Psychopharmacology Update

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

Naltrexone/bupropion
New Drugs Generic Brand Description Suvorexant Belsomra Orexin receptor antagonist Naltrexone/bupropion Contrave Chronic weight management agent Brexpiprazole Rexulti Serotonin-dopamine activity modulator The new drugs I will be covering are Vortioxetine and Levomilnacipran for the treatment of Major Depressive Disorder, and Aripiprazole ER injectable suspension approved for schizophrenia

Suvorexant (Belsomra®)
Manufactured by: Merck & CO., Inc FDA Approval Date: August 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 Major depressive disorder affects over 100 million people worldwide, and suicide is the 11th leading cause of death in America. Pts with MDD are at an increased burden for morbidity and mortality, and the direct and indirect cost for depression are approximately 53 billion dollars annually. Antidepressants remain the most widely used treatment for MDD. Vortioxetine is an antidepressant with a novel mechanism of action by being a selective serotonin reuptake inhibitor but also a serotonin receptor agonist at 5HT-1a receptors and an antagonist at 5HT3 receptors. Belsomra ®(suvorexant) Package Insert. Whitehouse, NJ: Merck & CO 2014

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 Like most drugs in the neurology/psychiatry realm, the precise mechanism of the antidepressant effect of vortioxetine is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through selective inhibition of serotonin reuptake. Vortioxetine is being tauted as a serotonin stabilizer because of its activity at so many serotonin receptor sites; however, the net result of this action and its role in the antidepressant effect of are so far unknown. Later on I’ll briefly discuss what hitting so many serotonin sites may mean. Despite hitting so many receptor sites, vortioxetine doesn’t appear to have activity at norepinephrine or dopamine reuptake sites. Pharmacol Rev 61:162–176, 2009

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 It is metabolized via the CYP 2D6 pathways which may require dosage adjustments when used with potent CYP inhibitors/inducers. The half life is quite long for an antidepressant at 66 hrs Belsomra ®(suvorexant) Package Insert. Whitehouse, NJ: Merck & CO 2014

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 The maximum dose is 20 mg/day. Pts who are poor metabolizers of CYP 2D6 or on interacting medicines they can start at 5 mg and top out at 10 mg/day. Clinicians should -Monitor for increased bleeding when used with anticoagulants/antiplatelets -NOT d/c abruptly Belsomra ®(suvorexant) Package Insert. Whitehouse, NJ: Merck & CO 2014

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) There is no data using vortioxetine with SSRIs, but in combination with bupropion, it was required to cut the vortioxetine dose in half due to CYP 2D6 inhibition by bupropion. An overdose situation of roughly 75 mg of the drug resulted in increased side effects, but no fatal issues. Belsomra ®(suvorexant) Package Insert. Whitehouse, NJ: Merck & CO 2014 Morris and Dickson Co. LLC; Vilazodone. Accessed 10 August 2015

Trial Design Patient population Adverse 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 years N= 291 Suvorexant mg QHS (high dose) N= 193 Suvorexant mg QHS (low dose) N= 291 Placebo (P) Somnolence: High dose 10.7% Low dose 5.1% Placebo 3.4% P029 725 patients aged years N= 286 Suvorexant mg QHS N= 145 Suvorexant mg QHS N= 286 Placebo (P) High dose 10.3% Low dose 8.4% Placebo 3.1% FDA approval was obtained through 3 similarly styled studies. We’ll look at 2 of them: -Study 1 looked at just over 500 pts randomized to 40 or 80 mg of Fetzima. Primary endpoint was change in MADRS score vs placebo at week 8. As expected, Fetzima showed significant improvement, and the difference was seen by week 4. Remember a difference was seen by week 2 for Brintellix. No surprises with the SE. -Study 2 had a similar design, and similar results. The only difference was that this study allowed other psychoactive agents (not elaborated on) which could dilute the validity of the results. Submission PM Extract from the Clinical Evaluation Report for Rivuley/ Silumbra/Vispli/ Belsomra

Results Suvorexant (Belsomra®) High dose vs. Placebo
sTST: subjective total sleep time sWASO: subjective wake time after sleep onset WASO: objective wake time after sleep onset sTSO: subjective time to sleep onset LPS: objective latency to persistent sleep High dose vs. Placebo Low dose vs. Placebo P028 Sleep maintenance sTST= 19.7 mins sWASO= -6.9 mins WASO= -22 mins sTST= 10.7 mins sWASO= -2.4 mins WASO= mins Sleep onset sTSO= -8.4 mins LPS= -9.4 mins sTSO= -5.2 mins LPS= -7.3 mins P029 sTST= 25.1 mins sWASO= -8.9mins WASO= mins sTST= 22.1 mins sWASO= -7.7 mins WASO= mins sTSO= mins LPS= -3.6 mins sTSO= -7.6 mins LPS= -0.3 mins Submission PM Extract from the Clinical Evaluation Report for Rivuley/ Silumbra/Vispli/ 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 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 The safety and efficacy was evaluated in 6 clinical trials. 4 regular trials, one elderly study, and one maintenance study. I’ll discuss one 8 wk study, the elderly study, and the maintenance study. -In this acute study vortioxetine only showed statistical difference from placebo at the 20 mg dose, which is not overly promising. However, positive results were seen as early as week 2. Submission PM Extract from the Clinical Evaluation Report for Rivuley/ Silumbra/Vispli/ Belsomra

Place in Therapy & Clinical Pearls
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 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 +

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. Mechanistically speaking, Fetzima is essentially a me-too SNRI Contrave (naltrexone /bupropion) [package insert]. Deerfield, Il; La Jolla, CA: Takeda Pharmaceuticals America, Inc., Orexigen Therapeutics, Inc. 2014

Pharmacokinetics 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 It is metabolized majorly through CYP3A4, so plenty of drug interactions available with this agent Contrave (naltrexone /bupropion) [package insert]. Deerfield, Il; La Jolla, CA: Takeda Pharmaceuticals America, Inc., Orexigen Therapeutics, Inc. 2014

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 Starting dose is 20 mg x 2 days, then increase to 40 mg/day. Max dose is 120 mg once daily -Similar contraindications and precautions as other SNRIs. Contrave (naltrexone /bupropion) [package insert]. Deerfield, Il; La Jolla, CA: Takeda Pharmaceuticals America, Inc., Orexigen Therapeutics, Inc. 2014

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 Drug interactions are the classic CYP3A4 inducers and inhibitors -SE and precautions are similar to other SNRIs -Similar to Effexor, you can adjust the dose in renal dysfunction, but no adjustment is needed for liver issues Contrave (naltrexone /bupropion) [package insert]. Deerfield, Il; La Jolla, CA: Takeda Pharmaceuticals America, Inc., Orexigen Therapeutics, Inc. 2014 Morris and Dickson Co. LLC; Contrave. Accessed 11 August 2015.

Trial Design Patient population Outcome/Conclusion COR-I Lancet.2010 Aug 21;376 (9741): 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 or 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< Pts with ≥5% wt loss: C32= 48%, C16= 39%, placebo= 16%; p< 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): N= 1742 (~90% women) -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 FDA approval was obtained through 3 similarly styled studies. We’ll look at 2 of them: -Study 1 looked at just over 500 pts randomized to 40 or 80 mg of Fetzima. Primary endpoint was change in MADRS score vs placebo at week 8. As expected, Fetzima showed significant improvement, and the difference was seen by week 4. Remember a difference was seen by week 2 for Brintellix. No surprises with the SE. -Study 2 had a similar design, and similar results. The only difference was that this study allowed other psychoactive agents (not elaborated on) which could dilute the validity of the results.

Trial Design Patient population Outcome/Conclusion COR-DM Diabetes Care. 2013 Dec;36(12): 56 week, randomized, double-blind, placebo-controlled, study. Primary endpoints: -percentage change in bodyweight -proportion of patients with a decrease in bodyweight ≥5% Type 2 DM aged 18-70 N= 505 (54% women) BMI 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< Pts with ≥5% wt loss: C32= 48%, C16= 39%, placebo= 16%; p< 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 Bupropion alone Obes Res. 2002 Oct;10(10): 26 week, randomized, double-blind, placebo-controlled study N= 384 BMI 30-44 -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 FDA approval was obtained through 3 similarly styled studies. We’ll look at 2 of them: -Study 1 looked at just over 500 pts randomized to 40 or 80 mg of Fetzima. Primary endpoint was change in MADRS score vs placebo at week 8. As expected, Fetzima showed significant improvement, and the difference was seen by week 4. Remember a difference was seen by week 2 for Brintellix. No surprises with the SE. -Study 2 had a similar design, and similar results. The only difference was that this study allowed other psychoactive agents (not elaborated on) which could dilute the validity of the results.

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 The million dollar quesiton, how does this relate to the older medicine, Savella? Fetzima is 1S, 2R Savella is 1S, 2R and 1R, 2S

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 This may be something to stash in your back pocket for pts who display a lot of apathy Accessed 13 August 2015

Brexpiprazole (Rexulti®)
Manufactured by: Otsuka/Lundbeck Pharmaceutical Co, LTD FDA Approval Date: July 2015 It was FDA approved last month, but is still not commercially available for purchase. Some ambulance drivers and other 1st responders do have access to it already

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

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 It is metabolized via the CYP 2D6 pathways which may require dosage adjustments when used with potent CYP inhibitors/inducers. The half life is quite long for an antidepressant at 66 hrs Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015

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 dementia-related psychosis The dosage unit works like a combination of an Epipen and a defibrillator. You pop the top to free the syringe. An automated voice gives instructions on placing the device on the body and when to give the injection. The voice component is battery operated, but one can still give the dose even if the batteries die out. -There is only ONE dose per device!!! Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015

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 $ for 30 days supply; “$15” manufacturer copay card Drug interactions are the classic CYP3A4 inducers and inhibitors -SE and precautions are similar to other SNRIs -Similar to Effexor, you can adjust the dose in renal dysfunction, but no adjustment is needed for liver issues Accessed 16 August 2015. Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015 Morris and Dickson Co. LLC; Rexulti. Accessed 16 August 2015.

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 Strong CYP3A4 inhibitors Strong/moderate CYP2D6 inhibitors with strong/moderate CYP3A4 inhibitors Patients Taking CYP3A4 Inducers Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks Rexulti (brexpiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2015

Trial Design Patient population Outcome/Conclusion Am J Psychiatry. 2015 Apr 16 6 week, randomized, double-blind, placebo-controlled, study. 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% mg 0 2mg  4.4% mg  1.45 kg 4mg  7.2% mg  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 N= 674 -Drug 1 mg 1 mg  -3.4 (not significant) 2mg  -3.1 (not significant) 4mg  -6.5 1 mg  4.2% mg  1.23 kg 2mg  4.8% mg  1.89 kg 4mg  6.5% mg  1.52 kg Placebo 7.1% Placebo 0.35 kg Only highest dose was effective; low akathisia rate FDA approval was obtained through 3 similarly styled studies. We’ll look at 2 of them: -Study 1 looked at just over 500 pts randomized to 40 or 80 mg of Fetzima. Primary endpoint was change in MADRS score vs placebo at week 8. As expected, Fetzima showed significant improvement, and the difference was seen by week 4. Remember a difference was seen by week 2 for Brintellix. No surprises with the SE. -Study 2 had a similar design, and similar results. The only difference was that this study allowed other psychoactive agents (not elaborated on) which could dilute the validity of the results. Int J Clin Pract. 2015 Aug 6

Trial Design Patient population Outcome/Conclusion Thase et al. J Clin Psychiatry 2015 /JCP.14m09688 6 week, randomized, double-blind, placebo-controlled, study. Primary endpoints: -Change in MADRS score Adults aged 18-65 N= 379 Randomized to: -Drug 2 mg -Placebo Change in MADRS vs placebo: 2mg  -3.1 Akathisia Weight gain 2mg  7.4% mg  1.64 kg Placebo 1% Placebo 0.37 kg Effective treatment; high rate of akathisia /JCP.14m09689 N= 677 -Drug 1 mg -Drug 3 mg 1 mg  -1.3 (not significant) 3mg  -2 1 mg  4.4% mg  1.4 kg 3 mg  13.5% mg  1.4 kg Placebo 2.4% Placebo n/a Only higher dose was effective; high akathisia rate FDA approval was obtained through 3 similarly styled studies. We’ll look at 2 of them: -Study 1 looked at just over 500 pts randomized to 40 or 80 mg of Fetzima. Primary endpoint was change in MADRS score vs placebo at week 8. As expected, Fetzima showed significant improvement, and the difference was seen by week 4. Remember a difference was seen by week 2 for Brintellix. No surprises with the SE. -Study 2 had a similar design, and similar results. The only difference was that this study allowed other psychoactive agents (not elaborated on) which could dilute the validity of the results. Int J Clin Pract. 2015 Aug 6

Am I my brother’s keeper?
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 Additional dosage forms Orally dissolving tablet; oral solution Short acting injection Long acting injection Cost $895/month (coupon) $29.83 per pill $440/month (coupon) $14.67 per pill Accessed 17 August 2015 Int J Clin Pract. 2015 Aug 6 Abilify (aripiprazole) Package Insert. Tokyo, Japan: Otsuke Pharmaceutical Compnay, Ltd. 2014

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

Paliperidone palmitate extended release injectable suspension
New Indication Generic Brand Description Asenapine Saphris Bipolar mania in pediatrics pts (10-17 yo) Paliperidone palmitate extended release injectable suspension Invega Sustenna Schizoaffective disorder Lisdexamfetamine Vyvanse Binge eating disorder The new drugs that are simply just old drugs in new dosage forms we’ll look at are naloxone, buprenorphine/naloxone, desvenlafaxine, and loxapine.

Manufactured by: Shire US, Inc

Lisdexamfetamine (Vyvanse®)
Dosage & Administration Initiate at 30 mg every morning Increase by 20 mg weekly Effective dose 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) The maximum dose is 20 mg/day. Pts who are poor metabolizers of CYP 2D6 or on interacting medicines they can start at 5 mg and top out at 10 mg/day. Clinicians should -Monitor for increased bleeding when used with anticoagulants/antiplatelets -NOT d/c abruptly 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 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) There is no data using vortioxetine with SSRIs, but in combination with bupropion, it was required to cut the vortioxetine dose in half due to CYP 2D6 inhibition by bupropion. An overdose situation of roughly 75 mg of the drug resulted in increased side effects, but no fatal issues. Vyvanse ®(lisdexamfetamine) Package Insert. Wayne, PA: Shire US, Inc. 2015 Morris and Dickson Co. LLC; Vyvanse. Accessed 17 August 2015

Why binge eating disorder?
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 Int J Clin Pract. 2015 Apr;69(4):410-21

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

Trial Design Patient Population Outcome/Conclusion NCT 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 % Insomnia- 17.7% Headache- 13.5% Decreased appetite- 8.85% Irritability- 8.33% NCT N= 383 (85% female) -Drug  4.66 -Placebo 4.85 70 mg  -3.92; p< 0.001 Placebo -2.26 Dry mouth- 33% Headache % Insomnia- 10.5% Fatigue- 9.39% Nausea- 8.84% FDA approval was obtained through 3 similarly styled studies. We’ll look at 2 of them: -Study 1 looked at just over 500 pts randomized to 40 or 80 mg of Fetzima. Primary endpoint was change in MADRS score vs placebo at week 8. As expected, Fetzima showed significant improvement, and the difference was seen by week 4. Remember a difference was seen by week 2 for Brintellix. No surprises with the SE. -Study 2 had a similar design, and similar results. The only difference was that this study allowed other psychoactive agents (not elaborated on) which could dilute the validity of the results. Int J Clin Pract. 2015 Apr;69(4):410-21

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 Probably a better option than topiramate Int J Clin Pract. 2015 Aug 6

Paliperidone palmitate extended release injectable suspension
Kind of New Drug #1 Generic Brand Indication Paliperidone palmitate extended release injectable suspension Invega Trinza Schizophrenia In terms of new indication, I’ll go over Lurasidone’s recent approval for bipolar depression.

Paliperidone (Invega Trinza™)
Pharmacokinetics Absorption Tmax: days Deltoid muscle ~ 11-12% > than gluteal muscle Distribution Protein binding: >74% Metabolism Through CYP pathways: 3A4 and 2D6 in vitro Excretion t½: days deltoid; gluteal It is metabolized via the CYP 2D6 pathways which may require dosage adjustments when used with potent CYP inhibitors/inducers. The half life is quite long for an antidepressant at 66 hrs Invega Trinza (paliperidone palmitate) Package Insert. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2015

Dosage & Administration 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 mg 117mg  410 mg 156 mg 546 mg 234 mg 819 mg If GFR 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 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 The dosage unit works like a combination of an Epipen and a defibrillator. You pop the top to free the syringe. An automated voice gives instructions on placing the device on the body and when to give the injection. The voice component is battery operated, but one can still give the dose even if the batteries die out. -There is only ONE dose per device!!! Invega Trinza (paliperidone palmitate) Package Insert. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2015

Trial Design Patient population Outcome/Conclusion JAMA Psychiatry. 2015;72(8): 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= 506305 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 Placebo 4% Trinza was significantly more effective than placebo and well tolerated. FDA approval was obtained through 3 similarly styled studies. We’ll look at 2 of them: -Study 1 looked at just over 500 pts randomized to 40 or 80 mg of Fetzima. Primary endpoint was change in MADRS score vs placebo at week 8. As expected, Fetzima showed significant improvement, and the difference was seen by week 4. Remember a difference was seen by week 2 for Brintellix. No surprises with the SE. -Study 2 had a similar design, and similar results. The only difference was that this study allowed other psychoactive agents (not elaborated on) which could dilute the validity of the results.

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

Flibanserin (Addyi™) Manufactured by: Sprout Pharmaceuticals
FDA Approval Date: August 2015

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

Flibanserin (Addyi™) All three studies Demographics Study 1 (n=570)
24 weeks Caucasian= 88.6% Double-blind, randomized, placebo-controlled Black= 9.6% Asian= 1.5% Acquired HSDD (at least six months) Age yrs Study 1 (n=570) Study 2 (n= 737) Study 3 (n= 1068) Number of satisfying sexual events (per 28 days) Drug Placebo +1.6 +0.8 +1.8 +1.1 +2.5 +1.5 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 Accessed 23 August 2015. Addyi (flibanserin) Package Insert. Raleigh, NC: Sprout Pharmaceuticals, Inc 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.

Flibanserin (Addyi™) Place in Therapy & Clinical Pearls Man doing dishes much better than placebo

Tasimelteon (Hetlioz) Buprenorphine/Naloxone (Bunavail)
More Kind of New Drugs 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 minutes before meals … really FDA! In terms of new indication, I’ll go over Lurasidone’s recent approval for bipolar depression. Accessed 19 August 2015

Now generic! Medication Lunesta (eszopiclone) May 2014
Intuniv (guanfacine ER) December 2014 Namenda (memantine) January 2015 Abilify (aripiprazole) April 2015 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 Phone: Pager:

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