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Drug Therapy Update Looking back.summer 2016 Alex Crawley & Brent Jensen, BSP RxFiles Academic Detailing Program ASA-Annual Scientific Assembly Saskatoon Outline New Info on» Guidelines» Tools» SPDP & NIHB» From Industry» Health Canada warnings» Trials: Flame, Hope 3, Leader, Sprint Disclosure RxFiles Academic Detailing Receives grant from Saskatchewan Health through Saskatoon Health Region to provide academic detailing in Saskatchewan Government funding arm s s length Receives revenue from sale of book, app, and website subscriptions from outside Saskatchewan Not for profit, not for loss 3 No industry funding What s New Updated at: WWW.RxFiles.ca New Guidelines 2016» AHA 16 Update Heart Failure» AHA 16 DAPT Therapy with CAD» IAS USA 16 Adult HIV» Canmat 16 Canadian Major Depression» CCS 16 Canadian Dyslipidemia» CHEP 16 Hypertension» See www.rxfiles.ca or RxFiles Plus APP for updated drug charts. Go to 6 http://shirp.usask.ca from Drug Info tab

Tools For Practice 7 INFO POEMS $85/yr Read by QxMD Your personalized medical journal 10

New From the Sask Drug Plan Top 10 Prescribed Drugs-SPDP 1. Rosuvastatin 2. Atorvastatin over 100,000 people on statins 3. Levothyroxine concern with heart & osteoporosis 4. Metoprolol consider bisoprolol 5. Ramipril 6. Amlodipine use lower dose, switch, give HS 7. Rabeprazole aware of rebound hyperacidity 8. Venlafaxine less useful for mild depression 9. Amoxicillin? Viral, watchful wait, delayed Rx 10. Salbutamol Where is metformin, hydrochlorothiazide etc. Pantoprazole New Sask Full Formulary Amoxicillin + Clavulanate $23/10day Clavulin, generic Carvedilol $32/month Coreg, generic Escitalopram $25/month Cipralex, generic Fluticasone furoate $52 94/month Arnuity Ellipta Ipratropium + Salbutamol ~$42/month Combivent Respimat Levonorgestrel IUD $100/yr $17/month Jaydess Tecta, generic New Sask EDS & NIHB Prior Approval» NEW INHALERS» Incruse Ellipta (LAMA)» Tudorza Genuair (LAMA)» Seebri Breezhaler (LAMA)» Spiriva Respimat (LAMA)» Anoro Ellipta (LAMA/LABA)» Duaklir Genuair (LAMA/LABA) only SK EDS, not prior approval» Inspiolto Respimat (LAMA/LABA)» Ultibro Breezhaler (LAMA/LABA)» Breo Ellipta (LABA/ICS) 15» Onbrez Breezhaler (LABA) New Sask EDS» Breo Ellipta (fluticasone furoate/vilanterol) asthma» Cosentyx (secukinumab) for plaque psoriasis» Fibristal (ulpristal) for fibroids» Inflectra (infliximab) & Xeljanz (tofacitinib) for RA» Inspra (eplerenone) CHF EF<35%, NYHA II» Invokana, Jardiance & Komboglyze for diabetes» Myrbetriq (mirabegron) for urinary incontinence» Ofev (nintedanib) for idiopathic pulmonary fibrosis» Zaxine (rifaximin) for IBS NIHB

Alendronate New NIHB Full Formulary Ipratropium + Salbutamol $265/yr $190/yr ~$42 Fosamax, generic Fosavance, generic Estradiol $510/yr Climara Pro Ethinyl estradiol+norethindrone $295/yr Lolo Moxifloxacin $28/10 days Avelox, generic Risedronate $260/yr Actonel, generic Solifenacin $25 Vesicare, generic Tolterodine $27 Detrol LA, generic Combivent Respimat 19 New NIHB Prior Approval» Invokana, Jardiance & Komboglyze for diabetes» Fosrenol (lanthanum) Phosphate binder» Inflectra (infliximab) for rheumatoid arthritis BIOSIMILAR» Latuda (lurasidone) for schizophrenia» Monurol (fosfomycin) for UTI» Pennsaid (diclofenac) topical NSAID New From the Industry Health Canada Approved: non formulary» Brenzys (etanercept)» Brivlera (brivaracetam) for seizures» Bydureon (exenatide), Invokamet (canagliflozin & MF), Trulicity (dulaglutide) & Xigduo (dapagliflozin & MF) for diabetes» Descovy (emtricitabine & tenofovir alafenamine) for HIV? safer on bone & kidney» Epclusa (sofosbuvir & velpatasvir) & Sunvepra (asunaprevir) for hepatitis C 21 22 Health Canada Approved: non formulary» Fetzima (levomilnacipran) for depression» Invega Trinza (paliperidone) depot q3 months for schizophrenia» Lunesta (eszopiclone) for sedation» Natesto nasal testosterone gel» Praluent (alirocumab) & Repatha (evolocumab) PCSK9 inhibitors for cholesterol» Praxbind (idarucizumab) reversal agent for dabigatran» Striverdi Respimat (olodaterol) for COPD» Viberzi (eluxadoline) for IBS D» Zerbaxa (ceftolozane with tazobactam) for infections 23 New Generics with Price Reductions» Azilect (rasagiline)» Celebrex (celecoxib)» Inflectra (infliximab)» Keppra (levetiracetam)» Lyrica (pregabalin) Nexium (esomeprazole)» Nasocort (triamcinolone) nasal» Nasonex (mometasone) nasal» Sublinox (zolpidem) 24» Tecta (pantoprazole)

New Pan-Canadian Generic Drug Pricing -18 agents in total (4 new additions)» Donepezil» Ezetimibe» Quetiapine» Zopiclone Previously: amlodipine; citalopram, venlafaxine; clopidogrel; gabapentin; metformin; olanzapine & ramipril. PPI s: omeprazole, pantoprazole, rabeprazole; Products with Price Increase» Aventyl (nortriptyline)» Anafranil (clomipramine)» Combivent (Ipratropium + salbutamol) NEBS Statins: atorvastatin, rosuvastatin, simvastatin; 25 26 New OTC» Olex (omeprazole 20mg)» Nexium 24hr (esomeprazole 20mg)» Nasocort Aq (triamcinolone)» Hydrocortisone 1% cream & ointment» Advil 12hr (ibuprofen 600mg MR) 27 New From Health Canada» ADHD drugs: suicidal thoughts/behaviours» Atarax (hydroxyzine), domperidone: prolong QT, sudden cardiac death» Avonex (interferon): nephrotic syndrome» Codeine: avoid in kids, respiratory depression/fatal» Donepezil: rhabdomyolysis, neuro malignant syndrome» Flozins (SGLT-2) : diabetic ketoacidosis; acute kidney injury (FDA)» Gluconorm (repaglinide) : Contraindication with Clopidogrel» Lamasil: Contraindication if active or chronic hepatitis» Metoclopramide: EPS in children» Tecfidera (dimethyl fumarate): angioedema, PML» Uloric (febuxostat): Dress skin reaction New From RxFiles» Acetaminophen max daily doses; max 5 days pain, 3 days fever.» Diclofenac lower max of 100mg/day since CV risk with this NSAID» Ibuprofen: heart attack, stroke at high doses (2400mg/d) 30

CFP Aug 2016 New from RxFiles» Angina Treatment Chart» Drug Interactions Chart» DAPT/Triple Therapy Chart» Trials: info on RxFiles website» Empa-Reg (empagliflozin) for diabetes» Flame (Ultibro vs Advair) for COPD» Hope-3 (Crestor &/or Atacand Plus) for CV risk» Leader (liraglutide) for diabetes» Pegasus (ticagrelor) for Post-MI» Sprint (intensive BP control 120 vs 140) Is a LAMA + LABA Ultibro better than LABA + ICS Advair in COPD? Flame NEJM 2016, n=3362 over 52 wks Trial Summary» Indacaterol+Glycopyrronium daily Ultibro Breezhaler $98 vs Salmeterol+Fluticasone twice daily Advair $162/month» N= 3,362 over 52weeks, 4 week run-in period» ALL (mild, moderate, severe) exacerbations (ARR 0.5, p<0.001), but NOT severe exacerbations» pneumonia (ARR 1.6, NNT=63, p=0.02), influenza (ARR 1.3, NNT=77, p=0.026), & oral candidiasis (ARR 3.0, NNT=34, p<0.001)» Not reduced mortality, but effective, safer & less costly In intermediate CV risk patients is it better to give Crestor 10mg/day &/or Atacand Plus 16/12.5mg? Hope-3 NEJM 2016, n=12,705 over 5.6yrs Hope-3 Lipid Trial Summary» Rosuvastatin 10mg CRESTOR 10mg/day was more effective than placebo in reducing the LDL from 3.3 to 2.3 mmol/l - first coprimary outcome (composite of cardiovascular death, nonfatal MI, or nonfatal stroke), NNT=91 in 5.6 years, HR = 0.76, 95% CI 0.64 to 0.91 - secondary coprimary outcome (first coprimary outcome + heart failure, resuscitate cardiac arrest, or revasc), NNT=73, HR=0.75, 95% CI 0.64 to 0.88» Mortality not reduced» more risk of cataract surgery NNH=143, muscle pain or weakness NNH=91, DVT/PE NNH=346 / 5.6 years.

Hope-3 Trial Summary» For intermediate CV risk patients: In patients with intermediate CV risk without CVD, adding rosuvastatin 10mg/d may provide more benefit than adding candesartan+hctz. Does liraglutide (Victoza) reduce cardiovascular outcomes in high CV risk patients with diabetes? NEJM 2016, n=9,340 over 3.8yrs In subgroup of patients with SBP > 143.5mmHg, adding candesartan 16mg/d + HCTZ 12.5mg/d may be beneficial. But more dizziness, lightheadedness & hypotension. (BP 138/82 reduced to 134/79 or 128/76) Leader trial (liraglutide $690/3months)» GLP1-Analogue reduces A1C from 8.7 to 8.3%» N=9,340; high CV risk; many on MF & insulin» 1 st occurence of death from CV, nonfatal MI or stroke NNT=53/3.8yrs» Mortality reduced, but not non-fatal MI/stroke» Acute gallbladder dx NNH=84» D/C due to adverse event NNH=46»Nausea, vomiting, diarrhea» Lost about 2.3kg & lowered SBP ~1.2 mmhg Is intensive blood pressure lowering to 120 better than 140? SPRINT NEJM 2016 n=9,361 over 3.3yr Sprint SPRINT Research Group. A randomized trial of intensive versus standard bloodpressure control. N Engl J Med. DOI: 10.1056/NEJMoa1511939 (Nov 26, 2015) Xie X et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review & meta-analysis. Lancet Nov 7, 2015.

Sprint Open label, terminated early, BP meds required 2.8 vs 1.8 BP 140/78 to 135/76 or 122/64 BP 140/78 treated to 135/76 or 122/69 Only 17% of US hypertensives would be represented by the trial partly because NO diabetes, stroke or acute heart failure patients included in this trial Automated BP in ideal setting (120 equals? 135 or > ) unattended, after 5min rest More Serious Adverse Events NNH=45 -hypotension, syncope, renal injury More CKD progression Intensive treatment in SELECT (>15% CV risk) pts: -reduced CV events & all cause mortality NNT=63, but significant serious adverse events occur 46 Questions??? Interested to discuss Jensenb@rxfiles.ca 306 655 8506 47