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How do you spell that? 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 • • • • • • • • • alogliptin apixaban avanafil axitinib bedaquiline cabozantinib crofelemer enzalutamide icosapent Saturday, March 9, 13 • • • • • • • • • ingenol ivacaftor linaclotide lomitapide lorcaserin mipomersen mirabegron ocriplasmin pazopanib • • • • • • • 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