How do you spell that?
Chris Knight, MD, FACP
cknight@uw.edu
Twitter: @clknight
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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
• afatinib
• alogliptin
• bazedoxifene
• canagliflozin
• dabrafenib
• dolutegravir
• mipomersen
• ospemifene
• pomalidomide
• radium 223
• riociguat
• simeprevir
• sofosbuvir
• tilmanocept
Tc99m
• trametinib
• vilanterol
• vortioxetine
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 drugs
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
http://pmid.co/23607594
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
http://pmid.co/23907700
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
http://pmid.co/23883378
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
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 (78% of men, 10-15% of women)
• Increased pollakiuria
http://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 (4060% 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/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 treatments
http://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 unclear
http://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
http://pmid.co/24093499
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
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
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 antiretroviralinduced 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
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
http://pmid.co/22786606
Drug 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)
http://pmid.co/23877348
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
http://pmid.co/23265346; http://pmid.co/23992557
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/23076943; http://pmid.co/23860985
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
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
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
Cautions 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 2.53.5 (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
http://pmid.co/23613074
The 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 prescriptionstrength 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
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 1.041.55)
• Similar results for shape change but nonsignificant
due to fewer events
http://pmid.co/23277164
Thanks!
cknight@uw.edu