza vs. 172 days Sustenna vs. 58 days tablets

• Will it ever be possible to start Trinza without 4 months of Sustenna first?

• 819 mg injection $7200 Q3months ($2400/month)• Will it be covered well by insurance?• Public systems/ indigent pts?• Janssen Connect enrollment assistance



Morris and Dickson Co. LLC; Vyvanse. Accessed 17 August 2015 JAMA Psychiatry. 2015;72(8):830-839.

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Flibanserin (Addyi™)

Manufactured by: Sprout PharmaceuticalsFDA Approval Date: August 2015

http://www.addyi.com/ http://www.multivu.com/players/English/7583651-fda-approval-of-addyi-flibanserin/

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• Indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD) as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is NOT due to:– A co-existing medical or psychiatric condition– Problems within the relationship– The effects of a medication or other drug substance

• Most common form of female sexual dysfunction

• Affects up to 1 in 10 women in the US


Pharmacotherapy. 2013 Apr;33(4):411-21Addyi (flibanserin) Package Insert. Raleigh, NC: Sprout Pharmaceuticals, Inc 2015.

48

• MOA is unknown– 5-HT1A agonist– 5-HT2A, 5-HT2B, 5-HT2C antagonist– D4 antagonist

• Only for premenopausal women

• Taken (100 mg) every day at bedtime, not PRN

• Twice rejected by the FDA (2010, 2013)– Lack of efficacy– Side effect risk


Addyi (flibanserin) Package Insert. Raleigh, NC: Sprout Pharmaceuticals, Inc 2015.

49

Study 1 (n=570)

Study 2 (n= 737)

Study 3(n= 1068)

Number of satisfying sexual events (per 28 days)

DrugPlaceb

oDrug

Placebo

DrugPlaceb

o

+1.6 +0.8 +1.8 +1.1 +2.5 +1.5


• All three studies– 24 weeks– Double-blind, randomized,

placebo-controlled– Acquired HSDD (at least six

months)

• Demographics– Caucasian= 88.6%– Black= 9.6%– Asian= 1.5%– Age 19-55 yrs


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• Results were not so impressive• Increase sexual satisfying events by ~1 time per month• No mention of improvement in quality of intercourse• No mention of change/improvement in frequency of

orgasms

• Risks of syncope and somnolence increased with• Oral contraceptives• Many other common medications: (Cipro, Prozac, Xanax,

Diflucan, Prilosec, Nexium, Lipitor, Norvasc)

• Contraindicated with alcohol!• Alcohol risk trial conducted in a study that had 92% men!• SBP drop up to 54 mmHg; DBP drop up to 46 mmHg




http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm. Accessed 23 August 2015.

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• Price will be very high Viagra like ~ $40 per pill

• Prescriber/pharmacy must complete training program (REMS)• Buprenorphine/naloxone (Suboxone, et al.)• Clozapine (Versacloz)• Olanzapine extended release injection (Zyprexa Relprevv)

• Drug approved by FDA on 8/18/15• Drug company (Sprout) purchased on 8/20/15 by Valeant

Pharmaceuticals for $1 billion

• Seems like an FDA fail and a marketing success

• Bupropion may be a safer option for now




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http://www.whattoexpect.com/pregnancy/photo-gallery/the-best-push-presents-for-moms.aspx#08

Man doing dishes much better than placebo

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Drug Indication Pearls

Tasimelteon (Hetlioz)

Non-24-hour sleep-wake

disorder

• Melatonin 1 & 2 agonist (similar to Rozerem)

• Only to be used in totally blind people

• For some reason FDA labeling doesn’t say this

Buprenorphine/Naloxone (Bunavail)

The maintenance of opioid

dependence

• Buccal patch applied inside cheek

• No mention in clinical trials how long to wear patch each day

Amphetamine

(Evekeo)

-Narcolepsy-ADHD

-Exogenous obesity

• First “pure” amphetamine• All others are enequal

combinations of detxroamphetamine and levoamphetamine

• For obesity it is dosed 30-60 minutes before meals … really FDA!

More Kind of New Drugs

http://www.rxlist.com/hetlioz/bunavail/evekeo-drug.htm. Accessed 19 August 2015

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Medication

Lunesta (eszopiclone) May 2014

Intuniv (guanfacine ER) December 2014

Namenda (memantine) January 2015

Abilify (aripiprazole) April 2015

Now generic!

PL Detail-Document, Anticipated Availability of First-Time Generics. Pharmacist’s Letter/Prescriber’s Letter. January 2014

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Questions?

Kayode Giwa, Pharm.D., BCPPClinical Pharmacy Specialist IHouston Methodist Hospital6565 Fannin St., Houston, TX

77030Phone: 713-441-0671Pager: [email protected]://shadownurse.tumblr.com/post/9295275217/psychiatric-disorders

mailto:[email protected]

Documents

Psychopharmacology Update Kayode Giwa, PharmD, BCPP Clinical Pharmacy Specialist August 29 th, 2015