Background 1 and Objective Background Many new medications are released each year 41 were approved in 2014

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1 Disclosure The authors declare no real or potential conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Ashley Lorenzen, PharmD, BCPS Audrey Kostrzewa, PharmD, MPH, BCPS Rachel Kavanaugh, PharmD Background 1 and Objective Background Many new medications are released each year 45 were approved in were approved in 2014 Providers may not be familiar with the new agents and may not even be aware of their release until patients ask Objective To review a few of the commonly used or asked about new medications in primary care from 2015 FDA approval date: September 16, 2014 Movantik (naloxegol) 2 4 FDA Indication Class Opioid antagonist Treatment of opioid induced constipation (OIC) in adult patients with chronic non cancer pain Mechanism of Action Peripherally acting antagonist at the mu opioid receptor site acting on the tissues of the GI tract to decrease constipation Movantik (naloxegol) mg orally once daily in the morning Adjustments Start dose at 12.5mg daily if creatinine clearance < 60mL/min Administration Take on an empty stomach 1 hour prior or 2 hours after a meal Analgesic dosing modification NOT needed prior to initiation of naloxegol Discontinue maintenance laxative therapy prior to initiation of naloxegol Swallow tablets whole, do not crush or chew Discontinue naloxegol when opioid pain treatment discontinued 1

2 Movantik (naloxegol) 2 4 Adverse Reactions Abdominal pain, diarrhea, nausea, flatulence, vomiting, headache Contraindications Patients with known or suspected GI obstruction Patients using strong CYP3A4 inhibitors Pregnancy Category C May precipitate opioid withdrawal of the fetus due to immature blood brainbarrier of fetus Movantik (naloxegol) 2 Cost for 30 day supply Lexi Comp cash price $ for both strengths Blue Cross Tier 3 Security Health Plan Tier 4 Similar Agents Relistor (methylnaltrexone bromide) subcutaneous once daily injection FDA approved for opioid induced constipation with chronic non cancer pain OR with advanced illness Movantik (naloxegol) 5 Two phase III multicenter, randomized, doubleblind, placebo controlled trials N= 652 and N=700 1:1:1 randomization 12.5mg : 25mg : placebo daily for 12 weeks FDA approval date: August 18, 2015 Addyi (flibanserin) 6 8 FDA Indication Class Mixed 5 HT1A agonist / 5 HT2A antagonist 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, or The effects of a medication or other drug substance Mechanism of action Unknown, in vitro flibanserin demonstrated high affinity of the serotonin receptors Addyi (flibanserin) mg once daily at bedtime Adverse Reactions Dizziness, somnolence, nausea, fatigue, insomnia, dry mouth Precautions Notable drug interactions Oral contraceptives, weak CYP3A4 inhibitors, strong CYP2C19 inhibitors flibanserin concentrations CYP3A4 inducers flibanserin concentrations Digoxin digoxin concentrations REMS Program Due to risk of hypotension and syncope when used with alcohol Prescribers AND pharmacy must be certified through REMS program 2

3 Addyi (flibanserin) 6 Black Box Warning Addyi (flibanserin) 6 Pregnancy Category C No studies available in humans Cost for 30 days Lexi Comp cash price $ Blue Cross Tier 3 United Health Care Prior authorization (medically necessary) Similar Agents None Addyi (flibanserin) 9,10 Three phase III randomized, double blind, placebo controlled trials. N= 570, N=737, N=1,068 Randomized to receive flibanserin 100mg or placebo once daily at bedtime Addyi (flibanserin) 9,10 Jublia (efinaconazole) 11 Indication Class Topical azole antifungal Onychomycosis from Trichophyton rubrum and Trichophyton mentagrophytes Mechanism of action Azole antifungal that inhibits fungal lanosterol 14α demethylase in cell death FDA approval date: June

4 Jublia (efinaconazole) 11 Apply 1 drop to affected toenail once daily for 48 weeks Use a second drop if great toe affected Spread solution around the toenail using applicator brush Include nail bed, folds, hyponychium, and undersurface of the nail plate Application tips Nail should be clean and dry Avoid pedicures, nail polish, cosmetic nail products Wash hands with soap and water after each use Adverse reactions Ingrown nail, site dermatitis, vesicles, or site pain Jublia (efinaconazole) Precautions Keep away from eyes, nose, mouth, and ears Medication is flammable Pregnancy Category C Small amounts absorbed topically Cost Lexi Comp cash price $ Private insurance Not included in many plans Medicare or Medicaid Not preferred agent Similar agents Kerydin (tavaborole) Topical oxaborole antifungal for onychomycosis that inhibits fungal protein synthesis Jublia (efinaconazole) 11,12,14 Two phase III multicenter, randomized, double blind trials N = 870 and N = 785 Randomized 3 : 1 to efinaconazole 10% or vehicle 4 week posttreatment follow up Cure rate assessed at 52 weeks Complete cure % efinaconazole and % vehicle Nail improvement % efinaconazole and % vehicle Limitations Duration too short? FDA approval date: February 2015 Toujeo (insulin glarine) 15 Indication Class Long acting insulin Type 1 and Type 2 Diabetes mellitus Mechanism of action Regulates metabolism of carbohydrates, proteins, and fats Targets the liver (stimulates glycogen and fatty acid synthesis), skeletal muscle (increases protein and glycogen synthesis), and adipose tissues (increases lipoprotein breakdown) Increases cellular uptake of amino acids and potassium Toujeo (insulin glarine) 15 Initial dose 1/3 to ½ of total daily insulin requirement given once daily OR 0.2 units/kg once daily Converting from Lantus to Toujeo Use equivalent unit per dose NOTE may need a higher dose of Toujeo to achieve same glycemic control Converting from Toujeo to Lantus Use 80% of the initial dose of Toujeo (ie, a 20% dose reduction) Adverse reactions Hypoglycemia, hypertension, peripheral edema, depression 4

5 Toujeo (insulin glarine) 15 Storage Unopened prefilled pens: 2 8⁰ C (36 46⁰ F) until expiration date Opened pens: < 30⁰ C (< 86⁰ F) Use within 28 days Do not freeze Pregnancy Category C Similar outcomes to regular insulin, although theoretical concerns for adverse events in fetus Toujeo (insulin glarine) 15,16 Cost Lexi Comp cash price $ for Toujeo and $89.46 for Lantus Insurance coverage Generally NOT preferred Lantus is a preferred agent Savings program (COACH) A savings card for patients with commercial insurance for $15 per script for 1 year NOT for Medicare/Medicaid/VA patients coach/coach registration Toujeo (insulin glarine) 17,18 EDITION 1 26 week, multinational, open label, parallel group study 804 adults with type 2 diabetes requiring 42 units/day + mealtime insulin ±metformin U 300 non inferior to U 100 U 300 used 11% more basal insulin Less nocturnal hypoglycemia (CI , p<0.005) EDITION 2 26 week, multicenter, open label, two arm study 811 adults with type 2 Taking basal insulin + oral antidiabetic agents U 300 non inferior to U 100 Less nocturnal hypoglycemia (CI , p=0.038) Less weight gain (p=0.015) Toujeo (insulin glarine) 19,20, cont. EDITION 3 26 week, multicenter, open label, parallel study 878 adults with type 2 diabetes and oral antidiabetic therapy U 300 non inferior to U 100 (CI ) Less nocturnal hypoglycemia with U 300 (CI ) Meta analysis of EDITION 1, 2, and 3 U 100 and U 300 comparable for A1c lowering U 300 associated with less hypoglycemia at any time of the day U 300 associated with slightly less weight gain (CI , p=0.039) Toujeo (insulin glarine) 21, cont. EDITION 4 26 week open label trial 549 adults with Type 1 diabetes and basal + bolus insulin Randomized to U 100 or U 300, either morning or evening dosing in 1:1:1:1 ratio U 300 noninferior to U 100 Similar rates of low glucose levels at any time of the day Less nocturnal hypoglycemia in initial 8 weeks with U % vs 11.2% for U 300 vs U 100 respectively (CI ) Slower weight gain with U 300 (CI , p=0.037) Toujeo (insulin glarine) Similar agents Lantus Levemir Why Toujeo vs Lantus? Lantus onset is 3 4 hours vs 6 hours with Toujeo Possibly less nocturnal hypoglycemia with Toujeo Possibly less weight gain with Toujeo Toujeo approximately 2x the cost as Lantus 5

6 Lantus pens 100 units/ml 3 ml/pen 300 units/pen CAUTION!! Toujeo pens 300 units/ml 1.5 ml/pen 450 units/pen Other Concentrated Insulins Increased risk of errors Pharmacokinetics differ careful when converting Include both units and ml on prescription to be absolutely clear to pharmacist and patient Humalog KwikPen (insulin lispro) 200 units/ml Approved May 26, 2015 Short acting insulin Unit unit conversion recommended Humulin R U 500 (insulin regular) 500 units/ml only concentrated insulin until 2015 Approved October 28, 1982 Different pharmacokinetics, NOT unit unit conversion Prescribe TB syringes (ml) NOT insulin syringes (units based on 100 unit/ml concentration) TB Syringe (ml) 5 pens/box 1500 units/box 3 pens/box 1350 units/box Tresiba FlexTouch (insulin degludec) 200 units/ml Approved September 25, 2015 Long acting insulin Unit unit conversion of long or intermediateacting insulin daily dose Insulin Syringe (units based on 100 units/ml) Entresto (sacubitril/valsartan) 22 Indication Class Sacubitril neprilysin inhibitor (first in class) Valsartan angiotensin II receptor blocker (ARB) Heart failure NYHA Class II IV with reduced ejection fraction FDA approval date: July 7, 2015 Mechanism of Action Sacubitril Prodrug that inhibits neprilysin, leading to increased levels of peptides, including natriuretic peptides Valsartan Displaces AT2 from receptor, antagonizing AT1 actions Entresto (sacubitril/valsartan) 22 Initial dose 24/26 mg BID Current ACEI/ARB < 10 mg enalapril or 160 mg valsartan No current therapy egfr < 30 ml/min/1.73m 2 Child Pugh class B 49/51 mg BID Current ACEI/ARB > 10 mg enalapril or 160 mg valsartan Titration schedule Double dose as tolerated every 2 4 weeks to 97/103 mg BID Entresto (sacubitril/valsartan) 22,23 Available formulations (price = $450/60 tablets (30 day supply)) Sacubitril 24 mg, 49 mg, 97 mg Valsartan 26 mg, 51 mg, or 103 mg Clinical trials based on combined dosage (i.e., 50 mg, 100 mg, and 200 mg) so be cautious. To reduce error risk, include both doses. Valsartan in Entresto more bioavailable than valsartan alone (equal to 40 mg, 80 mg, and 160 mg, respectively) Adverse reactions Hypotension, hyperkalemia, increased creatinine 6

7 Entresto (sacubitril/valsartan) 22 Contraindications History of angioedema Concomitant ACEI (allow for 36 hour wash out) Increased risk for angioedema Concomitant aliskiren in patients with diabetes Dual blockade of renin angiotensin system Hypersensitivity Black Box Warning Pregnancy Entresto (sacubitril/valsartan) 24 PARADIGM HF Sacubitril/valsartan 200 mg BID vs enalapril 10 mg BID in HFrEF following run in period 8,442 NYHA Class II IV patients with <40% EF Primary outcome Composite of death from cardio vascular causes or first hospitalization from HF 914 (21.8%) vs 1,117 (26.5%) in favor of sacubitril/ valsartan (HR 0.80; 95% CI 0.73 to 0.87; P<0.001) Trial stopped early at 27 months Entresto (sacubitril/valsartan) 24 Summary Many new medications are FDA approved every year A few common ones for primary care from the previous year include: Movantik Opioid induced constipation (OIC) in adult patients with chronic non cancer pain Addyi Acquired, generalized hypoactive sexual desire disorder (HSDD) Jublia Onychomycosis Toujeo Type 1 and Type 2 Diabetes Ernesto Heart failure NYHA Class II IV with reduced ejection fraction References 1. Hirschler, B. Drug approvals at 19 year high belie industry challenges. Health. January 4, pharmaceuticalsapprovals iduskbn0ui Accessed January 5, Naloxegol. In: Lexi Drugs [database online]. Hudson, OH: Lexicomp; Movantik (naloxegol) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; January Movantik for U.S. Health Care Professionals. Updated April Accessed January Tack J, Lappalainen J, Diva U, et al. Efficacy and safety of naloxegol in patients with opioid induced constipation and laxative inadequate response. United European Gastroenterology Journal; 2015:3(5) Flibanserin. In: Lexi Drugs [database online]. Hudson, OH: Lexicomp; Addyi (flibanserin) [prescribing information]. Raleigh, NC: Sprout Pharmaceuticals; August Addyi for U.S. Health Care Professionals. care professionals. Accessed January Katz M, DeRogatis LR, Ackerman R, et al. Efficacy of flibanserin in women with hypoactive sexual desire disorder: Results from the BEGONIA trial. J Sex Med; Simon JA, Kingsberg SA, Shumel B, et al. Efficacy and safety of flibanserin in postmenopausal women with hypoactive sexual desire disorder: results of the SNOWDROP trial. Menopause: The Journal of The North American Menopause Society; 2013: 23(6) 11. Efinaconazole. In: Lexi Drugs [database online]. Hudson, OH: Lexicomp; Goldstein AO. Onychomycosis. In: Uptodate. Dellavalle RP, Levy ML, and Rosen T (Ed), UpToDate, Waltham, MA (Accessed December 5, 2015) 13. Tavaborole. In: Lexi Drugs [database online]. Hudson, OH: Lexicomp; References, cont. 14. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, doubleblind studies. J Am Acad Dermatol. 2013;68(4): Insulin Glargine. In: Lexi Drugs [database online]. Hudson, OH: Lexicomp; Toujeo. Sanofi Diabetes. Updated December Accessed January Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using basal and mealtime insulin: Glucose control and hypoglycemia in a 6 month randomized controlled trial (EDITION 1). Diabetes Care. 2014;37: Yki Jarvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using oral agents and basel insulin: Glucose control and hypoglycemia in a 6 month randomized controlled trial (EDITION 2). Diabetes Care. 2014;37: Bolli GB, Riddle MC, Bergenstal RM, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in insulin naïve people with type 2 diabetes on oral glucose lowering drugs: a randomized controlled trial (EDITION 3). Diabetes, Obesity, and Metabolism. 2015;17(4): Ritzel R, Roussel R, Bolli GB, et al. Patient level meta analysis of the EDITION 1, 2, and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab. 2015;17(9): Home PD, Bergenstal RM, Bolli GB, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 1 diabetes: a randomized, phase 3, open label clinic trial (EDITION 4). Diabetes Care. 2015; 38: Sacubitril and valsartan. In: Lexi Drugs [database online]. Hudson, OH: Lexicomp; Entresto [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; McMurray JJ, Packer M, Desai AS, et al; PARADIGM HF Investigators and Committees. Anigiotensin neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11): DOI /NEJMoa

8 Ashley Lorenzen, PharmD, BCPS Audrey Kostrzewa, PharmD, MPH, BCPS Rachel Kavanaugh, PharmD 8