1. Deborah Sturpe, PharmD, BCPS Associate Professor
New Drug Update
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 Body System Brand (generic) Cardiovascular
Brilinta (ticagrelor)
Edarbi (azilsartan)
Xarelto (rivaroxaban)
CNS
Horizant (gabapentin enacarbil)
Viibryd (vilazodone)
Endocrine
Tradjenta (linagliptin)
HEENT
Zioptan (tafluprost)
Infectious Disease
Natroba (spinosad)
Sklice (ivermectin lotion)
Pulmonary
Arcapta (indacaterol)
Daliresp (roflumilast)

4. Other Drugs Approved Jan 2011-April 2012
Brand (generic)
Indication(s)
Caprelsa (vandetanib)
Thyroid cancer
Dificid (fidaxomicin)
C. diff infection
Edurant (rilpivirine)
HIV
Evivedge (vismodegib)
Basal cell carcinoma
Ferriprox (deferiprone)
Iron chelation
Incivek (telaprevir)
Hepatitis C
Inlyta (axitinib)
Renal cell carcinoma
Jakafi (ruxolitinib)
Myelofibrosis
Kalydeco (ivacaftor)
Cystic fibrosis
Omontys (peginesatide)
Anemia in dialysis
Onfi (clobazam)
Lennox-Gastaut syndrome
Picato (ingenol mebutate)
Actinic keratosis
Potiga (ezogabine)
Partial-onset seizures
Victrelis (boceprevir)
Xalkori (crizotinib)
Lung cancer
Zelboraf (vemurafenib)
Melanoma
Zytiga (abiraterone)
Prostate cancer

5. New Dosage Forms of Interest
Brand (generic)
What’s New?
Combivent Respimat (ipratropium/albuterol)
Non-CFC MDI formulation
Duexis (ibuprofen/famotidine) 800 /26.6 mg
Combination agent
Forfivo XL (bupropion) 450 mg
New strength
Gralise (gabapentin) 300 mg, 600 mg
Once daily formulation
Intermezzo (zolpidem) 1.75 mg, 3.5 mg
Sublingual tablet
Janumet XR (sitagliptin/metformin) 50/500 mg, 50/1000 mg, 100/1000 mg
Extended release
Jentadueto (linagliptin/metformin) 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg
Juvisync (sitagliptin/simvastatin) 100/10 mg, 100/20 mg, 100/40 mg
Oxecta (oxycodone) 5 mg, 7.5 mg
Does not crush/dissolve
Qnasl (beclomethasone)
Nasal dry powder formulation
Rezira (hydrocodone/pseudoephedrine) 5/60 mg
Zetonna (ciclesonide)
Zutripro (hydrocodone/chlorpheniramine/pseudoephedrine) 5/4/60 mg
Zyclara (imiquimod) 3.75%

6. New First Time Generics
Now Available
Anticipated by End 2012
Avapro
Avalide
Boniva
Avandamet
Caduet
Avandaryl
Femcon Fe
Provigil
Geodon
Plavix
Levaquin
Lescol XL
Lexapro
Lunesta
Lipitor
Clarinex
Ritalin LA
Tricor
Seroquel
Actos
Teveten
Alocril
Xyzal
Singulair
Zyprexa
Diovan and Diovan HCT
Exforge
Foxalin XR
Atacand

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
% Ticagrelor (n=9333)
% Clopidogrel (n=9291)
NNT
Vascular death, MI, and CVA
9.8
11.7 53
Planned invasive treatment
8.9
10.6 59
Day 1-30
4.8
5.4
167
Day
5.3
6.6 77
Stent thrombosis
1.3
1.9
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:

9. Ticagelor Safety - PLATO
% Ticagrelor (n=9333)
% Clopidogrel (n=9291)
NNH
Major bleeding
11.6
11.2 NS
Life-threatening/fatal bleeding
5.8
Nonintracranial fatal
0.1
0.3
500
Intracranial fatal
0.01
1111
Non-CABG related major bleeding
4.5
3.8
143
Major or minor bleeding
16.1
14.6 99
Dyspnea
13.8
7.8 17
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:

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)
candesartan
eprosartan
irbesartan
losartan
olmesartan
telmisartan
valsartan

12. Azilsartan Efficacy & Safety – Package Insert
Study 1 (n=1285)
Study 2 (n=989)
BP Δ from baseline
(158/93)
(159/92)
Azilsartan 40 mg
-15/-6
-12/-7
Azilsartain 80 mg
-15/-5
-16/-9
Olmesartan 40 mg
-11/-5
-13/-7
Valsartan 320 mg
-10/-4 NA
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 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 AFib ROCKET HF1
% rivaroxaban (n=6958)
% warfarin (n=7004)
NNT/NNH
Stroke or systemic embolism
2.1
2.4 NS
Major and nonmajor bleeding
14.9
14.5
Fatal bleed
0.2
0.5
333
GI bleed
3.2
2.2
100
Intracranial hemorrhage
0.4
0.8
250
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:
2. Connolly SJet al. NEJM 2010; 361:

16. Rivaroxaban Efficacy Post THR/ TKR VTE Incidence
NNT ~ 62
Turun S, et al. Thrombosis Research 2011; 127:

17. Rivaroxaban Safety Post THR/ TKR Major Bleeding
Turun S, et al. Thrombosis Research 2011; 127:

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 $ • 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
600 mg
(n=115)
1200 mg
(n=113)
Placebo
(n=97)
Δ IRLS score*
-13.8
-13
-9.8
Proportion of responders per CGI-I* (%) 73 77 45
Dizziness (%)
10.4
24.3
5.2
Somnolence
21.7 18
2.1
Δ EES score (daytime sleepiness)
-2.8
-2.9
-2.4
Headache
14.8
13.5
8.3
*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:

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
8 week follow-up
Khan et al.
Rickels et al.
Vilazodone
Placebo
Mean Change in Montgomery-Asberg Depression Rating Scale*
-13.3
-10.8
-12.9
-9.6
Mean Change in Hamilton Depression Rating Scale
-10.7
-10.1
-10.4
-8.6
Diarrhea %
30.6
10.7
Nausea % 26
5.6
Headache %
12.8
10.3
Dry mouth %
8.9
3.9
Dizziness %
Insomnia %
7.2 3
MADRS – max score 60 = more severe
*statistically significant
As with other antidepressants, risk of suicide increased and highest age < 18
Khan A, et al. J Clin Psychiatry 2011;72:
Rickels K, et al. J Clin Psychiatry 2009;70:

24. Vilazodone and Sexual Side Effects
MADRS – max score 60 = more severe
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
Δ HgbA1c from baseline
Linagliptin
Control
Monotherapy vs. placebo
-0.4
0.1
Add-on to metformin: linagliptin vs. placebo
-0.5
0.15
Add-on to metformin: linagliptin vs. glimepiride
-0.6
Initial therapy with pioglitazone: linagliptin vs. placebo
-1.1
Add-on to sulfonylurea: linagliptin vs. placebo
-0.1
Add-on to sulfonylurea + metformin: linagliptin vs. placebo
-0.7
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)
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
Age range 6 months-68 years (mean ages in late teens)
Spinosad
Permethrin
Study 1
Study 2
Lice free 14 days after last treatment (%)* 84 88 45 42
Requiring only one treatment (%)* 62 86 37 40
Adherence (%)* 89
90.4
83.1
86.9
Application site erythema (%)*
3.1
6.8
Application site irritation (%)
0.9
1.5
*statistically significant
Tidbits of Interest
Non-toxic by any other administrative route
No combing necessary
Stough D, et al. Pediatrics 2009; 124:e

36. Ivermectin Lotion Efficacy & Safety
Age >= six months
Ivermectin
Placebo
Study 1
Study 2
Lice free 14 days after last treatment (%)* 76 71 16 19
Tidbit of Interest
No other information available, either in package insert or via Medline search
Stough D, et al. Pediatrics 2009; 124:e

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
Moderate to severe COPD – ICS allowed
Indacaterol group
Comparator group
Indacaterol 150 mcg daily vs. salmeterol 50 mcg BID (6 mo)1
SGRQ score
TDI score improvement of >= 1 unit (%)
Days with no rescue (%)*
Days able to perform activities (%)*
-5.0
60.5 60 43
-4.1
53.6 55 38
Indacaterol 150 mcg daily vs. tiotropium 18 mcg daily (12 wk)2
SGRQ score*
TDI score*
-5.1
-2.01 46
-3.0
-1.43 41
* Statistically significant difference
N=330 per group
SGRQ = St George Respiratory Questionnaire. 4 pts meaningful
TDI = dyspnea index. 1 pt meaningful
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:
2. Buhl R, et al. Eur Respir J 2011; 38:

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 Roflumilast Placebo
SABA
LABA
LAAC
Moderate or severe exacerbation
(mean per year)
1.14* NA
1.37
Mild, moderate or severe exacerbation (mean per year)
1.9
1.8
2.4
2.2
Median days to first exacerbation
80*
83*
80.5 71
74.5
*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:
Fabbri LM, et al. Lancet 2009; 374:

43. Roflumilast Safety ADRs Significantly Higher than Placebo
Other Rare ADRs of Concern
Decreased appetite
Diarrhea
Headache
Insomnia
Nausea
Weight loss (minor)
Depression
Suicide
Cancer
Weight loss (significant)
Calverley PMA, et al. Lancet 2009; 374:
Fabbri LM, et al. Lancet 2009; 374:
Pharmacists Letter July Detail Document

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
Brand (generic)
What’s New?
Combivent Respimat (ipratropium/albuterol)
Non-CFC MDI formulation
Duexis (ibuprofen/famotidine) 800 /26.6 mg
Combination agent
Forfivo XL (bupropion) 450 mg
New strength
Gralise (gabapentin) 300 mg, 600 mg
Once daily formulation
Intermezzo (zolpidem) 1.75 mg, 3.5 mg
Sublingual tablet
Janumet XR (sitagliptin/metformin) 50/500 mg, 50/1000 mg, 100/1000 mg
Extended release
Jentadueto (linagliptin/metformin) 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg
Juvisync (sitagliptin/simvastatin) 100/10 mg, 100/20 mg, 100/40 mg
Oxecta (oxycodone) 5 mg, 7.5 mg
Does not crush/dissolve
Qnasl (beclomethasone)
Nasal dry powder formulation
Rezira (hydrocodone/pseudoephedrine) 5/60 mg
Sklice (ivermectin)
Topical lotion
Zetonna (ciclesonide)
Zutripro (hydrocodone/chlorpheniramine/pseudoephedrine) 5/4/60 mg
Zyclara (imiquimod) 3.75%

46. Closer Focus New Dosage Form and Drugstore.com cost
Comparative Options and Drugstore.com cost
Duexis 800 mg /26.6 mg
#90
[AWP = $176]
Ibuprofen 800 mg
Famotidine 20 mg
$13
$20
Generic components save
Forfivo XL 450 mg
#30
Unknown
Bupropion XL 150 mg
#90 = $160
Must await pricing on Forfivo
Gralise 300 mg or 600 mg
[AWP = $81]
Gabapentin 100 mg
Gabapentin 300 mg
#90 = $44
#60 = $16
Only use if once daily really needed
Intermezzo 1.75 mg, 3.5 mg
[AWP = $232]
Zaleplon 5-10 mg
#30 = $18-35
Using generic Sonata saves
Oxecta 5 mg, 7.5 mg
#100
[AWP = $320]
Oxycodone 5 mg
#100 = $113
Generic oxycodone cheaper

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.

51. Thanks for Attending!