New Drug Update 2011-2012

1. New Drug Update 2011-2012 Deborah Sturpe, PharmD, BCPS Associate Professor The speaker has NO actual or potential conflicts of interest in relation to this educational activity or presentation.

2. Objectives • Identify pertinent package insert information for each drug presented • Define place in therapy for each drug presented • Review significant new dosage forms

3. Today’s Drugs of Focus

4. Other Drugs Approved Jan 2011-April 2012

5. New Dosage Forms of Interest

6. New First Time Generics

7. Brilinta (ticagrelor) • Indication(s) – reduction in thrombotic CV events s/p ACS • Mechanism of Action – reversible P2Y12 platelet inhibitor • Dosing – 180 mg load, followed by 90 mg BID • Contraindication – moderate to severe hepatic disease • Significant Drug Interaction(s) • ASA doses > 100 mg/day reduce effectiveness of ticagrelor • Avoid concurrent strong CYP3A4 inducers and inhibitors • Competing Agent(s) • clopidogrel • prasugrel

8. Ticagelor Efficacy - PLATO • PLATO included patients hospitalized with STEMI and non-STEMI, with symptom onset in past 24 hours • Major exclusion criteria only high risk of bradycardia and concurrent strong CYP3A4 drugs • Treatment groups: • Ticagrelor 180 mg load, then 90 mg BID + low-dose aspirin • Clopidogrel 300 mg load, then 75 mg daily + low-dose aspirin • Key demographics • 72% men • 91% Caucasian • 85% age < 75 Wallentin L, et al. NEJM 2009; 361:1045-57

9. Ticagelor Safety - PLATO • Overall conclusion from PLATO: In ACS patients, ticagrelor reduces cardiovascular endpoints with this benefit offset by non-procedure-related bleeding. Wallentin L, et al. NEJM 2009; 361:1045-57

10. Ticagrelor Place in Therapy • Clopidogrel issue – nonresponders • Prasugrel issue – higher bleeding than clopidogrel Per 9th edition American College of Chest Physician Antithrombotic Therapy Guidelines: Ticagrelor + ASA is preferred regimen post ACS Drugstore.com pricing • Brilinta [$276 is AWP] • Effient $215 • Plavix $205 • BUT... • Plavix goes generic this year • ASA or Plavix remain drug of choice for established CAD • Plavix remains drug of choice for LV thrombus in combination with ASA and warfarin Vandvik PO, et al. CHEST 2012; 141:637s-668s

11. Edarbi (azilsartan) • Indication(s) - HTN • Mechanism of Action - ARB • Dosing – 80 mg daily • Consider 40 mg if taking high dose diuretics • Pregnancy Category D • Significant Drug Interaction(s) • Concurrent NSAIDs  renal dysfunction • Competing Agent(s)

12. Azilsartan Efficacy & Safety – Package Insert • No report of side effects compared to active control. • Compared to placebo, only diarrhea noted (2% vs. 0.5%) • Although azilsartan may be touted for it’s additional BP lowering with good tolerability, no studies have examined cardiovascular outcomes! Edarbi PI. Takeda Pharmaceuticals. Nov 2011.

13. Azilsartan Place in Therapy Drugstore.com pricing • Edarbi $90 • Diovan $135 • Benicar $135 • losartan $90 • irbesartan $96 • Edarbyclor (azilsartan/chlorthalidone) “Me-too” drug – avoid in favor of ARBs with outcomes data unless dual chlorthalidone desired. Vandvik PO, et al. CHEST 2012; 141:637s-668s

14. Xarelto (rivaroxaban) • Indication(s) – AFib; VTE prevention post knee/hip surgery • Mechanism of Action – Factor Xa inhibitor • Dosing • 20 mg po with evening meal (AFib) – reduce to 15 mg if CrCl 15-50 mL/min. Do not use CrCl < 15. • 10 mg once daily (VTE prevention). Do not use if CrCl < 30 mL/min. • Significant Drug Interaction(s) • Avoid strong CYP3A4 and P-gp inhibitors/inducers • Phenytoin, CBZ, and rifampin increase elimination – increase VTE ppx dose to 20 mg • Competing Agent(s) • warfarin − enoxaparin • dabigatran − fondaparinux

15. Rivaroxaban Efficacy & Safety for AFibROCKET HF1 • Additional notes: • Time in the therapeutic range for warfarin only 55% (most in clinical trials achieve 64-68%) • Third AFib option – Pradaxa (dabigatran) had similar bleeding rates compared to warfarin, but superior efficacy (especially in those with poor INR control)2 1. Patel MR, et al. NEJM 2011; 365:883-91. 2. Connolly SJet al. NEJM 2010; 361:1139-51.

16. Rivaroxaban Efficacy Post THR/ TKRVTE Incidence NNT ~ 62 Turun S, et al. Thrombosis Research 2011; 127:525-34.

17. Rivaroxaban Safety Post THR/ TKRMajor Bleeding Turun S, et al. Thrombosis Research 2011; 127:525-34.

18. Rivaroxaban Place in Therapy CHEST guidelines • Recommended post THR/TKR, but enoxaparin preferred • No comment for AFib or VTE Drugstore.com pricing • Xarelto [AWP is $262] • warfarin $14 • Pradaxa $245 • enoxaparin $808 • THOUGHTS – not a huge player…yet: • Dabigatran is preferred non-warfarin alternative (over rivaroxaban) for AFib • Future potential for rivaroxaban as treatment for acute VTE (EINSTEIN and EINSTEIN-PE) • Will insurance coverage drive post THR/TKR to rivaroxaban despite CHEST guidelines? CHEST 2012; 141 supplement

19. Horizant (gabapentin enacarbil) • Indication(s) – restless leg syndrome • Mechanism of Action – gabapentin prodrug • Dosing – 600 mg with dinner. • Avoid CrCl < 30 mL/min. • Dosing NOT equivalent between this and plain gabapentin • Competing Agent(s) • gabapentin

20. Gabapentin enacarbil Efficacy & Safety *statistically significant • No evidence of better efficacy or tolerability compared to gabapentin • No direct comparisons to other RLS agents, but IRLS score reduction similar Lee DO, et al. Journal of Clinical Sleep Medicine 2011; 7:282-92.

21. Gabapentin enacarbil Place in Therapy • Dopamine agents generally first line for RLS • Potential uses of gabapentin in RLS • Intolerance to dopamine agents • Concurrent pain symptoms Drugstore.com pricing • ropinirole $26 • pramipexole $84 • gabapentin $16 • Horizant [AWP $118] THOUGHTS – reasonable to try Horizant for patients needing gabapentin product who have wearing off effects in middle of night with generic immediate release formulation (or consider Gralise)

22. Viibryd (vilazodone) • Indication(s) – major depression • Mechanism of Action – SSRI plus partial agonist at 5-HT1A receptor • Dosing – 40 mg once daily with food • Starting titration: 10 mg x 7 days; 20 mg x 7 days; then 40 mg • Reduce dose to 20 mg with strong CYP3A4 inhibitors • Significant Drug Interaction(s) • Monoamine oxidase inhibitors • Other serotonergic agents • Competing Agent(s) • SSRIs (es/citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) • SNRIs (desvenlafaxine, duloxetine, venlafaxine)

23. Vilazodone Efficacy & Safety *statistically significant • As with other antidepressants, risk of suicide increased and highest age < 18 Khan A, et al. J Clin Psychiatry 2011;72:441-47. Rickels K, et al. J Clin Psychiatry 2009;70:326-33.

24. Vilazodone and Sexual Side Effects Viibryd Package Insert. Forest Laboratories 2011.

25. Vilazodone Place in Therapy • True efficacy / safety comparison not yet available – active comparisons needed Drugstore.com pricing • Viibryd 40 mg $136 • bupropion XL 150 mg $100 • escitalopram 20 mg $130 • sertraline 100 mg $16 • venlafaxine XL 150 mg $124 THOUGHTS – reasonable to try in patients who fail established options – especially if next step is addition of second agent

26. Tradjenta (linagliptin) • Indication(s) – Type 2 DM • Mechanism of Action – DPP-4 inhibitor • Dosing – 5 mg once daily • Significant Drug Interaction(s) • Avoid strong CYP3A4 inducers • Competing Agent(s) • saxagliptin • sitagliptin

27. Linagliptin Efficacy & Safety – Package Insert • No direct comparisons to other DPP-4 inhibitors • Appears A1c lowering capability similar to other drugs in its class • Little to no side effects as with other DPP-4 inhibitors Tradjenta PI. Boehringer Ingelheim Pharmaceuticals, 2011.

28. ADA & EASD Guidelines: Type 2 DM Inzucchi SE, et al. Diabetologia 2012

29. Linagliptin Place in Therapy Drugstore.com pricing • Tradjenta $241 • Januvia $235 • Onglyza $236 No reason not to consider linagliptin as a DPP-4 inhibitor of choice – with no clear advantage/disadvantage as compared to its competitors. Final decision likely driven by insurance coverage.

30. Zioptan (tafluprost) • Indication(s) – glaucoma • Mechanism of Action – prostaglandin analog, preservative free • Dosing – 1 drop in affected eye(s) q PM • Competing Agent(s) • Bimatoprost (Lumigan) • Latanoprost (Xalatan) • Travoprost (Travatan Z)

31. Tafluprost Efficacy Uusitalo H, et al. Acta Ophthalmol 2010; 88:12-19

32. Tafluprost Safety* • *Both agents contained benzalkonium chloride preservative • Patients intolerant to latanoprost switched to preservative-free tafluprost+ • No change in intraocular pressure pre/post switch • 50% reduction in ocular side effects Uusitalo H, et al. Acta Ophthalmol 2010; 88:12-19 +Uusitalo H, et al. Acta Ophthalmol 2010; 88:329-36

33. Tafluprost Place in Therapy • American Academy of Ophthalmology has not designated first-line class • Prostaglandin agents often selected over beta-blockers due to once daily dosing Drugstore.com pricing • Zioptan [AWP $116] • latanoprost $23 • Lumigan $100 • Travatan Z $95 Only clear reason for selection at this time is rare need for preservative-free product

34. Natroba (spinosad) and Sklice (ivermectin lotion) • Natroba (spinosad) • Indication – head lice (age ≥ 4) • Dosing • Shake bottle • Fully cover scalp & dry hair x 10 minutes • Repeat after 7 days prn. • Sklice (topical ivermectin) • Indication – head lice (age ≥ 6 mo) • Dosing • Fully cover scalp & dry hair x 10 minutes. Competing Agent(s) • permethrin • Ovide (malathion) • Ulesfia (benzyl alcohol) • Stromectol (oral ivermectin)

35. Spinosad Efficacy & Safety *statistically significant • Tidbits of Interest • Non-toxic by any other administrative route • No combing necessary Stough D, et al. Pediatrics 2009; 124:e389-95.

36. Ivermectin Lotion Efficacy & Safety • Tidbit of Interest • No other information available, either in package insert or via Medline search Stough D, et al. Pediatrics 2009; 124:e389-95.

37. Spinosad and Ivermectin Lotion: Place in Therapy • American Academy of Pediatrics still recommends permethrin first-line • Drugstore.com pricing • Natroba [AWP $262] • Sklice [N/A] • Permethrin $18 • Ovide $185 • Ulesfia $63 • Stromectol $111 Based on current data, would consider spinosad as viable option(not ivermectin topical) in cases of permethrin failure and/or concern that adherence to combing or re-treatment will be low.

38. Arcapta (indacaterol) • Indication(s) – COPD • Mechanism of Action – long-acting beta agonist • Dosing – once daily inhalation (75 mcg) • Dry powder “NEOHALER” with externally loaded capsule • Dose finished when all powder inhaled (usually 1-2 inhalations) • Competing Agent(s) • formoterol • salmeterol

39. Indacaterol Efficacy & Safety * Statistically significant difference • COPD exacerbations, not yet studied/reported • No studies use FDA dose of 75 mcg • Adverse effects as expected 1. Kornmann O, et al. Eur Respir J 2011; 37:273-79. 2. Buhl R, et al. Eur Respir J 2011; 38:797-803.

40. Indacaterol: Place in Therapy • Per 2011 GOLD Guidelines, choice of beta-agonist vs. anticholinergic driven by individual patient response and drug availability • Drugstore.com pricing • Arcapta [AWP $195] • Foradil $176 • Serevent $181 • Spiriva $261 Until clinically important outcomes proven with the FDA approved dose, stick with Foradil or Serevent unless once daily dosing critical for adherence.

41. Daliresp (roflumilast) • Indication(s) – severe COPD • Mechanism of Action – oral PDE-4 inhibitor that reduces lung inflammation • Dosing – 500 mcg once daily • Contraindication(s) – moderate to severe hepatic dysfunction • Significant Drug Interaction(s) • Strong CYP3A4 inducers • Strong CYP3A4 and CYP1A2 inhibitors • Competing Agent(s) • No direct competitors • May be option to inhaled steroids?

42. Roflumilast Efficacy *statistically significant • Calverley study: only short-acting bronchodilators allowed • Fabbri study: long-acting bronchodilators included • Neither allowed inhaled corticosteroids Calverley PMA, et al. Lancet 2009; 374:685-94. Fabbri LM, et al. Lancet 2009; 374:695-703.

43. Roflumilast Safety Calverley PMA, et al. Lancet 2009; 374:685-94. Fabbri LM, et al. Lancet 2009; 374:695-703. Pharmacists Letter July 2011. Detail Document 20709.

44. Roflumilast: Place in Therapy • Mentioned in 2011 GOLD Guidelines, but noted that no comparative efficacy to inhaled steroids exists • Clinical trials not designed to allow evaluation of best long-acting drug class in combination with roflumilast • Drugstore.com pricing • Daliresp [AWP $207] Maintain inhaled bronchodilators first line. Possibly consider if oral therapy desired over additional inhaled or if concerned over risk of pneumonia with inhaled steroids.

45. New Dosage Forms of Interest

46. Closer Focus

47. Special Administration Devices

48. Combivent Respimat • Dosing only 1 puff QID • Must discard 3 months after cartridge inserted • On first use: cartridge inserted, then clear base attached • Prime using same general steps as inhalation – ready when spray appears • Patient use • Hold upright and turn clear base on it clicks • Flip orange cap open • Press dose release button as slow inhalation happens • Hold breath for 10 seconds Combivent Respimat PI. Boehringer Ingelheim Pharmaceuticals, 2012.

49. Arcapta Neohaler • Remove inhaler cover • Tilt back mouthpiece • Open capsule blister • Place capsule into inhaler device • Close mouthpiece • Pierce capsule by squeezing pink tabs • Exhale away from mouthpiece • Wrap lips and inhale steady, fast – should hear whirring noise • Hold breath x 10 seconds • Inspect capsule to assure all powder gone – if not repeat inhalation Arcapta PI. Novartis, 2011.

50. Qnasl • Before first use – prime with four sprays • Device has dose counter • Patient use • NOT sniff and spray as with other nasal steroids • Instead, hold breath – then spray into nostril and continue to hold breath for 5 seconds • Exhale through mouth • Repeat as needed to get all doses Qnasl patient instruction leaflet. Teva Respiratory, 2012.