DRUGS AND DEVICES UPDATE
Joseph R. Lex, Jr., MD, Assistant Professor of Emergency Medicine, Temple University School of Medicine,
Philadelphia, PA
| New drugs withdrawn: Palladone—extended-release formulation of hyrodromorphone; introduced in 2005; voluntarily
withdrawn in July of same year because of severe side effects when ingested with alcohol; coingestion produced
up to 6-fold increase in peak serum concentration of hydromorphone; several deaths reported; NeutroSpec—
Technetium 99m Tc-labeled fanolesomab; imaging drug approved for scanning for appendicitis; voluntarily withdrawn
in December 2005 after report of 2 deaths, 15 life-threatening events, and 46 other adverse events; Darvocet
(propoxyphene)—withdrawn from market in United Kingdom in 2005 because of too many associated deaths
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| New “black box” warning: promethazine on market since 1951; Food and Drug Administration (FDA) recently issued
black box warning against use in children
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| Noninsulin injectables: approved for patients with diabetes to help tightly control blood glucose; Symlin (pramlintide
acetate)—synthetic amylin; natural amylin synthesized by pancreatic beta cells and increases with insulin after
glucose load; slows gastric emptying, suppresses glucagon and glucose output, and increases satiety; decreases absorption
of oral drugs; should not be used with other drugs that slow gastrointestinal motility (eg, anticholinergics)
or certain other diabetes drugs (eg, acarbose [Precose], miglitol [Glycet]); recommended that no other medications
be taken 1 hr before or 2 hr after Symlin injection; separate injection (cannot be mixed with insulin); Byetta
(exenatide)—mimics gut incretins (gastric inhibitory polypeptide and glucagon-like peptide-1); incretins responsible
for ≤70% of insulin secretion in body; exenatide isolated from saliva of gila monsters; inhibits glucagon secretion,
slows gastric emptying, promotes satiety, and produces tight glucose control; can cause hypoglycemia; unlike
insulin, does not cause weight gain; supplied in self-injecting pen; long-term effects unknown
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| Antimeningococcal polysaccharide (groups A, C, Y, and W-135; Menactra): and diphtheria toxoid conjugate vaccine
became available in 2005; meningococcal disease devastating illness (10% fatality rate associated with meningitis,
40% with meningococcemia; 20% of survivors have permanent disability); however, disease burden small (<2000
cases/yr); efficacy of vaccine good (80%-90%); population most susceptible to meningococcal disease individuals
17 to 19 yr of age; American Academy of Pediatrics (AAP) recommends immunization with Menactra at 11- to 12-
yr visit, entry into high school, and for college students living in dormitory; 3 injections now recommended, with
possibility of further recommendations as vaccine becomes more widely available; however, because of low disease
burden, question whether this immunization policy cost-effective (prevents ≈3 deaths per year; $7-20 million per
death); in September 2005, 5 cases reported of Guillain Barré syndrome developing after Menactra immunization
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| Human papillomavirus (HPV) vaccines: Gardasil, Cervarix; HPV “nearly ubiquitous” in sexually active women and
proven primary cause of cervical cancer; kills 3700 women per year in United States; when given before woman’s
first sexual contact, both vaccines 100% effective in preventing HPV and, therefore, 100% effective in preventing
cervical cancer; 1 vaccine manufacturer recommends administration before 12 yr of age, other recommends before
10 yr of age; speaker suggests that delays in FDA approval (Gardasil approved in 2006; Cervarix submitted but not
yet approved) largely for political reasons (eg, religious groups have objected that giving vaccine to young women
would be license to engage in premarital sex); results of administration of vaccine to boys unknown
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| Acamprosate (Campral): third drug approved by FDA for maintenance of alcohol abstinence in alcoholics who no
longer wish to drink; in 3 trials, proven more effective than placebo if patient has already stopped drinking for few
days, and if he or she gets strong psychosocial support; however, no better than placebo if no psychosocial support
or patient has not stopped drinking; unlikely to be helpful or prescribed in emergency department (ED), but ED
physicians may encounter patients already on this medication; fairly safe (no apparent abuse; low potential for drug
interactions)
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| Tigecycline (Tygacil): first in new class of antibiotics; derived from tetracyclines; indicated for complicated skin and
soft tissue infections; not for nosocomial infections (no Pseudomonas coverage); not affected by cytochrome P450
(CYP450 ); highly protein bound (can displace digoxin or warfarin); as effective as vancomycin/aztreonam combination
therapy; $40/dose
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| Isosorbide and hydralazine (BiDil): race-specific medication purportedly developed to treat congestive treat heart failure
(CHF) in black patients; approved by FDA in 2005; combination of drugs first introduced separately 50 yr ago;
while some black patients may have lower nitric oxide levels, and some are less responsive to angiotensin-converting
enzyme (ACE) inhibitors, also true for some white patients (ie, anomalies not race-specific, but part of continuum);
FDA initially denied approval for BiDil in 1997 due to lack of evidence; African American Heart Failure
Study—data that led to eventual approval; >1000 self-identified black patients with New York Heart Association
Class III or IV dysfunction given BiDil vs standard care; study stopped at 12 mo; relative reduction in mortality
rate over 12 mo 43%, absolute reduction 4% (number needed to treat [NNT] 25 to save 1 life in 1 yr); rate of hospitalization
for CHF showed relative reduction of 33%, absolute reduction of 8%); NNT to prevent 1 hospitalization
12.5; problem that patient population self-selected; no evidence BiDil better in one racial group than another; reasons
physicians stopped using isosorbide and hydralazine in treatment of CHF—isosorbide is nitrate (patients
cannot take phosphodiesterase-4 [PDE4] inihibitors, eg, sildenafil, vardenafil, tadalafil); hydralazine causes lupus-
like symptoms (20% of women who receive 200 mg/day develop drug-induced lupus after 3 yr of use); cost—
$2.17/dose of BiDil, generic equivalents of same drugs cost $0.45/dose; ED physicians who see patients on BiDil
should understand it is “pure marketing” of 2 older drugs
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| Eszopiclone (Lunesta): nonbenzodiazepine insomnia medication; became available in 2005; stereoisomer of parent
drug (zopliclone); FDA originally denied approval because use appeared to increase incidence of cancer; classified
as Schedule IV controlled substance; not restricted to long-term use; appears well tolerated with few withdrawal
symptoms (possibly some rebound insomnia first night); no central nervous system depression seen with overdose
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| Ramelteon (Rozerem): receptor agonist works at melatonin receptor; not controlled substance; also not effective;
speaker cites drug as example of how statistical significance and data-oriented evidence can overrule clinical significance
and patient-oriented evidence (in studies, patients given ramelteon fell asleep just 15 min faster, and gained
total extra time in bed of ≤19 min; while efficacy not impressive, results did reach statistical significance; based on
this, drug approved by FDA; 33% of patients on drug long term develop increased prolactin levels, which can lead to
hypogonadism, infertility, decreased libido, and osteoporosis
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| Pregabalin (Lyrica): introduced in 2005; approved by FDA for treatment of diabetic peripheral neuropathy (DPN)
and postherpetic neuralgia (PHN), and as supplementary antiseizure medication for partial-onset seizures; just like
gabapentin (Neurontin); pregabalin not approved for generalized seizures, bipolar disorder; miscellaneous pain disorders,
or attention-deficit disorder; speaker mentions this because, in 2003, $430 million fine levied against manufacturer
for aggressive promotion of Neurontin for these off-label uses (in same, year Neurontin grossed $3.2
billion); for this reason, speaker thinks it likely clinicians will see patients placed on Lyrica for some of these nonapproved
indications; neither Lyrica nor Neurontin works well, even for approved indications; study data—
patients who did not respond to gabapentin not allowed to enter pregabalin trials; while trials for pregabalin reported
statistically significant lowering of pain, in every study reviewed by speaker, regardless of dose of medication,
<50% of patients got pain relief; in those who did get relief, pain reduction, at best, barely clinically
significant; pharmacology—pregabalin has linear pharmacokinetics; modulates voltage-gated calcium channels;
not protein bound; not metabolized; produces no known adverse drug reactions; classified as Schedule V controlled
substance (some withdrawal reported); clinicians should be aware generic gabapentin available for patients with
DPN or PHN
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| Extended-release azithromycin (Zmax): single-dose (2 g) therapy for community-acquired pneumonia (CAP) and
acute bacterial sinusitis (ABS); absorbed from small intestine; has half life of 59 hr; study supporting Zmax for
treatment of CAP found 1 dose equivalent to 7 days of levofloxacin or clarithromycin (however, these drugs not
first-line for treatment of CAP); in another study on ABS, Zmax also found equivalent to 7 days of levofloxacin
(neither drug first-line treatment for ABS); another flaw in CAP trial that many illnesses treated do not classify as
CAP; may be possible role for this drug in treatment of patients with sexually transmitted diseases, although not yet
approved for this use; bottom line—if patient requires azithromycin, clinician should write prescription for generic
drug
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| CYP450 genotyping system (AmpliChip): ≈20% of population metabolizes drugs differently from other 80%; 10% of
white population, and smaller percentage of Asians and blacks lack CYP2D6; this anomaly leads to many adverse
drug reactions and intoxications; AmpliChip system uses polymerase chain reaction to analyze DNA and detect
variations in genes for CYP2D6 and CYP2C19; important because these 2 enzymes control metabolism of 25% of
all prescription drugs; patients classified as ultrarapid, extensive, intermediate, or poor metabolizers; test currently
marketed only to psychiatrists (test expensive, takes 8 hr); however, speaker thinks strong possibility that, over
next 10 yr, test may become routine in EDs; variability in CYP2D6 may explain patient who claims codeine does
not work for him or her, or patient who has unexpected adverse reaction to 2 mg of intravenous (IV) morphine, or
patient who reports sleeping for 3 days after taking 1 Vicodin tablet (hydrocodone/acetaminophen); may eventually
see patients wearing medical bracelets that identify them as poor or ultrarapid metabolizers; this information would
make difference in how medications prescribed when patient presents to ED, and medications prescribed at discharge
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| Virucidal tissues (Kleenex): virucidal Kleenex; works against influenza A and B (including avian influenza A subtype
H5N1), rhinoviruses type 1A and 2, and respiratory syncytial virus (RSV); kills 99.9% of viruses on tissue within
15 min; 3-ply tissue; middle layer contains 7.5% citric acid (destroys rhinoviruses) and 2% sodium lauryl sulfate
(disrupts lipid envelope of other viruses); three-arm study—subjects infected with virus; asked to blow nose into
medicated tissue, placebo tissue, or into hands; volunteers directed to shake hands with subjects; goal to determine
how well antiviral tissue prevented virus from spreading; proved extremely effective (only 2 of 62 subjects had virus
on hands; neither transmitted virus by shaking hands; of patients who used placebo tissue, 26 of 42 had virus on
hands, and 7 of 26 transmitted virus by shaking hands; of subjects who blew nose into hands, 20 of 24 cultured positive
for virus, and 19 of 20 transmitted virus by shaking hands); this is speaker’s nomination for best product of
2006; worth considering if following Centers for Disease Control and Prevention (CDC) recommendations on how
to treat respiratory illness in ED
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Educational Objectives
| The goal of this issue is to provide an update and review of recently introduced drugs and devices. After hearing and assimilating
this program, the listener will be better able to
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 | 1. Describe the mechanisms of action and efficacy of the hypoglycemic agents pramlintide and exenatide.
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| 2. List indications for the use of tigecycline in the emergency department (ED).
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| 3. Discuss the studies and evidence used to support the role of BiDil as a race-specific congestive heart failure medication.
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| 4. Explain the limiting factor in the use of extended-release azithromycin suspension (Zmax).
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| 5. Describe the function of the AmpliChip CYP450 genotyping system and explain its potential benefits in the ED.
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Discussed on This Program
Acamprosate calcium [Campral]
Acarbose [Precose]
Amlodipine [AmVaz, Norvasc]
AmpliChip CYP450 genotyping system
Azithromycin, extended release [Zmax]
Aztreonam [Azactam]
Clarithromycin [Biaxin, Biaxin XL]
Clopidogrel bisulfate [Plavix]
Codeine PO4
Daptomycin [Cubicin]
Digoxin [Digitek, Lanoxicaps, Lanoxin]
Disulfiram [Antabuse]
Eszopiclone [Lunesta]
Exenatide [Byetta]
Flumazenil [Romazicon]
Gabapentin [Neurontin]
Human papillomavirus recombinant vaccine, quadrivalent [Gardasil, Cervarix (investigational)]
Hydrocodone bitartrate and acetaminophen [Vicodin Tablets, others]
Hydromorphone HCl, extended release [Palladone] (withdrawn from market)
Insulin human (rDNA origin) injection powder [Exubera]
Isosorbide dinitrate and hydralazine hydrochloride [BiDil]
Kleenex anti-viral tissues
Levalbuterol HCl [Xopenex]
Levofloxacin [Levaquin, Quixin]
Linezolid [Zyvox]
Meningococcal vaccine [Menomune-A/C/Y/W-135, Menactra (Groups A,C,Y, and W-135)]
Miglitol [Glyset]
Morphine sulfate [several formulations and trade names]
Nalmefene HCl [Revex]
Naloxone HCl [Narcan]
Naltrexone HCl [ReVia]
Oxycodone and acetaminophen [Percocet, others]
Oxycodone HCl [several trade names]
Pramlintide acetate [Symlin]
Pregabalin [Lyrica]
Promethazine HCl [Phenadoz, Phenergan]
Propoxyphene napsylate and acetaminophen [Darvocet A500]
Quinupristin/dalfopristin [Synercid]
Ramelteon [Rozerem]
Sildenafil citrate [Revatio, Viagra]
Tadalafil [Cialis]
Technetium 99m Tc-labeled fanolesomab [NeutroSpec] (withdrawn from market)
Tigecycline [Tygacil]
Topiramate [Topamax]
Vancomycin [Vancocin, Vancoled]
Vardenafil HCl [Levitra]
Warfarin sodium [Coumadin]
Suggested Reading
American Academy of Pediatrics Committee on Infectious Diseases. Prevention and control of meningococcal disease: recommendations
for use of meningococcal vaccines in pediatric patients. Pediatrics 116:496, 2005; Bradford PA: Tygecycline: a
first in class glycylcycline. Clin Microbiol Newsletter 26:163, 2004; D’Ignazio J et al: Novel, single-dose microsphere formulation
azithromycin versus 7-day levofloxacin therapy for treatment of mild to moderate community-acquired pneumonia in adults.
Antimicrob Agents Chemother 49:4035, 2005; Drehobl MA et al: Single-dose azithromycin microspheres vs. clarithromycin
extended release for the treatment of mild-to-moderate community-acquired pneumonia in adults. Chest 128:2230, 2005; Egger T
el al: Cytochrome p450 polymorphisms in geriatric patients: impact on adverse drug reactions—a pilot study. Drugs Aging
22:265, 2005; Elkayam U, Bitar F: Effects of nitrates and hydralazine in heart failure: clinical evidence before the African American
heart failure trial. Am J Cardiol 96, 37i, 2005; Erman M et al: An efficacy, safety, and dose-response study of Ramelteon in
patients with chronic primary insomnia. Sleep Med 7:17, 2006; Halas CJ: Eszopiclone. Am J Health Syst Pharm 63:41, 2006;
Hayden GF et al: The effect of placebo and virucidal paper handkerchiefs on viral contamination of the hand and transmission of
experimental rhinoviral infection. J Infect Dis 152:403, 1985; Hollander PA et al: Pramlintide as an adjunct to insulin therapy
improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes
Care 26:784, 2003; Kalinowski L et al: Race-specific differences in endothelial function: predisposition of African Americans to
vascular diseases. Circulation 109:2511, 2004; Kiefer F et al: Comparing and combining naltrexone and acamprosate in relapse
prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry 60:92, 2003; Koutsky LA et al: A
controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 347:1645, 2002; Krystal AD et al: Sustained efficacy
of eszipiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with insomnia.
Sleep 26:793, 2003; Longini IM Jr, Monto AS: Efficacy of virucidal nasal tissues in interrupting familial transmission
of respiratory agents. A field trial in Tecumseh, Michigan. Am J Epidemiol 128:639, 1988; Lotsch J et al: Genetic predictors of
the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet 43:983, 2004; Mann K:
Pharmacotherapy of alcohol dependence: a review of the clinical data. CNS Drugs 18:485, 2004; Murray JJ et al: Efficacy and
safety of a novel, single-dose azithromycin microsphere formulation versus 10 days of levofloxacin for the treatment of acute bacterial
sinusitis in adults. Otolaryngol Head Neck Surg 133:194, 2005; Overman GP et al: Acamprosate for the adjunctive treatment
of alcohol dependence. Ann Pharmacother 37:1090, 2003; Ruggeberg JU et al: Meningococcal vaccines. Paediatr
Drugs 6:251, 2004; Ryan GJ et al: Pramlintide in the treatment of type 1 and type 2 diabetes mellitus. Clin Ther 27:1500, 2005;
Sarzi-Puttini P et al: Drug-induced lupus erythematosus. Autoimmunity 38:507, 2005; Shepard CW et al: Cost-effectiveness
of conjugate meningococcal vaccination strategies in the United States. Pediatrics 115:1220, 2005; Stebbing J et al: Incidence of
cancer in individuals receiving chronic zopliclone or eszopliclone requires prospective study. J Clin Oncol 23:8134, 2005; Villa
LL et al: Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women:
a randomized double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 6:271, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue the faculty reports nothing
to disclose.
Dr. Lex lectured at the 2006 Annual Scientific Assembly of the Pennsylvania Chapter of the American College of
Emergency Physicians (ACEP), held April 25-28, 2006, in Pittsburgh, PA. The Audio-Digest Foundation thanks Dr.
Lex and the ACEP for their cooperation in the production of this program.
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