how do you spell that? chris knight, md, facp [email protected] twitter: @clknight

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

[email protected]

Twitter: @clknight

The Twitter Experiment

Tweet questions to me:

@clknight

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!

What this talk isn’t

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

Brand new drugsBrand new drugs

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


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


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

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


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 pollakiuriahttp://pmid.co/23850055

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 remissionhttp://pmid.co/23964932; http://pmid.co/23964933

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 treatmentshttp://pmid.co/23152839

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 unclearhttp://pmid.co/22901346

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


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 estrogenshttp://pmid.co/23984673

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

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

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

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


Florbetapir to image Alzheimer’s

•18F 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

Drug updates for 2013Drug updates for 2013

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)


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/23592242; http://pmid.co/23385271; http://pmid.co/23557493

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/21307137; http://pmid.co/23440284

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


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


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


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


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)


Cautions and disappointmentsCautions and disappointments

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

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

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

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


The PharManure listThe PharManure list

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

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.

Things that make me grumpy

•Generic manufacturers and the FDA

Generic manufacturers and the FDA

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


[email protected]

how do you spell that? chris knight, md, facp [email protected] twitter: @clknight

Documents

clknight slide

co23863050 slide

co23850055 slide

grumpy slide

week course slide

remission patients

preceding slide new

treated patients