New Drugs 2015

Tom Frank, Pharm.D., BCPS Director of Research and Educaon UAMS Northeast • I have no conflicts of interest to report Afrezza® (insulin human inhalaon powder) Mannkind Insulin inhalaon Pharmacology

• Rapid acng inhaled insulin to improved glycemic control in adults with diabetes • Smulates peripheral glucose uptake by skeletal muscle and fat • Inhibits hepac glucose producon • Produced by recombinant DNA technology • Adsorbed to carrier parcles

Insulin inhalaon Pharmacokinecs • Peak concentraon reached in 12-15 minutes • Insulin levels back to baseline in 180 minutes • Peak glucose lowering at 53 minutes • Half life 28-39 minutes • Carrier parcles are not metabolized, eliminated unchanged • Drug interacons: albuterol (enhanced insulin effect); hyper and hypoglycemia associated drugs as with injected insulin; hypoglycemia symptom effects reduced when on sympathec inhibitors Insulin inhalaon Clinical Trials

• Inhaled insulin compared to insulin aspart, both added to basal, both given at mealme • Paents with type 1 diabetes, open label trial over 24 weeks • Pre-specified non-inferiority margin -0.4% HgbA1c • Change from baseline: -0.21% HgbA1c for inhaled and -0.4% HgbA1c for aspart • HgbA1c <7% rate: 13.8% vs 27.1% • FPG change from baseline: -25.3mg/dl vs. +10.2mg/dl

Insulin inhalaon Clinical Trials

• Paents with type 2 diabetes inadequately controlled on (a)meormin only or (b)two or more oral andiabec agents • Compared inhaled insulin to inhaled placebo, randomized, double-blind over 24 weeks • HgbA1c reducon -0.82% in the inhaled group, -0.42% in the placebo group • HgbA1c < 7%: 32% vs. 15% • FPG change: -11mg/dl vs. -3mg/dl

Insulin inhaled Adverse Effects • Cough • Throat pain • Hypoglycemia • Acute bronchospasm (avoid in chronic lung disease) • Decline in FEV1 over me • Lung cancer – 2 cases in clinical trials • Diabec ketoacidosis • Hypersensivity reacons • Hypokalemia • Fluid retenon/heart failure when used with TZD’s

Inhaled insulin Dosing

• Check baseline spirometry, repeat in 6 months and annually • Administer at beginning of a meal • Insulin naïve: inhale four units at each meal • Previous mealme insulin: 8 units injected = 8 units inhaled • 24 units per dose inhaled is maximum • If previous pre-mixed: divided TDD by 2 then split that number into 3 mealme doses • Stable 10 days at room temperature • Cartridge and inhaler at room temperature for 10 minutes before dose • Replace inhaler every 15 days

Jardiance® (empagliflozin) Boehringer Ingelheim Empagliflozin Pharmacology

• Inhibits the SGLT2 receptors in the proximal renal tubule, reduces reabsorpon of filtered glucose from the filtered lumen • Lowers the renal threshold for glucose, increases urinary glucose excreon • Benefit in diabetes is as an adjunct to diet and exercise

Empagliflozin Pharmacokinecs • Peak concentraon in 1.5 hours • Protein binding 86% • Metabolism by glucuronidaon but no major metabolites • Primarily excreted unchanged in urine and feces • Increased exposure in paents with renal or hepac impairment • Drug interacons: none detected with meormin, glimeparide, pioglitazone, sitaglipn, warfarin, verapamil, ramipril, simvastan, hydrochlorothiazide, digoxin, oral contracepves Empagliflozin Clinical Trials • Double-blind, placebo controlled trial T2DM • Paents received empagliflozin 10mg or 25mg daily or placebo over 24 weeks • Baseline HgbA1c was 7.9% • Change from placebo in HbA1c: -0.7% and -0.9% • HgbA1c <7%: 35% on 10mg and 44% on 25mg • FPG change: -19mg/dl, -25mg/dl and +12mg/dl in the placebo group • Weight change: -2.5kg, -2.8kg and -0.4kg respecvely

Empagliflozin Clinical Trials • Empagliflozin 10mg and 25mg daily compared to placebo when added to meormin • Baseline HgbA1c 7.9% • Difference in HgbA1c from meormin/placebo: empagliflozin 10mg/meormin -0.6%, empagliflozin 25/meormin -0.6% • Rates of HgbA1c < 7%: 38%, 29% and in the meormin/placebo group 13%

Empagliflozin Clinical Trials • Empagliflozin has been as add-on therapy and compared to placebo in paents not adequately controlled with insulin or insulin plus oral agents over 78 weeks • Basal insulin with or without meormin and/ or sulfonylureas: added empagliflozin 10mg, 25mg or placebo • Change in HgbA1c aer 78 weeks: -0.4%, -0.6% and +0.1% in the group that received placebo

Empagliflozin Adverse Effects • Urinary tract infecon • Female genital mycoc infecon • Upper respiratory infecon • Increased urinaon • Dyslipidemia • Arthralgia • Male genital mycoc infecon • Nausea • Increased serum creanine

Empagliflozin Dosing

• 10mg once daily in the morning with or without food • Dose may be increased to 25mg one daily if necessary • Assess renal funcon before iniang, do not start is eGFR is < 45ml/min/1.73m2 • Disconnue is eGFR falls to < 45ml/min/1.73m2

Tanzeum® (albiglude) GSK Albiglude Pharmacology

• A glucagon-like pepde (GLP-1) agonist indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes • GLP1 agonist that augments glucose dependent insulin secreon • Two repeats of GLP-1 fused to recombinant human albumin • Amino acid substuon to resist DPP-4

Albiglude Pharmacokinecs • Peak concentraon in 3-5 days • Metabolism as with nave human albumin • Half life 5 days • No pharmacokinec differences based on age, gender, race, body weight, mild or moderate renal or hepac impairment • Increased drug exposure in severe renal impairment • Drug interacon: simvastan Albiglude Clinical Trials • Albiglude 30mg and 50mg weekly compared to placebo in a 52 week randomized, double- blind trial of paents with type 2 diabetes inadequately controlled with diet and exercise • Change from baseline in HgbA1c: +0.2% with placebo, -0.7% with 30mg and -0.9% with 50mg • Changes in FBS from baseline: +18mg/dl, -16mg/dl and -25mg/dl

Albiglude Clinical Trials • Albiglude has been evaluated in a 104 week randomized, double-blind trial of paents with type 2 diabetes inadequately controlled with meormin • Paents assigned to: meormin/placebo, meormin/albiglude, meormin/sitaglipn or meormin/glimepiride • Change from baseline in HgbA1c was: meormin/ placebo +0.3%, meormin/albiglude -0.6%, meormin/sitaglipn -0.3% and meormin/ glimeparide -0.4% • The proporon achieving an HgbA1c < 7% was 16%, 39%, 32% and 31% respecvely

Albiglude Clinical Trials • Albiglude given weekly has been compared to liraglude given daily in a randomized, open-label non-inferiority trial over 32 weeks • Not controlled on monotherapy or combinaon of oral agents previously • Change in HgbA1c was -0.8% for albiglude and -1% for liraglude • Proporon with HgbA1c < 7%: 42% vs 52% • Change in body weight: -0.6kg vs -2.2kg

Albiglude Adverse Effects • Upper respiratory infecon • Diarrhea • Nausea • Injecon site reacon • Cough • Back pain • Arthralgia • Sinusis • Influenza

Albiglude Dosing • 30mg subcutaneous injecon once weekly • Dose can be increased to 50mg if inadequate response • Separate current dose from last dose by at least 4 days • If miss dose, give within three days of scheduled dose • Allow 15 minutes aer mixing steps for product to dissolve

Trulicity® (dulaglude) Lilly Dulaglude Pharmacology

• GLP-1 receptor agonist indicated as adjunct to diet and exercise for glycemic control in type 2 diabetes mellitus • 90% amino acid homology to endogenous human GLP-1 • Fusion protein with 2 chains containing N- terminal sequence linked to immunoglobulin G4 heavy chain • Increases insulin release, decreases glucagon, slows gastric emptying

Dulaglude Pharmacokinecs • Time to peak 24-72 hours • Steady state concentraon reached in 2-4 weeks • Bioavailability: 0.75mg- 65%, 1.5mg- 47% • Metabolized by protein catabolism pathways • Half life 5 days • Drug interacons: none detected Dulaglude Clinical Trials • Dulaglude compared to meormin in paents inadequately controlled on one oral agent • Received dulaglude 0.75mg, 1.5mg or meormin 1500-2000mg/d • Aer 52 weeks: HgbA1c changes: -0.7%, -0.8%, -0.6%; FBG changes: -26mg/dl, -29mg/dl, -24mg/dl

Dulaglude Clinical Trials • Add-on study to paents already on meormin in placebo-controlled study • Received either dulaglude 0.75mg, 1.5mg or sitaglipn 100mg over 104 weeks • Changes in HgbA1c: -0.1%, -1%, -1.2% and -0.6% for the sitaglipn group • Rates of HgbA1c < 7%: 22%, 56%, 62% and 39%

Dulaglude Clinical Trials • Paents previously treated with one or two daily doses of insulin • Stabilized over 7 week stabilizaon period • Randomized to dulaglude 0.75mg, 1.5mg or insulin glargine • All got pre-prandial insulin lispro • Aer 26weeks, HgbA1c changes: -1.6%, -1.6% and -1.4% respecvely

Dulaglude Adverse Effects

• Nausea • Diarrhea • Voming • Abdominal pain • Decreased appete • Dyspepsia • Pancreas

Dulaglude Dosing

• 0.75mg subcutaneously once weekly • May increased to 1.5mg once weekly for increased glycemic control • No dose adjustment needed for paents with renal impairment

Toujeo® (insulin glargine) Sanofi-Avens Insulin glargine Pharmacology

• Long acng insulin analog indicated for adults with diabetes mellitus • Smulates peripheral glucose uptake and inhibits hepac glucose producon • Soluble and buffered to pH of 4 • 300 unit/ml product has smaller surface area and 100 unit/ml • Redissoluon is reduced • Prolonged and consistent effect

Insulin glargine Pharmacokinecs • Onset of acon over 6 hours • Takes 12-16 hours to reach peak effect • Half life 19 hours • Intersubject variability at steady state: 21% • Insulin exposure similar with lower and higher doses • Drug interacons: risk of hypoglycemia with drugs that are prone to cause; glucose lowering effect decreased with atypicals, diurecs, niacin, OCP’s, SNS mimecs Insulin glargine Clinical Trials

• Gla-300 compared to Gla-100, paents with T2DM on ≥42 units/day plus oral agents • Six month study • Primary end point: change in HgbA1c, secondary end point: rates of hypoglycemia • HgbA1c changes: -0.57% vs -0.56% • 10% more units of Gla-300 on average • Less nocturnal hypoglycemia and severe hypoglycemia with Gla-300

Insulin glargine Clinical Trials

• Gla-300 compared to Gla-100, paents with T2DM using basal insulin ≥42 units/day plus mealme insulin with or without meormin over 6 months • Doses trated to preprandial 90-130mg/dl • Baseline HgbA1c 8.15% • Mean HgbA1c at end of study 7.25% with Gla-300 and 7.28% with Gla-100 • Insulin dose changes: Gla-300: 70 units/day to 103 units/day; Gla-100: 71 units/day to 94 units/day • Nocturnal hypoglycemia events: 36% vs. 46% respecvely

Insulin glargine Adverse Effects

• Nasopharyngis • Upper respiratory infecon

Insulin glargine Dosing • T1DM (insulin naïve): 0.2-0.4 units per Kg once daily • Maximum effect may take 5 days to manifest • May be insufficient effect in first 24 hours of use • T2DM (insulin naïve): 0.2 units per Kg once daily • T2DM already on insulin: • 1:1 conversion for paents on once-daily long acng insulin • When changing from twice daily NPH to Gla-300, give 80% of the total daily dose of NPH inially

Dalvance® (dalbavancin) Durata Dalbavancin Pharmacology

• Lipoglycopepde anbioc indicated for acute bacterial skin and so ssue infecon caused by suscepble strain of Gram posive bacteria • Bind to the C terminal D-alanyl-D alanine of pepdoglycan chains • Interferes with cell wall cross linking and polymerizaon • Staph aureus, Strep pyogenes, Strep agalacae, Strep arginosis

Dalbavancin Pharmacokinecs • 99% protein bound • 33% excreted as unchanged drug • Plasma clearance main route of excreon • Half life 8.5 days • Not a substrate inducer or inhibitor • No drug interacon studies yet Dalbavancin Clinical Trials • Dalbavancin has been compared to vancomycin in randomized, double-blind, double dummy trials • Opon to shi vanco oral linezolid aer 3 days • Cellulis, major abscesses or wound infecon • Dalbavancin 1gm then 500mg one week later • Primary end point: clinical response rate: 83% and 76% for dalbavancin; 81% and 76% for vancomycin groups in the two trials • Clinical success rate at 30d follow up: 83% and 87% for dalbavancin; 88% and 84% for vancomycin

Dalbavancin Adverse Effects

• Nausea • Headache • Diarrhea

Dalbavancin Dosing

• 1000mg followed one week later by 500mg IV • CrCl < 30ml/min and not on hemodialysis give 750mg followed one week later by 275mg • Infuse over 30 minutes

Sivextro® (tedizolid) Cubist Tedizolid Pharmacology

• Indicated for treatment of acute bacterial skin and skin structure infecons caused by suscepble Gram posive bacteria • Oxazolidinone class anbioc • Binds to 23s ribosomal RNA the 50s subunit • Inhibits protein synthesis • Staph aureus, Strep pyogenes, Strep agalacae, Strep arginosis, Enterococcus faecium and faecalis

Tedizolid Pharmacokinecs • Prodrug that is converted to acve form by phosphatases • Time to peak: 3hrs. • Bioavailability 91% • Can be given with or without food, not metabolized, eliminaon primarily hepac • Half life 10 hours • No dosing adjustments based on age, gender, race, ethnicity, weight, renal or hepac funcon Tedizolid Clinical Trials • Tedizolid 200mg once daily for 6 days compared to linezolid 600mg every 12 hours for 10 days in two trials of paents with acute bacterial skin and skin structure infecons • Non-inferiority trials • End point trial 1: lesion control at 48-72hrs and temp < 37.6C in 24 hours: 79% vs 79% • End point trial 2: 20% lesion size decrease at 48-72 hours: 85% vs 82%

Tedizolid Adverse Effects

• Nausea • Headache • Diarrhea • Voming • Dizziness

Tedizolid Dosing

• 200mg IV or orally once daily for six days

Orbacv® (oritavancin) The Medicines Company Oritavancin Pharmacology

• Indicated for acute bacterial skin and so ssue infecons • Lipoglycopepde anbioc • In vitro acvity against S. aureus, S. pyogenes and E. faecalis • Mechanism of acon involves inhibing polymerizaon of cell wall biosynthesis, inhibing pepde bridging for crosslinking and disrupon of cell membrane integrity

Oritavancin Pharmacokinecs • 85% protein bound • Half life 245 hours • Not metabolized, slowly excreted unchanged • No dose adjustment need for mild to moderate renal or hepac impairment • Drug interacons: warfarin, no heparin within 48 hours of dosing; PTT and INR can be increased Oritavancin Clinical Trials • Oritavancin 1200mg single dose compared to vancomycin q12h for 7-10 days • Adults with acute bacterial skin and skin structure infecons • Opons to add aztreonam or metronidazole • Non-inferiority trials • End point: early clinical response (82/80% receiving oritavancin and 78/82% receiving vancomycin • 20% or greater reducon in lesion area: 86/85% with oritavancin and 82/85% with vancomycin

Oritavancin Adverse Effects

• Nausea • Headache • Voming

Oritavancin Dosing

• 1200mg infused over 3 hours one me

Zerbaxa® (ceolozane/tazobactam) Cubist Ceolozane/tazobactam Pharmacology

• Cephalosporin/beta-lactamase inhibitor indicated for complicated urinary tract infecons and complicated intra-abdominal infecons (with metronidazole) • Binds to penicillin binding proteins (PBP) 1b, 1c and 3 plus irreversibly binds some beta lactamases • In vitro acvity against some ESBL’s but not KPC’s

Ceolozane/tazobactam Pharmacokinecs • Peak concentraon 74mcg/ml • Rapid distribuon, excellent lung penetraon • Low protein binding • Eliminated in urine as unchanged drug • Half life 3.1 hours • Reduce dose in moderate or severe renal impairment • Drug interacons: probenecid Ceolozane/tazobactam Clinical Trials • Ceolozane/tazobactam plus metronidazole has been compared to meropenem in paents with complicated intra-abdominal infecons • Efficacy end point (clinical response or significant improvement): 83% vs. 87% • Ceolozane/tazobactam compared to levofloxacin in paents with complicated UTI • Efficacy end point (complete symptom resoluon or marked improvement of clinical symptoms and microbiological eradicaon); 76% vs. 68%

Ceolozane/tazobactam

Adverse Effects

• Nausea • Diarrhea • Headache • Pyrexia

Ceolozane/tazobactam

Dosing

• 1.5gm IV every eight hours in CrCl > 50ml/min • CrCl 30-50ml/min: 750mg every eight hours • CrCl 15-29ml/min 375mg every eight hours • ESRD on HD: 750mg LD followed by 150mg every eight hours

Avycaz® (ceazidime-avibactam) Forest Ceazidime-avibactam Pharmacology

• Third generaon cephalosporin plus beta lactamase inhibitor indicated for complicated intra-abdominal infecon (with metronidazole) and complicated urinary tract infecon • Reserved for paents with limited treatment opons or no treatment opons • Binds to penicillin binding proteins and hihibits cell was synthesis • Inhibits mulple types of beta lactamases including ESBL’s of Ambler class A, C and D

Ceazidime-avibactam Pharmacokinecs • Peak concentraon in two hours • Less than 10% protein bound • Excreted mainly by the kidneys unchanged • Half-life prolonged in paents with impaired renal funcon • No dosing adjustment based on age or gender • Drug interacon: probenecid Ceazidime-avibactam Clinical Trials

• Phase 2 trial comparing cef-avi 2.5gm every 8 hours plus metronidazole 500mg IV every 8 hours to meropenem 1gm every 8 hours • Paents with complicated intra-abdominal infecons • Excluded if CrCl < 50 ml/min • Primary end point was clinical response 2 weeks post- treatment • End point reached in 82% on cef-avi and 88% on meropenem • Phase 3 trial saw measurable difference in mortality 2.5% vs. 1.5%, ? Regarding renal dose adjustment

Ceazidime-avibactam Clinical Trials

• Cef-avi 625mg every eight hours compared to imipenem 500mg every 6 hours for complicated urinary tract infecon • Excluded paents with CrCl < 70 ml/min • Switch to ciprofloxacin 500mg bid was allowed aer at least four days IV therapy • Clinical response rates: 80% vs 73% respecvely

Ceazidime-avibactam Adverse Effects

• Voming • Nausea • Conspaon • Anxiety • Decreased efficacy in paents with baseline CrCl 30-50 ml/min

Ceazidime-avibactam Dosing

• cIAI (combined with metronidazole) • Paents with normal renal funcon- 2.5gm every eight hours • Infused over 2 hours • cUTI (normal renal funcon) • Should be reserved for paents who have limited or no

alternave treatment opons • 2.5gm every eight hours • Reduced renal funcon doses detailed in package insert

Zonvity® (vorapaxar) Merck Vorapaxar Pharmacology

• Indicated for reducon of thromboc cardiovascular events in paents with history of myocardial infarcon or peripheral vascular disease • Protease-acvated receptor-1 antagonist • Inhibits platelet aggregaon • Pharmacologic effect is reversible but long half life leads to irreversible impact

Vorapaxar Pharmacokinecs • Peak concentraon in one hour • Bioavailability 100% • Highly protein bound • Extensive hepac metabolism by CYP 3A4 and 2D6 • Half life 3-4 days • Drug interacons: avoid use with ketoconazole or rifampin; avoid addive drugs Vorapaxar Clinical Trials • Vorapaxar compared to placebo, double blind randomized trial • Paents with acute coronary syndrome with ST segment elevaon • Both groups got aspirin and clopidogrel • End point : composite cardiovascular outcomes • End point reached in treatment group: 18.5%; control group 19.9% • Moderate to severe bleeding: 7.2% vs. 5.2% • Intracranial hemorrhage rates: 1.1% vs 0.2%

Vorapaxar Clinical Trials • Vorapaxar compared to placebo over median of 30 months • Paents with hx. Of MI, CVA or PVD (i.e. secondary prevenon) • End point: composite of death from CV causes, MI or CVA • DSMB prematurely stopped paents with CVA history (increased intracranial hemorrhage) • End point reached in 9.3% vs. 10.5% • Significant bleeding: 4.2% vs. 2.5% • Intracranial hemorrhage: 1% vs. 0.5%

Vorapaxar Adverse Effects

• Bleeding • Anemia • Depression • Rash

Vorapaxar Dosing

• One tablet once daily with or without food

Belsomra® (suvorexant) Merck Suvorexant Pharmacology

• Indicated for treatment of insomnia • Mechanism of acon involves blocking the binding of the neuropepdes orexin A and orexin B • Suppresses wakefulness

Suvorexant Pharmacokinecs • Bioavailability 82% • Peak concentraon in 2 hours • Can be given with or without food but faster effect if empty stomach • Hepac metabolism by CYP 3A • Half life 12 hours • Higher concentraon in obese, female and moderate hepac insufficiency • Drug interacons: ketoconazole, itraconazole, dilazem, rifampin Suvorexant Clinical Trials • Randomized, double-blind trials comparing suvorexant 20mg (15mg in elderly paents), and placebo over three months • Baseline me to sleep onset 66-69 minutes • Aer three months: the reducon in me to sleep onset was 35 minutes in the first study treatment group and 27 minutes in the placebo group • In the second study the difference was a reducon of 29 minutes in both groups • Subjecve assessment was a reducon of 23 minutes and 17 minutes respecvely (first study) and 28 minutes and 21 minutes (study 2)

Suvorexant Clinical Trials • WASO at baseline 115-120 minutes • Reducon in WASO study 1: 42 minutes vs 25 minutes; study 2 56 minutes vs 25 minutes • Paent esmated total sleep me at baseline 315-322 minutes • TST improved by 52 minutes and 41 minutes respecvely (study 1); 60 minutes and 38 minutes respecvely (study 2)

Suvorexant Adverse Effects • Next day impairment • “sleep driving” menoned • Suicidal ideaon • Cauon if impaired respiratory funcon • Sleep paralysis • Hallucinaon • Cataplexy-like syndromes • Headache • Somnolence • Dizziness

Suvorexant Dosing

• 10mg once at night • Can increase to 20mg if smaller dose tolerated but not effecve • Allow 7 hours for sleeping

Contrave® (naltrexone/bupropion) Takeda/Orexigen Naltrexone/bupropion Pharmacology

• Indicated for chronic weight management as adjunct to diet and increased physical acvity • Paents with (1)obesity or (2)overweight with one weight-related comorbidity • Bupropion increases firing of POMC neurons which releases alpha-melanocyte-smulang hormone and beta-endorphin • Naltrexone prevents the auto-inhibitory effects of beta-endorphin

Naltrexone/bupropion Pharmacokinecs • Time to peak: naltrexone 2hrs, bupropion 3 hrs • Taking with high fat meal increases exposure • Naltrexone metabolized to acve metabolites that have longer half life than parent compound • Bupropion metabolized by CYP 2B6 to acve metabolites • Significant impact of eliminaon in paents with decreased renal funcon Naltrexone/bupropion Pharmacokinecs • Drug interacons: bupropion inhibits metabolism of desipramine, citalopram, metoprolol; increased bupropion levels when given with clopidogrel; CYP 2B6 inducers lower bupropion levels; dopaminergic drugs- CNS toxicity, MAOI’s; false posive test for amphetamines possible Naltrexone/bupropion Clinical Trials • Naltrexone/bupropion plus intensive behavioral modificaon compared to placebo plus intensive behavioral modificaon over 56 weeks; paents were obese or overweight • Weight loss from baseline: -9.3% vs -5.1% • Weight loss from baseline among completers: -11.5% vs. -7.3% • Weight loss ≥ 5%: 66% vs. 42% • Drop out rates: 42% vs. 41%

Naltrexone/bupropion Adverse Effects

• Nausea • Conspaon • Headache • Dizziness • Insomnia • Dry mouth • Diarrhea

Naltrexone/bupropion Dosing • Iniate with one 8mg/80mg tablet once in the morning for a week • Increase to one tablet twice daily for a week • Then increase to two tablets in the morning and one in the evening for a week • From week four onward, give two tablets in the morning and two in the evening • Evaluate response aer 12 weeks • Avoid if on chronic opioids • Acute opioids may not produce their full effect

Saxenda® (liraglude) Novo Nordisk Liraglude Pharmacology

• Glucagon-like pepde agonist indicated as adjunct to diet and physical acvity for chronic weight management in adults who are obese or overweight with at least one weight- related comorbid condion • GLP-1 acts centrally to regulate appete and calorie intake, slows gastric emptying me

Liraglude Pharmacokinecs • Peak effects 11 hours aer dosing • Bioavailability 55% • Exposure increases proporonately in recommended dosing range • Metabolized by DPP-4 and neutral endopepdases • Half-life 13 hours • Exposure decreases as weight increases • Drug interacons: may have drug level changes due to slowed gastric emptying Liraglude Clinical Trials

• Liraglude 3mg SQ daily has been compared to placebo in a 56 week randomized, double-blind trial • Both groups got counseling in diet and exercise • Obese or overweight with one comorbid condion • Mean weight decrease from baseline: -7.4% for liraglude and -3% for placebo • 5% or greater weight loss: 62% vs. 34% • 10% or greater weight loss: 33% vs. 15%

Liraglude Clinical Trials

• Liraglude 3mg SQ daily compared to placebo in paents with T2DM • All got diet and exercise counseling • End of trial weight change from baseline in HgbA1c: -5.4% liraglude, -1.7% placebo • 5% or greater weight loss: 49% vs. 16% • 10% or greater weight loss: 22% vs. 5%

Liraglude Adverse Effects

• Boxed warning regarding medullary T-cell carcinoma in animals, human relevance undetermined • Do not use if personal or family hisotyr of MTC or MEN type 2 • Disconnue is pancreas suspected • Nausea • Diarrhea • Conspaon • Voming • Dyspepsia • Hypoglycemia in T2DM paents • Decreased appete

Liraglude Dosing

• Start with 0.6mg SQ daily • Increase by 0.6mg weekly unl reach 3mg/day • Disconnue is not able to tolerate 3mg dose • Do not use with insulin • Reduce dose of oral secretagogues to reduce hypoglycemia risk • Disconnue if have not lost 4% aer 16 weeks

Movank® (naloxegol) Astra Zeneca Naloxegol Pharmacology

• Mu receptor opioid antagonist indicated for treatment of opioid induced conspaon in adults • PEGylated derivave of naloxone • PEG moiety reduces passive permeability so does not reach CNS • Peripheral antagonist acvity

Naloxegol Pharmacokinecs • Low protein binding • Peak concentraon in 2 hours • High fat meal increases absorpon • Metabolized by CYP 3A • Fecal excreon • Half life 6-11 hours • Reduce dose for impaired renal funcon • Drug interacon: ketoconazole, dilazem, quinidine Naloxegol Clinical Trials

• Paents on chronic opioids with <3 SBM’s per week • Randomized to naloxegol 12.5mg 25mg or placebo once daily for 12 weeks • Primary end point: ≥ 3 SBM’s per week and a change of ≥1 SBM for at least 9 of the 12 study weeks and 3 out of last 4 weeks • End point reached: 41%, 42% and 29% first study; 35%, 40% and 29% second study

Naloxegol Adverse Effects

• Do not use if GI obstrucon present • Abdominal pain • Diarrhea • Nausea

Naloxegol Dosing

• Disconnue maintenance laxaves • 25mg tablet swallowed whole on empty stomach in the morning • Reduce dose to 12.5mg if unable to tolerate or CrCl < 60ml/min • Avoid consumpon of grapefruit • Disconnue the is medicaon if opioid disconnued

Sayvasa® (edoxaban) Daiichi Sankyo Edoxaban Pharmacology

• Factor Xa inhibitor indicated for reducing stroke and systemic embolism risk in non- valvular atrial fibrillaon • Also indicated for DVT and PE following 5-10 days of parenteral ancoagulant • Inhibits factor Xa and prothrombinase and thrombin-induced platelet aggregaon

Edoxaban Pharmacokinecs • Bioavailability 62%, protein binding 55% • Food does not influence absorpon • Eliminated primarily in unchanged form • Renal clearance, reduce dose for CrCl < 50ml/ min • Drug interacons: does not inhibit P450; avoid other ancoagulants and rifampin Edoxaban Clinical Trials • Edoxaban has been compared to warfarin in randomized, double-blind, double-dummy trial in paent with atrial fibrillaon • Primary end point: occurrence of stroke or systemic embolism, safety end point: major bleeding • Primary end point annualized rate: warfarin 1.5%, edoxaban high dose 1.18%, edoxaban low dose 1.61% • Annualized rate of major bleeding: warfarin 3.43%, 2.75% high dose, 1.61% low dose

Edoxaban Clinical Trials • Edoxaban has been compared to warfarin in paents being treated for DVT in a randomized, double-blind, non-inferiority trial • Comparing edoxaban 60mg once daily, 30mg once daily and warfarin treated for 3-12 months • Primary end point: recurrent thromboembolism, safety end point: major or clinically relevant non- major bleeding • End point reached: edoxaban 3.2%, warfarin 3.5% • Safety end pint reached: edoxaban 8.5%, warfarin 10.3%

Edoxaban Adverse Effects

• Major bleeding • Intracranial hemorrhage • Clinically relevant non-major bleeding • Gastrointesnal bleeding • Intersal lung disease

Edoxaban Dosing • NVAF: 60mg once daily • 30mg daily if CrCl 15-50ml/min; don’t use if CrCl > 95ml/min

• DVT and PE • 60mg once daily following 5-10 days of inial therapy with parenteral ancoagulant • 30mg daily if CrCl 15-50ml/min or weight less than 60kg • Transion to/from warfarin

Sovaldi® (sofosbuvir) Gilead Sofosbuvir Pharmacology

• Hepas C neucleode analog NS5B polymerase inhibitor indicated for treatment of chronic hepas C • When the prodrug is converted to the acve form it is incorporated into the HCV RNA by NS5B polymerase and acts as the chain terminator

Hepas C Replicaon Cycle Sofosbuvir Pharmacokinecs • Peak concentraon in 0.5-2 hours • Can be administered without regard to food • Protein binding 61-65% • Extensively metabolized by hydrolysis to acve form • Further metabolism by cathepsin, esterase and dephosphorylaon • Half life 27 hours (acve metabolite) • No dose adjustments based on race, gender, advanced age; mild-moderate renal dysfuncon, hepac impairment • Drug interacons: Pgp inducers (may decrease plasma levels); avoid use with pranivir/ritonavir Sofosbuvir Clinical Trials

• Open label trial of treatment naïve paents • HCV genotype 1 or 4, treated over 12 weeks • Combined with interferon and ribavirin • Baseline HCV RNA greater than 6 log 10 IU per ml • Sustained viral response (SVR) seen in 90% with genotype 1 and 96% with genotype 4 • Relapse rate was 9%

Sofosbuvir Clinical Trials

• Paents with HCV genotype 2 and 3, open label, acve-controlled trial • Sofosbuvir/ribavirin compared to interferon/ribavirin • Paents were strafied by cirrhosis status, HCV genotype and baseline HCV RNA • SVR rates aer 12 weeks of sofosbuvir/ribavirin 67%; SVR aer 24 weeks of interferon/ribavirin 67% • Relapse rates 30% and 21%

Sofosbuvir Clinical Trials

• Sofosbuvir in paents coinfected with HCV and HIV • Evaluated safety and efficacy of sofosbuvir over 12 and 24 weeks • SVR rates: genotype 1- 76% (24 weeks treatment), genotype 2 – 88% (12 weeks treatment), genotype 3 – 92%

Sofosbuvir Adverse Effects

• Fague • Headache • Nausea • Insomnia • Pruris • Anemia • Diarrhea

Sofosbuvir Dosing

• 400mg once daily with or without food • Should be used with ribavirin or in combinaon with interferon • Genotype 1 or 4 – 12 weeks [with interferon and ribavirin] • Genotype 2 – 12 weeks [with ribavirin] • Genotype 3 – 24 weeks

Harvoni® (ledipsavir/sofosbuvir) Gilead Ledipasvir/sofosbuvir Pharmacology

• Fixed dose anviral indicated for treatment of chronic hepas C genotype 1 in adults • Ledipsavir inhibits hepas C NS5A protein • Sofosbuvir inhibits hepas C NS5B RNA- dependent RNA polymerase

Ledipasvir/sofosbuvir Pharmacokinecs • Added to sofosbuvir discussion…. • Ledipsavir peak 4 hours, lower in HCV paents than healthy paents • Presence of food does not influence absorpon • Ledipsavir protein binding >99.8% • Metabolism by slow oxidaon • Half life 47 hours • Primarily fecal eliminaon • No significant changes based on renal impairment, advanced age or race Ledipasvir/sofosbuvir Pharmacokinecs • Drug interacons: P-gp inducers reduce levels; anconvulsants (hepac metabolized) decreased concentraon of ledipsavir/ sofosbuvir; rosuvastan (increased stan levels); tenofovir (increased tenofovir levels; Stribild®- change regimens due to tenofovir; acid reducing drugs- reduces ledipasvir levels Ledipasvir/sofosbuvir Clinical Trials • Paents with HCV, genotype 1, treatment naïve, no cirrhosis • Compared Harvoni® for 8 weeks to Harvoni® for 12 weeks and Harvoni® plus ribavirin for 8 weeks • End point: sustained viral response • SVR reached in 94% and 96%, ribavirin did not produce increased response • Relapse rates: 5% in 8 weeks group and 1% in 12 week group

Ledipasvir/sofosbuvir Clinical Trials • HCV paents treatment naïve • Strafied based on cirrhosis status and whether genotype 1a or 1b • Compared Harvoni® for 12 weeks, Harvoni® for 12 weeks plus ribavirin and Harvoni® plus ribavirin for 24 weeks • SVR rates were: 97%, 98% and 99% • No addional benefit seen with ribavirin

Ledipasvir/sofosbuvir Clinical Trials • Paents with HCV, genotype 1, failed previous treatment • Compared four groups: Harvoni® for 12 weeks, Harvoni® plus ribavirin for 12 weeks, Harvoni® for 24 weeks, Harvoni® plus ribavirin for 24 weeks • Paents strafied based on cirrhosis status, genotype 1a or 1b and failure to reach SVR with previous therapy • SVR rates 94%, 96%, 99%, 99% • Lowest SVR rates in genotype 1b for 12 weeks (87%) and cirrhosis treated for 12 weeks (86%)

Ledipasvir/sofosbuvir Adverse Effects

• Fague • Headache • Nausea • Diarrhea • Insomnia

Ledipasvir/sofosbuvir Dosing

• One tablet once daily with or without food for 12 weeks • For treatment-experienced paent with cirrhosis treat for 24 weeks

Viekira PAK® (ombitsavir, paritaprevir, ritonavir; dasabuvir) AbbVie Viekira PAK® Pharmacology

• Treatment regimen containing three direct acng anviral agents for genotype 1 HCV • Ombitsavir inhibits NS5A • Paritaprevir is protease inhibitor NS3/4A • Dasabuvir is non-nucleoside inhibitor of RNA polymerase at NS5B gene • Ritonavir is CYP 3A inhibitor to increase levels of pareitaprevir

Viekira PAK® Pharmacokinecs • Ombitasvir- food, highly protein bound, amide hydrolysis, fecal, half life 21-25 hours • Paritaprevir- highly protein bound, CYP 3A4, ritonavir boosted, fecal, half life 5.5 hours • Ritonavir- highly protein bound, CYP 3A, fecal, half life 4 hours • Dasabuvir- highly protein bound, CYP 2C8, fecal, half life 5.5-6 hours Viekira PAK® Pharmacokinecs • Drug interacons: DO NOT USE alfuzosin, efavirenz, carbamazepine, ergotamine, ethinyl estradiol, gemfibrozil, lovastan, midazolam, phenytoin, pimozide, rifampin, sildenafil, simvastan, St. Johns wort Viekira PAK® Clinical Trials • Viekira PAK® has been compared to placebo in HCV genotype 1a and 1b, treatment naïve, without cirrhosis, HBV or HIV over 12 weeks • SVR12 primary end point • End point reached in 96% on treatment, compared to 78% with historical control (teleprivir, ribavirin, interferon)

Viekira PAK® Clinical Trials • Viekira PAK® has been evaluated in randomized, open-labeled trial in paents with HCV genotype 1 and compensated cirrhosis; 12 and 24 weeks treatment groups • All got ribavirin • Primary end point of SVR12 was reached in 92% receiving 12 weeks and 96% receiving 24 weeks

Viekira PAK® Clinical Trials • Viekira PAK® has been evaluated in a randomized, open-label trial evaluang the combinaon plus ribavirin for 12 and 24 weeks • Treatment naïve and experienced paents with HCV genotype 1 plus HIV (paents with cirrhosis included) • End point of SVR12 reached in 93% aer 12 weeks and 90% aer 24 weeks

Viekira PAK® Adverse Effects

• Fague • Nausea • Pruris • Skin reacons • Insomnia • Asthenia • Consider ribavirin side effects also

Viekira PAK® Dosing

• Two pink tablets (ombitsavir, paritaprevir, ritonavir) each morning • One beige tablet (dasbuvir) twice daily • Add ribavirin for all except genotype 1a without cirrhosis