Psychopharmacology Update
Kayode Giwa, PharmD, BCPP
Clinical Pharmacy Specialist
August 29th , 2015
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
2
New Drugs
Generic
Brand
Description
Suvorexant
Belsomra
Orexin receptor antagonist
Naltrexone/bupropion
Contrave
Chronic weight management agent
Brexpiprazole
Rexulti
Serotonin-dopamine activity modulator
3
Suvorexant (Belsomra®)
Manufactured by: Merck & CO., Inc
FDA Approval Date: August 2014
4
http://www.belsomra.com/
http://www.multivu.com/players/English/7412251-merck-belsomra-insomnia/
Suvorexant (Belsomra®)
Therapeutic
Class
Indication
Mechanism
of Action
Orexin receptor antagonist
The treatment of insomnia, characterized
by difficulties with sleep onset and/or
sleep maintenance
Antagonism of orexin receptors
5
Belsomra ®(suvorexant) Package Insert. Whitehouse, NJ: Merck & CO 2014
http://behavenet.com/suvorexant
Suvorexant (Belsomra®)
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
6
Suvorexant (Belsomra®)
Pharmacokinetics
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
7
Belsomra ®(suvorexant) Package Insert. Whitehouse, NJ: Merck & CO 2014
Suvorexant (Belsomra®)
Initiate at 10 mg within 30 mins of going to bed
(with at least 7 hrs before planned awakening)
Dosage &
Administration
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
Belsomra ®(suvorexant) Package Insert. Whitehouse, NJ: Merck & CO 2014
8
Suvorexant (Belsomra®)
Drug Interactions
•CNS active agents (alcohol)
•Inhibitors/inducers of CYP3A4
Adverse effects
•Headache (7%)
•Somnolence (7%)
•Dizziness (3%)
•Abnormal dreams (2%)
Special
populations
Cost
•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
•~ $10.50 per tablet (5 mg, 10 mg, 20 mg)
•~ $315 (30 days supply)
Belsomra ®(suvorexant) Package Insert. Whitehouse, NJ: Merck & CO 2014
9
Morris and Dickson Co. LLC; Vilazodone. Accessed 10 August 2015
Suvorexant (Belsomra®)
Trial
Design
•Randomized, double-blind,
placebo-controlled, parallel-group
(3 months)
P028
•Primary efficacy endpoint:
sleep onset and sleep maintenance
via self report and via
polysomnography at 1 month and
3 months
•Randomized, double-blind,
placebo-controlled, parallel-group
(3 months)
P029
Patient
population
•Primary efficacy endpoint:
sleep onset and sleep maintenance
via self report and via
polysomnography at 1 month and
3 months
Adverse
effects
775 patients aged 18-87 years
Somnolence:
N= 291 Suvorexant 30-40 mg QHS
(high dose)
N= 193 Suvorexant 15-20 mg QHS
(low dose)
N= 291 Placebo (P)
•High dose 10.7%
•Low dose 5.1%
•Placebo 3.4%
725 patients aged 18-87 years
Somnolence:
N= 286 Suvorexant 30-40 mg QHS
(high dose)
N= 145 Suvorexant 15-20 mg QHS
(low dose)
N= 286 Placebo (P)
Submission PM-2013-00325-1-1 Extract from the Clinical Evaluation Report for Rivuley/ Silumbra/Vispli/ Belsomra
•High dose 10.3%
•Low dose 8.4%
•Placebo 3.1%
10
Suvorexant (Belsomra®)
Results
sTST:
subjective total
sleep time
sWASO:
subjective wake
time after sleep
onset
High dose vs.
Placebo
P028
WASO:
objective wake
time after sleep
onset
sTSO:
subjective time
to sleep onset
P029
LPS:
objective
latency to
persistent sleep
Low dose vs.
Placebo
Sleep
maintenance
sTST= 19.7 mins
sWASO= -6.9 mins
WASO= -22 mins
sTST= 10.7 mins
sWASO= -2.4 mins
WASO= -16.3 mins
Sleep onset
sTSO= -8.4 mins
LPS= -9.4 mins
sTSO= -5.2 mins
LPS= -7.3 mins
Sleep
maintenance
sTST= 25.1 mins
sWASO= -8.9mins
WASO= -29.4 mins
sTST= 22.1 mins
sWASO= -7.7 mins
WASO= -31.1 mins
Sleep onset
sTSO= -13.2 mins
LPS= -3.6 mins
sTSO= -7.6 mins
LPS= -0.3 mins
11
Submission PM-2013-00325-1-1 Extract from the Clinical Evaluation Report for Rivuley/ Silumbra/Vispli/ Belsomra
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
484 patients
•N= 322- Suvorexant 30-40 mg QHS
Study Arms
•N= 162- Placebo
After 12 months:
•Subjective total sleep time 27.5 mins vs placebo
•Subjective time to sleep onset -9.7 mins vs placebo
Results
Conclusion
Adverse effects- Somnolence
•Drug 13%
•Placebo 3%
Suvorexant was safe and well tolerated for long term use
12
Submission PM-2013-00325-1-1 Extract from the Clinical Evaluation Report for Rivuley/ Silumbra/Vispli/ Belsomra
Suvorexant (Belsomra®)
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
13
Ann Gen Psychiatry. 2012; 11: 15
BMJ 2012;345;e8343
Naltrexone/bupropion
®
(Contrave )
Manufactured by: Takeda Pharmaceuticals America, Inc
and Orexigen Therapeutics, Inc
FDA Approval Date: September 2014
+
14
http://www.takeda.us/responsibility/patient_assistance_program.aspx
http://www.rxlist.com/contrave-drug.htm
Naltrexone/bupropion (Contrave®)
Therapeutic
Chronic weight management
Class
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)
Naltrexone and bupropion have effects on two
separate areas of the brain involved in the regulation of
Mechanism food intake: the hypothalamus (appetite regulatory
of Action center) and the mesolimbic dopamine circuit (reward
system). The exact neurochemical effects leading to
weight loss are not fully understood.
15
Contrave (naltrexone /bupropion) [package insert]. Deerfield, Il; La Jolla, CA: Takeda Pharmaceuticals America, Inc., Orexigen Therapeutics, Inc. 2014
Naltrexone/bupropion (Contrave®)
Pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
• Naltrexone- Tmax: 2 hours
• Bupropion- Tmax: 3 hours
• DO NOT take with high fat meal
•Protein binding:
•Naltrexone 21%
•Bupropion 84%
• Naltrexone- active metabolite 6-beta-naltrexol
• Bupropion- 3 active metabolites
• Metabolized by CYP 2B6
• Inhibits CYP 2D6
• Naltrexone- T½: 5 hours
• Bupropion- T½: 21 hours
16
Contrave (naltrexone /bupropion) [package insert]. Deerfield, Il; La Jolla, CA: Takeda Pharmaceuticals America, Inc., Orexigen Therapeutics, Inc. 2014
Naltrexone/bupropion (Contrave®)
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
Contrave (naltrexone /bupropion) [package insert]. Deerfield, Il; La Jolla, CA: Takeda Pharmaceuticals America, Inc., Orexigen Therapeutics, Inc. 2014
17
Naltrexone/bupropion (Contrave®)
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
Contrave (naltrexone /bupropion) [package insert]. Deerfield, Il; La Jolla, CA: Takeda Pharmaceuticals America, Inc., Orexigen Therapeutics, Inc. 2014
18
Morris and Dickson Co. LLC; Contrave. Accessed 11 August
Naltrexone/bupropion (Contrave®)
Trial
COR-I
Lancet.2010 Aug
21;376 (9741):
595-605.
Design
56 week, randomized, doubleblind, placebo-controlled,
study.
•Primary endpoints:
-percentage change in
bodyweight
-proportion of patients with a
decrease in bodyweight ≥5%
COR-BMOD
Obesity (Silver
Spring). 2011
Jan;19(1):110-20.
56 week, randomized, doubleblind, placebo-controlled,
study.
•Primary endpoints:
-percentage change in
bodyweight
-proportion of patients with a
decrease in bodyweight ≥5%
Patient
population
•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)
•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
Outcome/Conclusion
•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
•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
•Difference between drug and placebo seen as
early as week 4
•Wt loss sustained for 56 weeks
•Adverse effects: nausea (34% vs. 10.5%), 19
headache, constipation, dizziness
Naltrexone/bupropion (Contrave®)
Trial
COR-DM
Diabetes
Care. 2013
Dec;36(12):4022-9.
Bupropion alone
Obes Res. 2002
Oct;10(10):1049-56
Design
56 week, randomized, doubleblind, placebo-controlled,
study.
Patient
population
•Type 2 DM aged 18-70
•Wt loss C32= -6.1 kg
•Wt loss = -1.4 kg; p<0.00001
•N= 505 (54% women)
•Pts with ≥5% wt loss: C32= 48%,
C16= 39%, placebo= 16%; p<0.00001
•Primary endpoints:
-percentage change in
bodyweight
•BMI 27-45 with: A1c 7-10%
and FBS < 270
-proportion of patients with a
decrease in bodyweight ≥5%
•Randomized to:
-Contrave 32 mg (C32)
-Placebo (Pbo)
•26 week, randomized,
double-blind, placebocontrolled study
•N= 384
•Primary endpoints:
-percentage change in
bodyweight
-proportion of patients with a
decrease in bodyweight ≥5%
Outcome/Conclusion
•BMI 30-44
•Randomized to:
-Wellbutrin SR 400 mg/day
-Placebo
•Difference between drug and placebo
seen as early as week 4
•Wt loss sustained for 56 weeks
•Adverse effects: nausea (43% vs 7.1%),
headache, constipation, dizziness
•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
20
Naltrexone/bupropion (Contrave®)
Place in Therapy & Clinical Pearls
• “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
21
Naltrexone/bupropion (Contrave®)
Place in Therapy & Clinical Pearls
• Significant reports of nausea is a major concern
– Considerably higher than either agent alone
– Buproprion 300 mg13%; 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
http://www.goodrx.com. Accessed 13 August 2015
22
®
Brexpiprazole (Rexulti )
Manufactured by: Otsuka/Lundbeck Pharmaceutical Co, LTD
FDA Approval Date: July 2015
23
https://vimeo.com/133156164
Brexpiprazole (Rexulti®)
Therapeutic
Class
Serotonin dopamine activity stabilizer (SDAM)
-Adjunctive Treatment for Adults with Major Depressive Disorder
Indication
-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.
http://forum.schizophrenia.com/t/fda-approves-otsuka-and-lundbeck-s-rexulti-brexpiprazole/27691/7
Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015
24
Brexpiprazole (Rexulti®)
Pharmacokinetics
Absorption
• Tmax: 4 hours
• Absolute bioavailability 95%
• Can be given with or without food
Distribution
• Protein binding: >99%
Metabolism
• Through CYP pathways: CYP 3A4 and 2D6
Excretion
• 25% recovered in urine, 46% recovered in feces
• t½: 91 hours
25
Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015
Brexpiprazole (Rexulti®)
Dosage &
Administration
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
Contraindications
Hypersensitivity 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 dementia26
related psychosis
Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015
Brexpiprazole (Rexulti®)
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
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm
Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015
27
https://www.rexulti.com/us/mdd/. Accessed
16 August 2015.
Morris and Dickson Co. LLC; Rexulti. Accessed 16 August 2015.
Brexpiprazole (Rexulti®)
Factors
Adjusted Dosage
CYP2D6 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 Administer a quarter of the usual
with strong/moderate CYP3A4
dose
inhibitors
Patients Taking CYP3A4 Inducers
Strong CYP3A4 inducers
Double usual dose over 1 to 2 weeks
28
Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015
Brexpiprazole (Rexulti®)
Trial
Am J
Psychiatry. 2015
Apr 16
Design
6 week, randomized, doubleblind, placebo-controlled,
study.
•Primary endpoints:
-Change in PANSS score
Pts were hospitalized for
entire study duration
Schizophr
Res. 2015
May;164(1-3):12735
6 week, randomized, doubleblind, placebo-controlled,
study.
•Primary endpoints:
-Change in PANSS score
Pts were hospitalized for
entire study duration
Patient
population
•Adults aged 18-65
•N= 636
•Randomized to:
-Drug 0.25 mg
-Drug 2 mg
-Drug 4 mg
-Placebo
Outcome/Conclusion
Change in PANSS vs placebo:
•0.25 mg -2.9 (not significant)
•2mg
 -8.72
•4mg
 -7.64
Akathisia
•0.25 mg 0%
•2mg
 4.4%
•4mg
 7.2%
•Placebo 2.2%
Weight gain
0.25 mg 0
2mg
 1.45 kg
4mg
 1.28 kg
Placebo 0.42 kg
•Treatment doses were effective, and well
tolerated
•Adults aged 18-65
•N= 674
Change in PANSS vs placebo:
•1 mg  -3.4 (not significant)
•2mg  -3.1 (not significant)
•4mg  -6.5
•Randomized to:
-Drug 1 mg
-Drug 2 mg
-Drug 4 mg
-Placebo
Akathisia
•1 mg  4.2%
•2mg
 4.8%
•4mg
 6.5%
•Placebo 7.1%
Weight gain
1 mg  1.23 kg
2mg
 1.89 kg
4mg
 1.52 kg
Placebo 0.35 kg
•Only highest dose was effective; low
akathisia rate
Int J Clin Pract. 2015 Aug 6
29
Brexpiprazole (Rexulti®)
Trial
Thase et al. J Clin
Psychiatry 2015
10.4088/JCP.14m0
9688
Thase et al. J Clin
Psychiatry 2015
10.4088/JCP.14m0
9689
Design
Patient
population
6 week, randomized, doubleblind, placebo-controlled,
study.
•Adults aged 18-65
•N= 379
•Primary endpoints:
-Change in MADRS score
•Randomized to:
-Drug 2 mg
-Placebo
6 week, randomized, doubleblind, placebo-controlled,
study.
•Primary endpoints:
-Change in MADRS score
•Adults aged 18-65
•N= 677
•Randomized to:
-Drug 1 mg
-Drug 3 mg
-Placebo
Outcome/Conclusion
Change in MADRS vs placebo:
•2mg
 -3.1
Akathisia
•2mg
 7.4%
•Placebo 1%
Weight gain
2mg
 1.64 kg
Placebo 0.37 kg
•Effective treatment; high rate of akathisia
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
30
Int J Clin Pract. 2015 Aug 6
Brexpiprazole (Rexulti®)
Am I my brother’s keeper?
Rexulti
Abilify
Akathisia MDD
8.6%
25%
Akathisia
schizophrenia
5.5%
8%
Weight increase
MDD
6.7%
3%
Weight increase
schizophrenia
4%
n/a
Receptor affinity
Lower D2 antagonism
Higher 5HT1A/2 affinity
Orally dissolving tablet; oral solution
Short acting injection
Long acting injection
Additional dosage
forms
Cost
$895/month (coupon)
$29.83 per pill
$440/month (coupon)
$14.67 per pill
http://www.goodrx.com/abilify/price; http://www.goodrx.com/rexulty/price. Accessed 17 August 2015
Int J Clin Pract. 2015 Aug 6
Abilify (aripiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2014
31
Brexpiprazole (Rexulti®)
Place in Therapy & Clinical Pearls
• 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
Int J Clin Pract. 2015 Aug 6
32
New Indication
Generic
Brand
Description
Asenapine
Saphris
Paliperidone
palmitate
extended release
injectable
suspension
Invega
Sustenna
Schizoaffective disorder
Lisdexamfetamine
Vyvanse
Binge eating disorder
Bipolar mania in pediatrics pts (10-17 yo)
33
Manufactured by: Shire US, Inc
34
http://www.vyvanse.com/
http://geekandsundry.com/wp-content/uploads/2015/06/tumblr_n585jnSj0r1tagnkeo3_500.gif
Lisdexamfetamine (Vyvanse®)
Dosage &
Administration
Initiate at 30 mg every morning
Increase by 20 mg weekly
Effective 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)
35
Vyvanse ®(lisdexamfetamine) Package Insert. Wayne, PA: Shire US, Inc. 2015
Lisdexamfetamine (Vyvanse®)
•Acidifying agents (Vitamin C)- inc drug metabolism
•Alkalinizing agents (sodium bicarb)- dec drug
Drug Interactions
metabolism
•MAOIs
Adverse effects
Special
populations
Cost
•Dry mouth (36%)
•Insomnia (20%)
•Decreased appetite (8%)
•Increased heart rate (7%)
•Feel jittery (6%)
•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
•~ $9.11 per tablet
•~ $273 (30 days supply)
Vyvanse ®(lisdexamfetamine) Package Insert. Wayne, PA: Shire US, Inc. 2015
Morris and Dickson Co. LLC; Vyvanse. Accessed 17 August 2015
36
Lisdexamfetamine (Vyvanse®)
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
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Int J Clin Pract. 2015 Apr;69(4):410-21
Lisdexamfetamine (Vyvanse®)
DSM 5 Diagnostic Criteria
•
•
•
•
•
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
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing
38
Lisdexamfetamine (Vyvanse®)
Trial
Design
12 week, randomized,
double-blind, parallel group,
placebo-controlled, dose
optimization study.
NCT01718483
•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
12 week, randomized,
double-blind, parallel group,
placebo-controlled, dose
optimization study.
NCT01718509
•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
Int J Clin Pract. 2015 Apr;69(4):410-21
Patient
Population
•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
Outcome/Conclusion
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%
•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%
39
Lisdexamfetamine (Vyvanse®)
Place in Therapy & Clinical Pearls
• 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
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• Probably a better option than topiramate
Int J Clin Pract. 2015 Aug 6
Kind of New Drug #1
Generic
Paliperidone
palmitate
extended
release
injectable
suspension
Brand
Invega Trinza
Indication
Schizophrenia
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Paliperidone (Invega Trinza™)
Pharmacokinetics
Absorption
• Tmax: 30-33 days
• Deltoid muscle ~ 11-12% > than gluteal muscle
Distribution
• Protein binding: >74%
Metabolism
• Through CYP pathways: 3A4 and 2D6 in vitro
Excretion
• t½: 84-95 days deltoid; 118-139 gluteal
42
Invega Trinza (paliperidone palmitate) Package Insert. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2015
Paliperidone (Invega Trinza™)
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
Dosage &
Administration
If last dose of Invega Sustenna:
78 mg  273 mg
117mg  410 mg
156 mg 546 mg
234 mg 819 mg
If GFR 50-80 ml/min decrease dose for Invega Sustenna, then convert to Trinza
If GFR < 50 do not use
Not 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
43
Invega Trinza (paliperidone palmitate) Package Insert. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2015
Paliperidone (Invega Trinza™)
Trial
Design
Patient
population
29 week, double-blind, placebocontrolled, relapse prevention
study
JAMA Psychiatry.
2015;72(8):830839.
-17 weeks receive monthly Invega
Sustenna
-12 weeks receive 3 month Trinza
-Double blind Trinza vs placebo
(open-ended time period)
Outcome/Conclusion
•Adults aged 18-70
•N= 506305
Time to relapse:
•Trinza not determined (study ended early)
•Placebo 395 days p< 0.001
•Randomized to:
-Trinza (various doses)
-Placebo
Pts who relapsed
•Trinza  9%
•Placebo 29%
•Primary endpoints:
-Time to relapse
Relapse is:
•Hospitalization
•Inc in PANSS score by 25%
•Self injury or violent behavior
•HI or SI + aggressive behavior
Akathisia
•Trinza  4%
•Placebo 1%
Weight gain
Trinza  2.38 kg
Placebo 0.55 kg
Headache
•Trinza  9%
•Placebo 4%
•Trinza was significantly more effective than
placebo and well tolerated.
44
Paliperidone (Invega Trinza™)
Place in Therapy & Clinical Pearls
• 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
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Morris and Dickson Co. LLC; Vyvanse. Accessed 17 August 2015
JAMA Psychiatry. 2015;72(8):830-839.
Flibanserin (Addyi™)
Manufactured by: Sprout Pharmaceuticals
FDA Approval Date: August 2015
46
http://www.addyi.com/
http://www.multivu.com/players/English/7583651-fda-approval-of-addyi-flibanserin/
Flibanserin (Addyi™)
• 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
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Pharmacotherapy. 2013 Apr;33(4):411-21
Addyi (flibanserin) Package Insert. Raleigh, NC: Sprout Pharmaceuticals, Inc 2015.
Flibanserin (Addyi™)
• 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
48
Addyi (flibanserin) Package Insert. Raleigh, NC: Sprout Pharmaceuticals, Inc 2015.
Flibanserin (Addyi™)
• All three studies
• Demographics
– 24 weeks
– Double-blind, randomized,
placebo-controlled
– Acquired HSDD (at least six
months)
Study 1
(n=570)
Number of
satisfying
sexual events
(per 28 days)
–
–
–
–
Caucasian= 88.6%
Black= 9.6%
Asian= 1.5%
Age 19-55 yrs
Study 2
(n= 737)
Study 3
(n= 1068)
Drug
Placebo
Drug
Placebo
Drug
Placebo
+1.6
+0.8
+1.8
+1.1
+2.5
+1.5
49
Addyi (flibanserin) Package Insert. Raleigh, NC: Sprout Pharmaceuticals, Inc 2015.
Flibanserin (Addyi™)
Place in Therapy & Clinical Pearls
• 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
Addyi (flibanserin) Package Insert. Raleigh, NC: Sprout Pharmaceuticals, Inc 2015.
50
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm. Accessed 23 August 2015.
Flibanserin (Addyi™)
Place in Therapy & Clinical Pearls
• 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
Addyi (flibanserin) Package Insert. Raleigh, NC: Sprout Pharmaceuticals, Inc 2015.
51
Flibanserin (Addyi™)
Place in Therapy & Clinical Pearls
Man doing dishes much better than placebo
http://www.whattoexpect.com/pregnancy/photo-gallery/the-best-push-presents-for-moms.aspx#08
52
More Kind of New Drugs
Drug
Indication
Pearls
•
Tasimelteon
(Hetlioz)
Non-24-hour sleepwake disorder
•
•
Buprenorphine/
Naloxone
(Bunavail)
Amphetamine
(Evekeo)
The maintenance of
opioid dependence
-Narcolepsy
-ADHD
-Exogenous obesity
Melatonin 1 & 2 agonist (similar to
Rozerem)
Only to be used in totally blind
people
For some reason FDA labeling doesn’t
say this
•
•
Buccal patch applied inside cheek
No mention in clinical trials how long
to wear patch each day
•
•
First “pure” amphetamine
All others are enequal combinations
of detxroamphetamine and
levoamphetamine
For obesity it is dosed 30-60 minutes
before meals … really FDA!
•
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http://www.rxlist.com/hetlioz/bunavail/evekeo-drug.htm. Accessed 19 August 2015
Now generic!
Medication
Lunesta (eszopiclone)
May 2014
Intuniv (guanfacine ER)
December 2014
Namenda (memantine)
January 2015
Abilify (aripiprazole)
April 2015
54
PL Detail-Document, Anticipated Availability of First-Time Generics. Pharmacist’s Letter/Prescriber’s Letter. January 2014
Questions?
Kayode Giwa, Pharm.D., BCPP
Clinical Pharmacy Specialist I
Houston Methodist Hospital
6565 Fannin St., Houston, TX 77030
Phone: 713-441-0671
Pager: 713-735-6698
sgiwa@tmhs.org
http://shadownurse.tumblr.com/post/9295275217/psychiatric-disorders
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