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Chris Knight, MD, FACP
[email protected]
Saturday, March 9, 13
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 drugs without that!
Saturday, March 9, 13
What this talk isn’t
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alogliptin
apixaban
avanafil
axitinib
bedaquiline
cabozantinib
crofelemer
enzalutamide
icosapent
Saturday, March 9, 13
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ingenol
ivacaftor
linaclotide
lomitapide
lorcaserin
mipomersen
mirabegron
ocriplasmin
pazopanib
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peginesatide
perampanel
tafluprost
taliglucerase alfa
teriflunomide
vismodegib
ziv-aflibercept
What we will be talking about
• Interesting new drugs
(including a few from the last slide)
• New uses for old drugs
• Important drug updates
• Drugs that make me grumpy
Saturday, March 9, 13
Brand new drugs
Saturday, March 9, 13
Lorcaserin for weight loss
• Selective (5-HT 2C) serotonin receptor agonist
• Valve disease thought to be mediated by 5-HT 2B receptors
• 47.5% of pts lost 5% or more of body weight after 1 year (20.3%
in placebo group); weight more likely to stay off if lorcaserin
continued after first year
• No excess valvular disease, pulmonary hypertension
• 40-50% discontinuation rate (not unusual for weight loss
trials): headache, nausea, dizziness most common
• FDA debating controlled substance status
http://pmid.co/20647200
Saturday, March 9, 13
Mirabegron for overactive bladder
• ß3-specific beta receptor agonist with once-daily
dosing
• Modest reductions in incontinence episodes (-0.5/24h)
and micturitions (-0.6/24h) compared with placebo
• Much fewer anticholinergic adverse effects; dry mouth
and constipation minimal
• Hypertension comparable to placebo in studies but
labeling warns of possibility
http://pmid.co/21245183
Saturday, March 9, 13
Linaclotide for IBS with constipation
• Poorly absorbed guanylate cyclase-C agonist; once daily dosing
• Induces chloride secretion into intestinal lumen; may also
have indirect analgesic effects
• Composite endpoint including 30% pain reduction, increase in
bowel movements
• Response rate increased to 33% compared with 21% in placebo
group; NNT 8
• Diarrhea (20%) and flatulence (5%) most common adverse
effects; 5% of treatment arm stopped meds due to diarrhea
http://pmid.co/20647200
Saturday, March 9, 13
Ingenol mebutate for actinic keratoses
• Active ester in Euphorbia peplus 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
Saturday, March 9, 13
Fidaxomicin for C. difficile
• Macrolide antibiotic specific for clostridia with poor
oral absorption--bactericidal against C. difficile
• RCT comparing 10 days oral fidaxomicin to
vancomycin: 88% vs 86% cure (NS), 15% vs 25%
recurrence (p=0.005)
• No difference in patients with NAP1/B1/027
epidemic strain
• No studies in recurrent C. difficile
http://pmid.co/21288078
Saturday, March 9, 13
New agents for head lice
• Benzyl alcohol 5%:
- Kills lice topically (suffocation); 75% effective in unpublished
manufacturer data
• Spinosad 0.9%:
- Natural insecticide from S. spinosa; 85% effective in published data
• Ivermectin 0.5%:
- Natural insecticide from S. avermitilis; 70-75% effective in
unpublished data
• Oral ivermectin 95% effective, $10
http://pmid.co/23113480; http://pmid.co/20220184
Saturday, March 9, 13
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
• Sensitive but not specific for Alzheimer’s
• Prognostic role unclear, needs further study
• Requires skilled interpretation
http://pmid.co/20647200
Saturday, March 9, 13
Lomitapide for hyperlipidemia
• Inhibitor of microsomal triglyceride transfer
protein, key protein in fat absorption & lipoprotein
assembly
• Tested in 25 patients with homozygous familial
hypercholesterolemia on optimal therapy
• 50% reduction in LDL (336 mg/dl to 166 mg/dl)
• 80% of patients had GI side effects, 30%
transaminitis, most had increase in hepatic fat
http://pmid.co/23122768
Saturday, March 9, 13
Mipomersen for hyperlipidemia
• Antisense oligonucleotide for ApoB-100
• Tested in 58 patients with homozygous familial
hypercholesterolemia on optimal therapy
• 36% reduction in LDL (278 mg/dl to 174 mg/dl)
• 50% injection site reactions, 20% transaminitis, 13%
hepatic fat
http://pmid.co/23152839
Saturday, March 9, 13
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
Saturday, March 9, 13
Pasireotide for Cushing’s syndrome
• Somatostatin analog with broader binding affinity
than octreotide
•
162 patients randomized to paserotide 600 vs 900
mcg twice daily (no placebo arm)
• Dose-response decrease in urine free cortisol, with
decreases in lipids & BP that correlated with cortisol
• Diarrhea, nausea, hyperglycemia, cholelithiasis,
headache, fatigue all common (30-40%)
http://pmid.co/22397653
Saturday, March 9, 13
New uses for old drugs
Saturday, March 9, 13
Mifepristone for Cushing’s syndrome
• Progesterone receptor antagonist that also blocks
glucocorticoid receptors at high
• 50 adults with Cushing’s syndrome that failed
conventional therapy and diabetes or hypertension
• Hemoglobin A1C decreased by 1.1% (7.4 to 6.3%), 5.7%
weight loss; BP response in only 38% of patients
• Adverse effects included nausea, headache, fatigue
(almost 50%), hypokalemia, arthralgia, endometrial
thickening
http://pmid.co/22466348
Saturday, March 9, 13
Gabapentin for chronic cough
• 62 patients with chronic cough (40-60/hr) and
failed trials or tests for GERD, asthma, PND
• Gabapentin 1800 mg/d vs placebo; 6-day dose
titration
• Modest improvement in cough-specific quality of
life; better than placebo, less potent than opiates
• More adverse effects (dizziness, confusion, fatigue,
memory loss) in gabapentin arm
http://pmid.co/22951084
Saturday, March 9, 13
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
Saturday, March 9, 13
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
Saturday, March 9, 13
Nitroglycerin for anal fissure
• Topical nitroglycerin 0.4% relaxes anal sphincter; effective
in healing fissure about 50% of the time
• Nitropaste for cardiac use is 2%, 5x as strong
• 0.4% now available as manufactured (not compounded)
formulation
• Topical diltiazem 2% also effective with fewer adverse
effects but must be compounded
• Botox also seems comparable but higher risk of temporary
incontinence
http://pmid.co/22336789
Saturday, March 9, 13
Drug updates for 2013
Saturday, March 9, 13
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
Saturday, March 9, 13
Drugs that prolong the QT interval
• Citalopram (limited to 40 mg by FDA)
• Levofloxacin and moxifloxacin
• Macrolides
• Risperidone
• Ondansetron and other 5HT3 antagonists
• Antiarrhythmics
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm
Saturday, March 9, 13
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
Saturday, March 9, 13
Paroxetine + Pravastatin
• Analysis of FDA adverse events database suggests
increased risk of hyperglycemia with paroxetine/
pravastatin combined
• Magnitude of risk unclear, probably not large
• FDA finding was anticipated by a retrospective
analysis of internet search engine queries
http://pmid.co/23467469
Saturday, March 9, 13
New drug formulations: worth it?
• Effervescent alendronate may solve problems with
swallowing/esophagitis (although labeling is the same as
pills): $140/month vs $10
• New dry powder, HFA-propelled nasal steroid inhalers
(beclomethasone, ciclosenide): pricing similar to brand name
aqueous ($110-$150) but much more expensive then generic
fluticasone
• New injection-resistant oxycodone: $2.67 vs $0.15 per tablet
• Delayed release prednisone: faster for morning symptoms but
$100-200/month
Saturday, March 9, 13
The PharManure list
Saturday, March 9, 13
Drugs that make me grumpy
• Dymista: Too much fluticasone or not enough
azelastine?
• Intermezzo: maybe you’ll forget that it costs $6.50
for 1.75 mg zolpidem.
• Absorica: isotretinoin for $1400 instead of $550 a
month, but you don’t have to take it with food!
• Promiseb: $150 for a 30-gram tube of prescriptionstrength placebo
Saturday, March 9, 13
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.
Saturday, March 9, 13
Things that make me grumpy
• Generic manufacturers and the FDA
Saturday, March 9, 13
Generic manufacturers and the FDA
Saturday, March 9, 13
Generic manufacturers and the FDA
Saturday, March 9, 13
Generic manufacturers and the FDA
Saturday, March 9, 13
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
Saturday, March 9, 13
Recap
• Lorcaserin & Qsymia: not magic bullets but may help
• Ingenol mebutate: much faster topical therapy for AKs,
but costly
• Fidaxomicin: niche remains unclear, probably not
worth the current cost
• Ivermectin: effective topically, cheap orally
• New drugs for familial hyperlipidemia are effective but
have considerable side effects
Saturday, March 9, 13
Recap
• New drugs for Cushing’s might help if other options
exhausted
• Gabapentin may help with symptoms of chronic
cough
• C. difficile: bacteria to prevent, bacteria to cure,
antibiotics in between
• Nitroglycerin can help with anal fissure but make
sure it’s the right strength
Saturday, March 9, 13
Recap
• Once weekly exenatide looks promising already and
someday might be affordable
• The long QT list only gets longer
• 2nd-4th gen cephalosporins probably safe with PCN
allergy
• New formulations have advantages but beware cost
• Pay attention to changes in pill color with generics
Saturday, March 9, 13
Thanks!
[email protected]
Saturday, March 9, 13