New Drug Update 2011-2012

Deborah Sturpe, PharmD, BCPSAssociate Professor

The speaker has NO actual or potential conflicts of interest in relation to this educational activity or presentation.

Objectives

• Identify pertinent package insert information for each drug presented

• Define place in therapy for each drug presented

• Review significant new dosage forms

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)

Other Drugs Approved Jan 2011-April 2012Brand (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) Hepatitis C

Xalkori (crizotinib) Lung cancer

Zelboraf (vemurafenib) Melanoma

Zytiga (abiraterone) Prostate cancer

New Dosage Forms of InterestBrand (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 Combination agent

Juvisync (sitagliptin/simvastatin) 100/10 mg, 100/20 mg, 100/40 mg Combination agent

Oxecta (oxycodone) 5 mg, 7.5 mg Does not crush/dissolve

Qnasl (beclomethasone) Nasal dry powder formulation

Rezira (hydrocodone/pseudoephedrine) 5/60 mg Combination agent

Zetonna (ciclesonide) New strength

Zutripro (hydrocodone/chlorpheniramine/pseudoephedrine) 5/4/60 mg Combination agent

Zyclara (imiquimod) 3.75% New strength

New First Time GenericsNow 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

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

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 31-360 5.3 6.6 77

Stent thrombosis 1.3 1.9 167

Wallentin L, et al. NEJM 2009; 361:1045-57

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

Ticagelor Safety - PLATO% Ticagrelor

(n=9333)% Clopidogrel

(n=9291)NNH

Major bleeding 11.6 11.2 NS

Life-threatening/fatal bleeding 5.8 5.8 NS

Nonintracranial fatal 0.1 0.3 500

Intracranial fatal 0.1 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

Wallentin L, et al. NEJM 2009; 361:1045-57

Overall conclusion from PLATO: In ACS patients, ticagrelor reduces cardiovascular endpoints with this benefit offset by non-procedure-related bleeding.

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

Vandvik PO, et al. CHEST 2012; 141:637s-668s

BUT...Plavix goes generic this yearASA or Plavix remain drug of choice for established CADPlavix remains drug of choice for LV thrombus in combination with ASA and warfarin

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

Azilsartan Efficacy & Safety – Package Insert

Study 1 (n=1285) Study 2 (n=989)

BP Δ from baseline(158/93)

BP Δ from baseline(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

Edarbi PI. Takeda Pharmaceuticals. Nov 2011.

Although azilsartan may be touted for it’s additional BP lowering with good tolerability, no studies have examined cardiovascular outcomes!

No report of side effects compared to active control. Compared to placebo, only diarrhea noted (2% vs. 0.5%)

Azilsartan Place in TherapyDrugstore.com pricing•Edarbi $90 •Diovan $135•Benicar $135•losartan $90 •irbesartan $96

•Edarbyclor (azilsartan/chlorthalidone)

Vandvik PO, et al. CHEST 2012; 141:637s-668s

“Me-too” drug – avoid in favor of ARBs with outcomes data unless dual chlorthalidone desired.

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

Rivaroxaban Efficacy & Safety for AFibROCKET 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 NS

Fatal bleed 0.2 0.5 333

GI bleed 3.2 2.2 100

Intracranial hemorrhage 0.4 0.8 250

1. Patel MR, et al. NEJM 2011; 365:883-91.2. Connolly SJet al. NEJM 2010; 361:1139-51.

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

Rivaroxaban Efficacy Post THR/ TKRVTE Incidence

Turun S, et al. Thrombosis Research 2011; 127:525-34.NNT ~ 62

Rivaroxaban Safety Post THR/ TKRMajor Bleeding

Turun S, et al. Thrombosis Research 2011; 127:525-34.

Rivaroxaban Place in TherapyCHEST 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

CHEST 2012; 141 supplement

THOUGHTS – not a huge player…yet:Dabigatran is preferred non-warfarin alternative (over rivaroxaban) for AFibFuture potential for rivaroxaban as treatment for acute VTE (EINSTEIN and EINSTEIN-PE)Will insurance coverage drive post THR/TKR to rivaroxaban despite CHEST guidelines?

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

Gabapentin enacarbil Efficacy & Safety

Lee DO, et al. Journal of Clinical Sleep Medicine 2011; 7:282-92.

No evidence of better efficacy or tolerability compared to gabapentin No direct comparisons to other RLS agents, but IRLS score reduction similar

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

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)

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)

Vilazodone Efficacy & Safety

Khan A, et al. J Clin Psychiatry 2011;72:441-47.Rickels K, et al. J Clin Psychiatry 2009;70:326-33.

8 week follow-upKhan et al. Rickels et al.

Vilazodone Placebo 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 % 8.9 3.9

Insomnia % 7.2 3

*statistically significant

As with other antidepressants, risk of suicide increased and highest age < 18

Vilazodone and Sexual Side Effects

Viibryd Package Insert. Forest Laboratories 2011.

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

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

Linagliptin Efficacy & Safety – Package Insert

Δ HgbA1c from baseline

Linagliptin ControlMonotherapy vs. placebo -0.4 0.1Add-on to metformin: linagliptin vs. placebo -0.5 0.15Add-on to metformin: linagliptin vs. glimepiride -0.4 -0.6Initial therapy with pioglitazone: linagliptin vs. placebo -1.1 -0.6Add-on to sulfonylurea: linagliptin vs. placebo -0.5 -0.1Add-on to sulfonylurea + metformin: linagliptin vs. placebo -0.7 -0.1

Tradjenta PI. Boehringer Ingelheim Pharmaceuticals, 2011.

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

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Inzucchi SE, et al. Diabetologia 2012

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.

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)

Tafluprost Efficacy

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

Tafluprost Safety*

Uusitalo H, et al. Acta Ophthalmol 2010; 88:12-19+Uusitalo H, et al. Acta Ophthalmol 2010; 88:329-36

*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

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

Natroba (spinosad) and Sklice (ivermectin lotion)

Competing Agent(s)

•permethrin

•Ovide (malathion)

•Ulesfia (benzyl alcohol)

•Stromectol (oral ivermectin)

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.

Spinosad Efficacy & Safety

Stough D, et al. Pediatrics 2009; 124:e389-95.

Age range 6 months-68 years (mean ages in late teens)

Spinosad PermethrinStudy 1 Study 2 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

Ivermectin Lotion Efficacy & Safety

Stough D, et al. Pediatrics 2009; 124:e389-95.

Age >= six months

Ivermectin PlaceboStudy 1 Study 2 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

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.

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

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* •Days with no rescue (%)*

•-5.1•-2.01•46

•-3.0•-1.43•41

1. Kornmann O, et al. Eur Respir J 2011; 37:273-79.2. Buhl R, et al. Eur Respir J 2011; 38:797-803.

COPD exacerbations, not yet studied/reported No studies use FDA dose of 75 mcg

Adverse effects as expected

* Statistically significant difference

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.

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?

Roflumilast Efficacy

Calverley PMA, et al. Lancet 2009; 374:685-94.Fabbri LM, et al. Lancet 2009; 374:695-703.

Roflumilast Placebo

SABA LABA LAAC SABA LABA LAAC

Moderate or severe exacerbation(mean per year) 1.14* NA NA 1.37 NA NA

Mild, moderate or severe exacerbation (mean per year) NA 1.9 1.8 NA 2.4 2.2

Median days to first exacerbation 80* 83* 80.5 71 71 74.5

*statistically significant

• Calverley study: only short-acting bronchodilators allowed• Fabbri study: long-acting bronchodilators included• Neither allowed inhaled corticosteroids

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.

ADRs Significantly Higher than Placebo Other Rare ADRs of Concern

Decreased appetiteDiarrheaHeadacheInsomniaNauseaWeight loss (minor)

DepressionSuicideCancerWeight loss (significant)

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.

New Dosage Forms of InterestBrand (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 Combination agent

Juvisync (sitagliptin/simvastatin) 100/10 mg, 100/20 mg, 100/40 mg Combination agent

Oxecta (oxycodone) 5 mg, 7.5 mg Does not crush/dissolve

Qnasl (beclomethasone) Nasal dry powder formulation

Rezira (hydrocodone/pseudoephedrine) 5/60 mg Combination agent

Sklice (ivermectin) Topical lotion

Zetonna (ciclesonide) New strength

Zutripro (hydrocodone/chlorpheniramine/pseudoephedrine) 5/4/60 mg Combination agent

Zyclara (imiquimod) 3.75% New strength

Closer FocusNew Dosage Form and Drugstore.com cost Comparative Options and Drugstore.com cost

Duexis 800 mg /26.6 mg#90

[AWP = $176] Ibuprofen 800 mgFamotidine 20 mg

$13$20Generic components save

Forfivo XL 450 mg#30

Unknown Bupropion XL 150 mg #90 = $160Must await pricing on Forfivo

Gralise 300 mg or 600 mg#30

[AWP = $81] Gabapentin 100 mgGabapentin 300 mg

#90 = $44#60 = $16Only use if once daily really needed

Intermezzo 1.75 mg, 3.5 mg#30

[AWP = $232] Zaleplon 5-10 mg #30 = $18-35Using generic Sonata saves

Oxecta 5 mg, 7.5 mg#100

[AWP = $320] Oxycodone 5 mg #100 = $113Generic oxycodone cheaper

Special Administration Devices

Combivent Respimat

Combivent Respimat PI. Boehringer Ingelheim Pharmaceuticals, 2012.

• 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

Arcapta Neohaler

Arcapta PI. Novartis, 2011.

• 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

Qnasl

Qnasl patient instruction leaflet. Teva Respiratory, 2012.

• 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

Thanks for Attending!