New Drugs The Good The Bad and the

New Drugs The Good, The Bad, and the Worthless Bill Origer MD OAFP 2015

Disclosure • No commercial financial support • After the talk, you will understand why woriger@samheath. com 541 -768 -4558

Disclaimers • • • Not a comprehensive study of diseases All is based on high quality published research References & boring details available Prices are approximate & may vary New information is continuous, anything could change, and I could be wrong

How did I get into this? ? • • Private practice Albany, OR 1977 - 1996 Variety of administrative jobs since then Been doing drugs with the state since 2006 Oregon Health Resources Commission 2006 -11, – Chair, Pharmaceutical Subcommittee ‘ 08 -11 – Oregon Preferred Drug List Committee 2010 • Oregon P & T Committee, Chair, 2012 -15 • My credibility in this world is the strength of evidence

Another disclaimer • Research applies to populations • Physicians treat individuals • Medicine has thousands of unique & unusual people and situations • Do the right thing for each patient • There are times when a 4 th or 5 th choice is the best option for that patient

Using this in Health Care Reform • Lowers cost – avoid overpriced brands • Using evidence to improve outcomes • Avoid things that do not work

New evidence on old stuff

Same efficacy & toxicity within category May be differences in side effects, dosing, duration of action, price • • • • Alzheimer’s drugs ACE Inhibitors Angiotensin receptor blockers ADHD stimulant drugs Inhaled steroids for asthma Inhaled nasal steroids β agonists for asthma α blockers for PBH 5 α-reductase inhibitors- BPH Estrogens for menopause Oral contraceptives Muscle relaxants NSAIDS • Benzodiazepine receptor agonist sedatives • Opioids for long term use • H 2 blockers • PPIs • Statins (adjusted for potency) • Triptans for migraine • Anticholinergics & others for overactive bladder • DPE-5 inhibitors for erectile dysfunction • 2 nd generation antidepressants

Nicotine Replacement – 8 weeks. Period • Duration of nicotine replacement therapy– 8 weeks same as 24 or 52 weeks. • Only good end-point: continuous cessation at 1 yr. • Cluttered with lots of meaningless secondary & post-hoc end points. Who cares if the time to relapse was a few days different from one treatment to another? • JAMA Internal Medicine online 2/23/2015

Long Term Opiates Evidence of Safety & Effectiveness This page is intentionally blank

Long term Opiates No Data Proving Benefit There are no studies of opioid vs placebo or non-opioid therapy lasting > one year on outcomes related to pain, function, or quality of life. Most randomized studies <6 weeks Annals of IM online 1/13/2015

Long Term Opiates Adverse Effects Increased risk of Death – 16, 235 opioid OD deaths US 2013 Overdose, more w higher doses Fractures MI, especially with high doses Rx for testosterone & erectile dysfunction Motor vehicle accidents Addiction & diversion CDC mortality data 2015; Annals of IM online 1/13/2015

Comparison No evidence of risk or efficacy difference among products Minimal difference in efficacy, no difference in adverse effects between short acting narcotics given on schedule and timed release products Oregon P & T Committee evaluation March 2014

Lunesta FDA warning • The moth* bites back – FDA warning on Lunesta. Eszoplicone is a benzodiazepine receptor agonist with a long half -life - a good reason not to use it. • 3 mg dose can cause impairment of driving, memory, and coordination for up to 11 hours. • FDA warning - starting dose 1 mg for both men & women. *The Lunesta advertisement “butterfly” is a nocturnal moth Actias luna native to the eastern US. The adult lives 10 days, does not eat, mates, & dies. It’s a good mascot for a drug that should only be used short term. • The Medical Letter 6/9/2014

Tamiflu & Influenza • Neuraminidase inhibitors do little for influenza Early studies (1999) showed minor benefit – reducing recovery time by a day. • Roche and GSK suppressed publication of company research • 4½ year legal battle, the Cochrane Collaboration and BMJ obtained 160, 000 pages of documents. The results? Same as in 1999. • Oseltamivir reduced duration by 19 hours in adults, 29 hours in kids. • Zanamivir reduced duration by 14. 4 hours in adults, none in kids. • No reduction in sinusitis, pneumonia, hospitalization, or death by either • Modest effect if used for prevention, NNT 30 -50. • Contradicts recommendations from the CDC, WHO, American Academy of Pediatrics and others who should have known better. • >$7 billion worldwide since 2003 stockpiling this stuff, shelf-life 5 -7 yrs. • The Medical Letter 10/8/1999; CDC Emerging Infectious Diseases 10/1999; BMJ 4/12/2014

Tramadol –why it does not always work • It seemed like such a good idea…. • Parent molecule is SNRI, similar to venlafaxine, not a narcotic, and • Metabolized by CYP 2 D 6 into desmethyltramadol, which binds to μ opioid receptors, but…

Tramadol • Expression of 2 YP 2 D 6 is highly variable • 7% of Caucasians have no CYP 2 D 6 • 10% of Italians, Portuguese, and Greeks, and ⅓ of Arabians are ultra-rapid metabolizers & produce a high level of the drug • Drugs inhibiting CYP 2 D 6 will prevent formation of the active metabolite: fluoxetine, paroxetine, sertraline, bupropion, duloxetine, and cimetidine • JAMA Internal Medicine 12/8/2014

Dabigitran (Pradaxa) Unsafe at any speed

Dabigitran (Pradaxa) • Poor absorption 3 -7% • Two-step activation, hydrolysis, then glucuronide formation. • Major accumulation with declining renal function. • Small changes in any one of these variables can cause 500% fluctuation in serum levels on the same dose. • BMJ 7/26/2014

Dabigitran (Pradaxa) Fluctuating serum levels can produce over or under anticoagulation. Data from the manufacturer - optimal serum level between 40 - 200 ng/m. L No commercially available test. This contradicts the advertising hype that promised no testing. JAMA 3/10/2015

Dabigitran (Pradaxa) Rivaroxiban (Xarelto) similar – wide variations in plasma concentrations Apixaban (Eliquis) has not had this problem JAMA 3/10/2015

Lipid Guidelines • Lipid guidelines overestimate cardiac risk. • Harvard researchers applied the risk to a known population, 27, 542 women aged 45 -79 from the Women’s Health Study • Lipid measurements, + 10 years of FU for cardiac events • The calculator overestimates CV risk by at least 50%. • Editorial criticized the American College of Cardiology and the American Heart Association and recommends prompt revision of the guidelines to conform to published evidence. • JAMA IM 12/2014

Antiepileptic Drugs for Neuropathic Pain • Small benefit at best. Ten Cochrane reviews of 91 randomized double-blind studies of 17, 955 ambulatory adults with neuropathic pain or fibromyalgia • Only gabapentin & pregabalin showed reduced pain w diabetic or postherpetic neuropathy. Small benefit: 7 -25% of patients had pain reduction of ≥ 50% • Pregabalin alone helped fibromyalgia, small benefit: 7 -11% of patients had a 50% reduction in pain. • No benefit or poor quality studies: clonazepam, phenytoin, carbamazepine, lamotrigine, oxcarbazepine, topiramate, and lacosamide. • Side effects: 30% of patients withdrew by 12 weeks. Adverse effects in 80% of patients, usually dizziness and somnolence. • JAMA 7/9/2014

The Good

This week in 1952 • Measles declining, 29, 518 cases this week, season total 439, 297 • Polio at its lowest, 74 cases this week, seasonal total 28, 692; this time last year 33, 393 • Anthrax: 4 human and 327 animal cases this week • Four botulism deaths: 2 each in Oregon & California • Rabies: 191 animal cases, one human death in Tennessee • Scarlet fever: 2, 916 cases, 82 cases in a hospital in Massachusetts • Malaria: 41 cases in 20 states. • Typhoid: 28 cases in 16 states. • Meningococcal infections: 107 • Brucellosis & encephalitis: 27 each • Tularemia: 18; trichinosis: 5 • MMWR 4/19/1952

Good OTC Nasal Steroids • Triamcinolone acetonide (Nasacort Allergy 24 HR) • Fluticasone propionate (Flonase Allergy Relief) • Same as Rx Drugs, but only $12/bottle • Rx brand names discontinued; still are Rx generics • The Medical Letter 3/30/2015

Generic celecoxib (Celebrex) • 2 generic brands of celecoxib – Teva & Mylan • Price still >$2/pill for 200 mg, >$3/pill for 400 mg • But who cares, since it is no better or safer than other NSAIDs • BMJ 6/1/2002; FDA Bulletin 5/30/2014; Good. Rx. com 3/31/2015

MRSA IV, Inpatient Skin infections only Glycopeptides • Vancomycin $115 • Dalbavancin – Dalvance $2980 • Oritavancin– Orbactiv $2900 • Telavancin– Vibativ $2163 Oxazolidinones • Linezolid – Zyvox $2789 • Tedizolid phosphate – Sivextro $1410 Others • Ceftaroline fosamil – Teflaro $1260 • Daptomycin – Cubicin $2478 7 days Single dose 7 days 10 days 6 days 5 days 7 days The Medical Letter 1/5/2015 – cost for shortest recommend treatment

Hepatitis C The Good • Much better drugs – High efficacy >90% – Low toxicity/side effects < 5% • Off the chart prices, so must select those most likely to benefit • Treating all DMAP open card Hep C patients would double entire drug budget • Only 5 -20% will develop cirrhosis over 20 years

Hepatitis C Priority Oregon Health Plan Open Card • Stage 3 and 4 fibrosis without decompensated cirrhosis • Those receiving an organ transplant • Patients with extrahepatic manifestations, including: Type 2 or 3 cryoglobulinemia with end‐organ manifestations (vasculitis) Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis • Patients prescribed medication by or in consultation with a hepatologist or gastroenterologist with experience in Hepatitis C. Oregon P & T Committee 3/26/2015

Hepatitis C Drugs • Harvoni (ledipasvir and sofosbuvir) – Genotype 1 • Sovaldi (sofosbuvir) – Genotypes 1, 2, 3, 4 • Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) – Genotype 1 • Cost variable- $50, 000 - $120, 000

Naloxone Auto injector • Brand Evzio, kit for patient use in narcotic OD. Two prefilled auto-injector syringes containing 0. 4 mg naloxone • About $250, similar to Epi-pen, another cheap drug in an expensive package. • Cheaper, but off-label: 0. 4 mg of injectable naloxone (about $20) used intranasally. • The Medical Letter 6/9/2014

Placebo for cough in infants & toddlers • Placebo works for cough in infants and toddlers • Randomized controlled blinded study of nonspecific cough in 125 children ages 2 -47 months. • Agave nectar cough syrup compared to placebo & no treatment. Agave - sweet taste & consistency similar to honey. • Endpoints: parent questionnaires rating the severity, frequency, and bothersomeness of cough, congestion, and rhinorrhea, quality of sleep of child and parent, and a combined score of effectiveness. • Placebo and agave nectar- same improvement, all scores: 1. 5 - 3 out of 7 points. • Both better than no treatment. • JAMA Pediatrics October 2014

Metoprolol = carvedilol • Metoprolol is equal to carvedilol in preventing mortality in CHF patients. • Danish retrospective review. Heart Failure Registry of 11, 664 CHF patients • Mean age 69. 3 years, 71% male. Average followup 2. 5 years. All had an EF <40%. • Outcomes: all-cause mortality and CV mortality. • Mortality 18% for both groups. • Study limits: retrospective not randomized. JAMA IM 8/2014

The Bad

Alzheimer’s Rip offs • Aricept 23 mg same modest efficiency, but more side effects $475/mo. Generic $12/mo • Forest Labs planned to discontinue Namenda 5 & 10 mg & force switch to Namenda XR 7 -14 -21 -28 mg • Patent on 5 & 10 mg expires in Oct 2015 • Switch stopped by court order • Memantine hydrochloride extended-release + donepezil hydrochloride (Namzaric) approved, not marketed. Worthless combination. • Oregon P & T Committee, August 2014; FDA news Drug Daily Bulletin

Diabetes • (SGLT 2) inhibitors Induce renal glycosuria • Osmotic diuresis, dehydration, weight loss, renal failure, and hyperkalemia. • Genital mycotic infections – ♀7. 6% RR 527%. ♂, 2. 7% vs 900%. • Dapagliflozin (Farxiga) empagliflozin (Jardiance) dapagliflozin + metformin hydrochloride (Xigduo XR) & other combinations • BAD IDEA • Oregon P & T Committee 3/2015

Suvorexant (Belsomra) for Insomnia Bad Idea • New category orexin receptor agonist • Orexin neurons in lateral hypothalamus – Active during wakefulness & silent during sleep – Loss of orexin neurons in narcolepsy (cataplexy & hypnogogic hallucinations) • Drugs block orexin neuropeptides from binding to receptors • Doses: 5, 10, 15, 20 mg, $10/pill • Time to T MAX 1 -2 hrs fasting, 3 hrs fed • Long half life - 12 hrs

Suvorexant (Belsomra) Efficacy: dose related, lower value for 10 mg Sleep onset: 2 -20 minutes < placebo Sleep duration: 15 -40 min > placebo Adverse effects: Somnolence/daytime sleepiness 13 -20% Narcolepsy sx: (0. 013 -0. 018) 26 -36 x expected rate Slow onset, long half-life, and might induce narcolepsy Seems like a bad idea The Medical Letter 2/2/2015; Lancet Neurology 5/2014; Biologic Psychiatry 10/23/2014

The Worthless

Particularly Worthless • Droxidopa (Northera) for orthostatic hypotension • No study showed efficacy beyond 2 weeks of treatment • 100 -600 mg tid • $1, 000 - $8, 800 monthly cost • Oregon P & T Committee; Good. Rx

Still Worthless Ω- 3 • Omega-3 -carboxylic acids (Epanova) • EFFICACY —No convincing evidence that fish oil supplements either prevent cardiovascular disease or improve outcomes in patients who already have it. • Medical Letter Treatment Guidelines Jan 2014

Niacin Bombs Out • ASCVD prevention– increased risk no benefit. 26, 673 adults with vascular disease - niacin vs placebo added to statin. • Primary endpoint: 1 st CV event- nonfatal MI, coronary death, stroke, or revascularization • Men and women ages 50 -80, previous MI, stroke, peripheral artery disease, or diabetes with evidence of coronary artery disease. • No benefit in preventing CV events • Increased the rate of diabetes, poor diabetic control, infections, serious bleeding, plus GI, musculoskeletal, & skin side effects. • NEJM 6/17/2014

Long acting Injectable Paliperidone • Injectable paliperidone (Invega Sustenna) vs haloperidol inj. • 311 adult patients with schizophrenia. Median FU 466 days. • Primary end point: efficacy failure, psychiatric hospitalization, crisis requiring stabilization, or increase in outpatient visits. • Failure rates similar 32 -34% • Secondary outcomes: adverse medication events • No differences in involuntary movements, tardive dyskinesia, or Parkinson’s symptoms. Haloperidol patients - more motor restlessness (akathisia. ) • Paliperidone pts ↑ 6. 04 kg @ 24 months, haloperidol pts ↓ 3. 88 kg. • Paliperidone $859/month, haloperidol $32. • JAMA 5/21/2014, The Medical Letter Treatment Guidelines 6/2013

High dose Flu Vaccine Tiny Benefit • After age 65, the immune system declines. In theory, a higher dose flu vaccine might work better • 31, 989 patients mean age of 73 were randomized to receive either a standard flu vaccination or a high-dose vaccination • Endpoint: laboratory confirmed influenza • Rates: 1. 9% with standard vaccine, 1. 4% with high-dose vaccine • Absolute risk reduction 0. 5%. NNT 200 • Complications such as pneumonia were rare but same in both populations • Bottom line: 199 out of 200 elderly people will not benefit from the high-dose vaccine NEJM 8/14/2014

Luliconazole cream (Luzu) for tinea • Overpriced worthless new drug: luliconazole cream (Luzu) for tinea. 3 double blind studies, cure rates of 21 -27%. • Cost $380 for 2 weeks • Older OTC drugs such as clotrimazole, miconazole, & terbinafine, cure rates of 4060% and cost < $10. • Who buys this stuff? • The Medical Letter 6/23/2014; Journal Family Practice 1/2002

Worthless Tavaborole 5% (Kerydin) • Topical for onychomycosis $491. 20 for 4 cc ($3, 481/oz. ) Once/day 48 weeks • Complete cure(clinical & mycological) 6. 5 -9. 1% • And the spin: a novel endpoint “Almost complete” cure 15. 3 -17. 9% • The Medical Letter 3/2/2015 • Suggests other endpoints: almost non-fatal MI, almost successful CPR…

Me too • Avanafil (Stendra) another PDE-5 inhibitor for ED • Esomeprazole strontium (Anneal) The 9 th PPI – generic $60/mo; brand at $200/mo. Why? – OTC Prilosec & Prevacid $18/mo. • Indomethacin (Tivorbex) 20 & 40 mg – high rate of GI side effects. – “There is no good reason to use indomethacin in any dosage for treatment of mild to moderate pain. ” • Finafloxacin otic suspension 0. 3% (Xtoro) • Fluticasone furoate inhalation powder (Arnuity Ellipta) similar price to Flovent • The Medical Letter 5/12/2014, 7/21/2014

Me too, Diabetes • • GLP 1 agonists Albiglutide (Tanzeum) weekly inj $326/mo Dulaglutide (Trulicity) weekly inj $488/mo Liraglutide (Saxenda) – also approved for “chronic weight management” not available yet, recycled Victoza (daily inj)

Brimonidine gel (Mirvaso) for Rosacea Topical -2 adrenergic blocker Topical vasoconstrictor Temporarily reduces redness No effect on pustules or pathology of disease • About $300 for 30 grams • • • The Medical Letter 10/14/2013

Inhaled Insulin (Afrezza) • • Microspheres of carrier, rapidly absorbed in the lungs Only regular insulin, no long-acting formulation 2 sizes, 4 or 8 units. Multiple inhalations for larger doses Reduced A 1 C by half compared to insulin aspart (Novo. Log) (0. 2% versus 0. 4%. ) Patients with good control (A 1 C <7%) also half (13. 8% versus 27. 1%. ) • 25% of patients w cough, reduces FEV 1 in normal patients 40 cc, significance unknown. Contraindicated with asthma, COPD, & other lung conditions. Long-term safety & efficacy unknown • Cost: 2 -5 X Novo. Log. Save your breath. Clinical Therapeutics 8/2014; Afrezza package insert; Price: Goodrx. com 2/27/2015

Roflumilast (Daliresp) • Oral drug added to long-acting beta agonists and inhaled steroids to prevent COPD flares. • Mechanism of action is similar to theophylline. • Reduced exacerbations by 13. 2% vs placebo. Defined as an episode requiring steroids, hospital admission, or was fatal. • 1 yr study, placebo patients had 0. 927 exacerbations/yr vs 0. 805/yr w drug. Prevents 0. 122 exacerbations/yr. IE prevents 1 exacerbation over 8. 19 years. • Reduces hospitalizations by 0. 075 exacerbations/yr vs placebo. 13. 15 yrs to prevent 1 hospitalization, if the patient lived that long. • Cost about $300/mo. $29, 484 to prevent one exacerbation; $48, 000 to prevent one hospitalization. • 67% of patients receiving roflumilast w adverse drug effect. • Lancet online 2/13/2015

Vytorin 10 mg ezetimibe + 40 mg simvastatin • IMPROVE IT study 18, 144 high risk patients w acute STEMI, NSTEMI, or unstable angina w previous MI, previous CABG, or diabetes. • Randomized to simvastatin 40 mg or Vytorin daily. Add-on, not a substitute for statins. • Endpoints: composite of CV death, nonfatal MI or stroke, hospitalization for unstable angina, or coronary revascularization. Duration 7 years • Absolute risk reduction was 2%, from 34. 7% to 32. 7%. NNT 50 to prevent one event over 7 years. • Vytorin is $210 per month, $2, 520 per year. High-dose atorvastatin 40 or 80 mg is $17 per month, $204 per year. Hype warning: Full data not published. Small benefit to a narrow population. Remain skeptical. AHA Scientific Sessions, 11/19/2014. Prices: good Rx. com

Intra articular Hyaluronic Acid –wide use, little benefit • Meta-analysis, Archives IM 2012 - minimal clinical benefit • American Academy of Orthopedic Surgeons 2013 Practice Guideline: “We cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee. ” • 2012 Medicare Part B paid for 1, 161, 924 intra-articular hyaluronic acid injections. Mean rate 39 injections /1000 • Half the national rate in the Portland area • 10% below the national rate in Bend & Eastern Oregon • 10% above the national rate in Eugene, Albany, & Corvallis • 2 -3 times the national rate in Salem area JAMA Internal Medicine 8/25/2014

Vitamin D USPSTF recommends against screening for vitamin D deficiency Current evidence is insufficient to demonstrate benefit (or harm) of screening for vitamin D deficiency in asymptomatic adults. • Annals of IM 11/25/2014

And finally…. . The Strange

Contrave Diet Pill, A Strange Combination • Do believe in magic? Another diet pill So far no pill for weight loss is both safe and effective long-term. , • Contrave, combines opioid antagonist naltrexone with the antidepressant bupropion. • Weight loss of 3 -5% more than placebo at 1 yr. No longer studies. • Most previous drugs lost effectiveness 2 nd year. • Side effects: ⅓ of patients had nausea. Also, headache, constipation, dizziness, and dry mouth. • Interacts with inhibitors of CYP 2 B 6, such as antidepressants, antipsychotics, beta blockers, ticlopidine, and clopidogrel. • Naltrexone can be used only by the portion of population not on Vicodin. • The Medical Letter 11/10/2014

Strange FDA Approval • Peramivir (Rapivab): IV drug for influenza • Neuraminidase inhibitor, similar to oseltamivir (Tamiflu) • FDA approved only for treatment of uncomplicated influenza • Not approved for use in hospitalized or critically ill patients • Did not significantly reduce the time to clinical resolution in hospitalized patients • 600 mg IV once $950. 00 • Why? ? • The Medical Letter Feb 2, 2015

Zecuity Sumatriptan Battery Powered Patch • “Coming soon” since 2001 • Efficacy same as oral

Zecuity

Adasuve, inhaled loxapine for acute agitation

Adasuve, inhaled loxapine for acute agitation in schizophrenia & bipolar • 1 st generation antipsychotic from 1975 • Generic tabs, about $1. 50, rarely used • Single use $140 device. Vaporizes 10 mg of the drug, inhaled, absorbed via lungs • Downside: bronchospasm and respiratory distress, especially in patients with asthma or COPD.

Adasuve A special safety program is required. (I did not make this up, honest!) 1) Ask the patient if he/she has asthma or COPD or is taking a medication for either, and/or check records 2) Examine for respiratory abnormalities 3) Open Adasuve foil packet & remove inhaler 4) Pull tab to activate. A green light will go on when it is ready. Administer in 15 minutes, or the battery dies 5)If the light goes out, it will not work, so open another

Adasuve 6) Patient exhales fully to empty the lungs 7) Patient inhales a steady breath through the mouthpiece 8) After full inhalation, patient holds breath 10 seconds. 9) If inhalation successful, green light goes out. It the light is still on, repeat with same inhaler. 10) Monitor, including chest auscultation every 15 minutes for one hour. 11) If bronchospasm occurs, treat with short acting beta agonist. May administer once in 24 hours

Adasuve How to do this with an acutely agitated psychotic patient is not explained Simpler alternative: injectable Haldol, $1. 90/dose. • Adasuve package insert & website; The Medical Letter 4/14/2014, price: Goodrx. com.

Vitamin D does not reduce the adverse impact of earthquakes on healthy adults. • Vitamin D is purported to benefit mental health. • A series of earthquakes started 9/4/2010 in Christchurch, NZ lasting months, widespread destruction, no fatalities. • The VIDARIS study of vitamin D and respiratory infections was underway in Christchurch at the time • 322 healthy adults were randomized to high-dose Vit D or placebo for 18 months from Feb 2010 - Nov 2011 • 308 participants completed an earthquake impact questionnaire about psychological after effects, comparing vitamin D users to placebo users • The incidence of fatigue, stress, anxiety, and insomnia did not differ between the vitamin D and placebo groups. BMJ 12/15/2014