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How do you spell that? Chris Knight, MD, FACP

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Presentation on theme: "How do you spell that? Chris Knight, MD, FACP"— Presentation transcript:

1 How do you spell that? Chris Knight, MD, FACP cknight@uw.edu Twitter: @clknight

2 The Twitter Experiment Tweet questions to me: @clknight

3 Disclosure I am NOT a pharmacist or pharmacologist I don’t work for or knowingly invest in pharmaceutical or medical device companies I do work for medical journals, UpToDate, CME publishers, and the National Board of Medical Examiners, but I won’t be promoting them today. I will bring up a few off-label uses—can’t do a talk on new drugs without that!

4 What this talk isn’t afatinib alogliptin bazedoxifene canagliflozin dabrafenib dolutegravir mipomersen ospemifene pomalidomide radium 223 riociguat simeprevir sofosbuvir tilmanocept Tc99m trametinib vilanterol vortioxetine

5 What we will be talking about Interesting new drugs (including a few from the preceding slide) New uses for old drugs Important drug updates Drugs that make me grumpy

6 Brand new drugs

7 http://pmid.co/23607594 Sofosbuvir for hepatitis C Oral inhibitor of HCV RNA polymerase Cure rates comparable to interferon (60-70%) when used with ribavirin alone; up to 90% when added to interferon Fewer adverse effects than interferon: less fatigue, insomnia, flu-like symptoms Best option for patients who can’t tolerate interferon $1000/dose = $84,000 for 12 week course

8 http://pmid.co/23907700 Simeprevir for Hep C genotype 1 Oral protease inhibitor, similar to telaprevir and boceprevir Improves cure rates from 30-50% to 70-80% when used with interferon for genotype 1 disease Advantages: once daily dosing, less anemia Disadvantages: 35% of patients have viral polymorphism (NS3 Q80K) that confers resistance $66,000 per 12 week course

9 http://pmid.co/23883378 Riociguat for pulmonary htn Oral guanylate cyclase stimulator, mimics effects of nitric oxide 12 week trial: improved 6-min walk distance by 30 meters compared with 6 meter loss in placebo arm Open label extension showed continued increase for another 12 weeks Benefit seen in both treatment-naive and previously treated patients

10 Radium-223 for prostate cancer Alpha-emitting (high energy, short range) calcium analog; 11.4 day radiologic half-life 3 month increase in median survival in patients with prostate cancer and bony metastases 6 month increase in time to first symptomatic skeletal event (e.g. fracture) Adverse effects less common than placebo arm http://pmid.co/23863050

11 Canaglifozin for diabetes SGLT2 inhibitor inhibits glucose uptake in renal tubule, causes glycosuria Compared with glimepiride in patients taking metformin: Similar reduction in hemoglobin A1C (0.8-0.9%) Lower rates of hypoglycemia with canaglifozin Higher rates of yeast infections with canaglifozin (7- 8% of men, 10-15% of women) Increased pollakiuria http://pmid.co/23850055

12 Vedolizumab for IBD Monoclonal Ab that selectively blocks lymphocyte trafficking in the gut (spares the brain) Studied in patients with UC and Crohn’s who had not responded to at least one other treatment (40- 60% had anti-TNF failure) Patients with UC: 47% initial response, of whom 40% had sustained remission Patients with Crohn’s: 15% initial response, of whom 40% had sustained remission http://pmid.co/23964932http://pmid.co/23964932; http://pmid.co/23964933http://pmid.co/23964933

13 Brimonidine for rosacea Topical alpha-2 agonist: causes vasoconstriction 50-60% of patients showed improvement in facial redness compared with 30-40% of placebo arm Adverse effects uncommon: most often flushing (10%) No impact on papulopustular manifestations No comparison with light-based treatments http://pmid.co/23152839

14 Vortioxetine for depression Potent SSRI with “multimodal” agonist/antagonist effects at serotonin receptors More effective than placebo, comparable to but not better than active controls (duloxetine, paroxetine) Maybe fewer sexual side effects than SSRIs but numbers are small Specific niche remains unclear http://pmid.co/22901346

15 Bazedoxifene/CEE for menopausal sx Combines a SERM (bazedoxifene) with estrogen Improves hot flashes/atrophic vaginitis Increases BMD (longest study 24 mos) No endometrial hyperplasia No apparent increase in DVT or breast cancer risk http://pmid.co/24093499

16 Ospemifene for atrophic vaginitis Another SERM Reduced dyspareunia compared with placebo Increased endometrial thickening, 40% increase in rates of DVT Black box warning for endometrial CA, stroke, DVT Contraindicated in women with history of DVT, stroke, MI No comparison with vaginal estrogens http://pmid.co/23984673

17 Ospemifene for atrophic vaginitis Another SERM Reduced dyspareunia compared with placebo Increased endometrial thickening, 40% increase in rates of DVT Black box warning for endometrial CA, stroke, DVT Contraindicated in women with history of DVT, stroke, MI No comparison with vaginal estrogens http://pmid.co/23984673

18 New cancer drugs Ibrutinib for relapsed CLL Regorafenib for metastatic colorectal cancer Dabrafenib for metastatic melanoma Trametinib for metastatic melanoma Afatinib for metastatic lung cancer Cabozantinib for metastatic medullary thyroid cancer Axitinib for advanced renal cell carcinoma

19 New cancer drugs: themes Therapies are now much more disease and mechanism specific than traditional cytotoxic agents Expect weird adverse effects Expect high cost Success of therapy may depend more on genotype of cancer than on phenotype of cancer

20 Ivacaftor for cystic fibrosis Specifically targets G551D mutation in CFTR receptor (4-5% of patients with CF) 161 patients randomized to placebo vs. ivacaftor twice daily, mean age 26 y/o 10% improvment in FEV1, 3 kg weight gain, 55% reduction in exacerbations Adverse effects lower in treatment group http://pmid.co/22047557

21 Crofelamer for ARV diarrhea Made from the sap of the Sangre de Drago tree Inhibits intestinal chloride channels (CF in a bottle) Minimal systemic absorption 17% clinical response rate in HIV patients with antiretroviral- induced diarrhea refractory to loperamide http://pmid.co/23863919

22 Ingenol mebutate for actinic keratoses Active ester in Euphorbia peplus (petty spurge) sap Placebo-controlled trial in 547 patients with AKs 42.2% clearance at two months with 2-3 days of treatment Local reaction peaked in 4 days, decreased in 8, resolved in 30 Much shorter course than 5-FU but more expensive http://pmid.co/22417254

23 http://pmid.co/22786606 Florbetapir to image Alzheimer’s 18 F radiolabeled ligand that binds to ß-amyloid plaques in vivo; lights up amyloid on PET scan Good correlation with autopsy studies 18-month study shows higher rates of cognitive decline in pts with high amyloid burden Requires skilled interpretation

24 Drug updates for 2013

25 Rifaximin for hepatic encephalopathy 120 patients in India with overt encephalopathy (mean MELD 24.6) followed during hospital stay Randomized to rifaximin 400 mg tid vs placebo All got lactulose titrated to 3 stools/day 76% reversal of encephalopathy vs 50% (NNT 4) LOS decreased by 2 days (5.8 vs 8.2) 24% mortality in rifaximin group vs 49% (NNT 4) http://pmid.co/23877348

26 New uses for ACE inhibitors Limited data: as good as beta blockers for migraine prophylaxis Improved walk time and quality of life with ramipril in claudication due to peripheral arterial disease ACE/ARB reduce rates of recurrent atrial fibrillation in meta-analysis including both paroxysmal AF and persistant AF post-cardioversion http://pmid.co/23592242http://pmid.co/23592242; http://pmid.co/23385271; http://pmid.co/23557493http://pmid.co/23385271http://pmid.co/23557493

27 Once-weekly exenatide GLP-1 agonist; microsphere formulation reaches steady state in 6-7 weeks of weekly dosing Multiple studies showing slightly greater A1C reduction (1.5% vs 1%) than with twice-daily exenatide, comparable to liraglutide Less nausea (14% vs 35%), more injection site reactions (5% vs 2.5%) Case control study: doubled risk of hospitalization for pancreatitis with both exenatide and sitagliptin http://pmid.co/21307137http://pmid.co/21307137; http://pmid.co/23440284http://pmid.co/23440284

28 Colchicine and the heart 282 patients with stable CAD on statins and ASA and/or clopidogrel randomized to colchicine 0.5 mg (?!?) daily vs placebo 3 yr followup: rate of composite endpoint (ACS, ischemic CVA, cardiac arrest) 5.3% on colchicine, 16.0% on placebo (NNT 11) Colchicine 0.5 mg qd-bid for 3 months (!) reduced persistent symptoms, recurrence, hospitalizations in patients with acute pericarditis http://pmid.co/23265346http://pmid.co/23265346; http://pmid.co/23992557http://pmid.co/23992557

29 New uses for steroids In sore throat treated with antibiotics, steroids increased likelihood of resolution within 24 hours Most studies used dexamethasone 8-10 mg IM, but one with 60 mg prednisolone also showed benefit No data in sore throat without antibiotic tx Also, adding methylprednisolone & vasopressin to epinephrine for in-hospital cardiac arrest protocol improved neurologic outcomes at discharge http://pmid.co/23076943http://pmid.co/23076943; http://pmid.co/23860985http://pmid.co/23860985

30 Cephalosporins in penicillin allergy Use of cephalosporins in patients with penicillin allergy causes concern Only a few cephalosporins (cefoxitin, cefaclor, cephalexin, cefadroxil, cefprozil) have penicillin-like side chains Overall risk of cross-reactivity is 1-3%; probably lower if one avoids cephalosporins listed above http://pmid.co/21742459

31 Probiotics to prevent C. difficile Loss of healthy gut microbiome is important in pathogenesis of C. difficile infection (CDI) Meta-analysis of studies looking at probiotics (Lactobacilli, Saccharomyces boulardii) for prevention of CDI in patients receiving antibiotics 66% relative risk reduction; if baseline risk 5%, NNT 33 to prevent once case of CDI Beware in immunocompromised patients, those with central lines: case reports of fungemia http://pmid.co/23362517

32 Fecal transplant for recurrent CDI First randomized trial of fecal microbiota transplant (FMT); numerous case reports of success 43 patients with recurrent CDI randomized to vancomycin, vancomycin + bowel lavage, or vancomycin - lavage - FMT FMT delivered through nasoenteral tube All but one of 16 patients in FMT group had cure without recurrence vs. 20-30% in other groups (P<0.001) http://pmid.co/23323867

33 Cautions and disappointments

34 Saxagliptin for diabetes: doesn’t work? RCT of 16,492 patients with type 2 DM randomized to saxagliptin 5 mg daily vs placebo for 2 years HbA1C levels lower in saxagliptin group (7.5-7.7% vs 7.8-7.9%) No reduction in major cardiovascular events (saxagliptin group slightly higher) Significant increase in heart failure hospitalization and hypoglycemia in saxagliptin group http://pmid.co/23992601

35 TMP/SMX unnecessary for cellulitis 146 patients with nonpurulent (max pustule 3 mm) cellulitis treated with high-dose cephalexin (1 gm tid-qid) and randomized to TMP/SMX vs placebo No difference in cure rates (85% vs 82%) No difference in adverse events (diarrhea, C. diff, nausea, rash, abscess formation, yeast infections) Supports IDSA guideline NOT to cover MRSA in nonpurulent cellulitis http://pmid.co/23457080

36 Dabigatran worse for mechanical valves 252 patients with AVR/MVR randomized to dabigatran vs warfarin adjusted to INR of 2-3 or 2.5- 3.5 (based on embolic risk) 12 weeks of follow-up: 5% risk of stroke and 2% risk of MI in dabigatran group vs. none in warfarin group Major bleeding: 4% in dabigatran group vs 2% in warfarin group; any bleeding 27% vs. 12%’ Reasons for differences are unclear; high dabigatran dose may have contributed to bleeding http://pmid.co/23991661

37 Autism risk from prenatal valproate Population-based study using massive Danish health system database: 655,615 live births included 5437 with autism spectrum disorder, 2067 with childhood autism 508 children exposed to valproate in utero: absolute risk 4.42% (HR 2.9) for autism spectrum disorder, 2.5% (HR 5.2) for childhood autism Association persisted after adjusting for maternal epilepsy http://pmid.co/23613074

38 The PharManure list

39 Drugs that make me grumpy Lucentis: Avastin tweaked and repackaged for wet macular degeneration at a 4000% markup Vituz: hydrocodone/chlorpheniramine for cough: not enough delirium from codeine alone? Liptruzet: cheap drug + drug that might not work = $165/month Intermezzo: is 1.75 mg zolpidem enough to help you forget that it costs $6.50 a pill? Promiseb: $150 for a 30-gram tube of prescription- strength non-steroidal cream for seb derm

40 Promiseb ingredients Promiseb Topical Cream is comprised of Purified Water, Isohexadecane, Butyrospermum parkii, Pentylene glycol, Ethylhexyl palmitate, Cera alba, PEG-30 Dipolyhydroxystearate, Bisabolol, Polyglyceryl-6 polyricinoleate, Tocopheryl acetate, Hydrogenated castor oil, Acifructol complex, Butylene glycol, Magnesium sulfate, Piroctone olamine, Allantoin, Magnesium stearate, Disodium EDTA, Vitis vinifera, Ascorbyl tetraisopalmitate, Glycyrrhetinic acid, Propyl gallate, and Telmesteine.

41 Things that make me grumpy Generic manufacturers and the FDA

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45 Pill color and adherence Retrospective analysis of 60,741 patients with private insurance who filled their first antiepileptic drug after 1/1/2002 Odds ratio for break in therapy (failure to refill on time) after change in pill color 1.27 (95% CI 1.04- 1.55) Similar results for shape change but nonsignificant due to fewer events http://pmid.co/23277164

46 Thanks! cknight@uw.edu


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