DRUG UPDATE 2005
From 2005 CEP Emergency Medicine Symposium, sponsored by the California Emergency Physicians Medical
Group
Joe Lex, MD, Assistant Professor of Emergency Medicine, Temple University School of Medicine, Philadelphia
| Stages of drugs: 1) panacea stage (“this is the greatest thing since ”), 2) demonization stage (“how in the
world did this drug get approved?”), 3) acceptance (noted for its advantages and side effects; physicians
learn how to use it appropriately)
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| Drugs discussed: no drug discussed is new; all have been on market in Europe, or available in United States
for different indications and now being used for new indication or in new formulation
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| Acetadote: intravenous (IV) N-acetylcysteine; used for years in Europe for acetaminophen overdose; have
only oral version in United States, which has been used off-label IV; 56,000 emergency department (ED)
visits annually for acetaminophen toxicity
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 | Acetaminophen overdose in Europe: overdoses virtually eliminated by putting acetaminophen in small
bottles (cannot buy >10 g at time), placing pills in blister packs (suicidal patients run out of energy before
they can take lethal dose), and using hydrocodone and oxycodone alone (not in combination with
acetaminophen)
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| Use of Acetadote: treatment time 20.25 hr vs 72 hr with oral agent; speaker suspects same dosing can be
used with IV oral agent with equal efficacy at fraction of cost of Acetadote ($18 for oral vs $416 for IV
formulation); need study looking at efficacy of oral preparation given IV using 20.25-hr protocol
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| Caduet: combination of amlodipine (Norvasc) and atorvastatin (Lipitor); these drugs expensive (Norvasc in
lower dose costs $549/yr, Lipitor $850/yr for low dose; combination saves patients few dollars); Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)—showed hydrochlorothiazide
just as good as amlodipine and lisinopril (Zestril) for lowering blood pressure and better than
amlodipine and angiotensin-converting enzyme (ACE) inhibitors at preventing heart attack or death; concluded
diuretics best treatment for hypertension, both medically and economically, and that current practice
has probably caused harm to patients; common ploys—used by companies to extend patents include 1)
getting drug approved for pediatric use (extends patent by 6 mo), 2) combining with another drug (extends
patent another 6 mo); lipid-lowering arm of ALLHAT—>10,000 patients with high risk for coronary disease
started on statin; 83% stayed on statins 8 yr; 8000 average–risk patients with slight cholesterol elevations
started on statin; found no change in death rate or other outcomes in any subgroup, except that black subjects
developed less heart disease; speaker concludes that Framingham data showing people with low cholesterol
do better does not mean that lowering cholesterol in people with high cholesterol improves their
outcomes; similar results in another study that looked at pravastatin in elderly individuals at risk for vascular
disease; this study found 1 excess cancer per 100 subjects at end of 4 yr (statistically significant)
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| Ertaczo: sertaconazole; new topical antifungal cream; came on market last year; available in Europe for
years; high skin concentrations without absorption; no better than anything else on market but more expensive
(costs $46, compared to $4 for miconazole)
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| Ketek: telithromycin; new antibiotic; indicated for oral treatment of mild-to-moderate community-acquired
pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis; new class of antibiotics
called ketolides; derived from erythromycin; more acid-stable when taken orally; company claim
that drug “overcomes the usual mechanisms of macrolide resistance” simply means drug not yet overprescribed
enough to cause resistance; coverage and cure rates similar to those of azithromycin and
clarithromycin; rapidly absorbed; good peak concentration; half-life 10 hr; looks promising; “unsurpassed
efficacy” means “just as good as”; same contraindications as for macrolides; drug levels increased
with itraconazole and ketoconazole, decreased to subtherapeutic levels with rifampin, carbamazepine (Tegretol),
and dilantin; decreases absorption of sotalol (Betapace); cannot take theophylline concurrently;
use cautiously with other drugs that prolong QT interval
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| Adverse effects: gastrointestinal (GI) side effects, blurred vision, diplopia, and difficulty focusing especially
in women <40 yr of age; prolonged QT interval; 2 deaths in patients with myasthenia gravis
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| Costs: $114 for one course, compared to $22 for doxycycline, and $47 for azithromycin
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| Third-generation quinolones: do not use in outpatient population; save them for inpatients (“the sickest of
the sick”)
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| NovoSeven: recombinant coagulation factor VIIa; approved in March 1999 for use in hemophilia; current off-
label use to stop bleeding in gunshot wounds
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| How it works: inactive before it gets to injury site; binds to tissue factor in platelets and promotes conversion
of prothrombin to thrombin; does not appear to cause systemic thrombosis
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| Evidence: largely anecdotal; randomized study of patients undergoing prostate surgery; of 16 receiving
NovoSeven, none needed blood vs 7 of 12 in placebo group; in another study, bleeding stopped in 8 patients
with severe hemorrhage from esophageal varices; study of patients with intracerebral hemorrhage
showed 90-day mortality went from 29% to 18% when treated with NovoSeven (ischemic stroke
developed in some); used by military for battlefield victims; in study of 8 patients on warfarin who
needed surgery and had international normalized ratios (INRs) of 2 to 7, INR reduced to ≤1.5 within
30 min of receiving 2 µg/kg of NovoSeven
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| Dosing: 90 to 120 µg/kg
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| Cost: ≈$10,000/dose
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| Provigil: modafinil; used to treat excessive daytime sleepiness associated with narcolepsy; now being used
for excessive sleepiness due to shift-work sleep disorder; works on γ-aminobutyric acid (GABA) receptors
to inhibit sleep-promoting neurons; instead of stimulating brain, it prevents brain from becoming
tired; 200 mg modafinil better than placebo and as good as 600 mg caffeine (6 cups of coffee); no withdrawal,
no effect on nighttime sleep, no headache, no nervousness; 2 anecdotal reports of hypertensive
encephalopathy in previously normotensive patients; some euphoria reported, but speaker predicts this
agent will not become popular street drug because it takes 2 to 3 hr to feel effects; 200 mg taken 1 hr before
night shift; costs ≈$6/tablet; long-term safety unknown; about to come off patent; R-enantiomer of
modafinil about to be marketed as armodafinil (Nuvigil); military using this for soldiers on night patrol;
also used by airline pilots
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| Spiriva: tiotropium; long-acting inhaled anticholinergic; once-daily maintenance treatment for bronchospasm
and chronic obstructive pulmonary disease (COPD); available in Europe for last few years;
binds to muscarinic receptors; inhibits bronchoconstrictive and secretory effects of acetylcholine; terminal
half-life 5 to 6 days; bronchodilation begins in 30 min, peaks in 3 hr, and persists for >24 hr, but
long-term effect not felt until day 8; patients switching to tiotropium from ipratropium (Atrovent) must
continue ipratropium for 1 wk, ie, until full effect of tiotropium achieved; study—535 patients in double
blind randomized trial showed daily tiotropium better than qid ipratropium in number of patients
with exacerbations; improved forced expiratory volume in 1 sec (FEV1 ) and decreased use of rescue
β2 -agonists; dry mouth most common side effect; costs $115 compared to $68 for qid ipratropium
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| Conclusion: long-acting, reduces symptoms, improves quality of life, improves lung function, and decreases
exacerbations; favorable review in Medical Letter; COPD patients like it
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| Tindamax: tinidazole; new drug promoted instead of metronidazole for trichomoniasis, giardiasis, amebiasis,
and amebic liver abscess; second-generation nitroimidazole; oral antiprotozoal; used in Europe for years
(trade name Fasigyn); also covers Helicobacter and Bacteroides; just as effective as single-dose metronidazole
for Trichomonas and Giardia; side effects same as for metronidazole, ie, metallic taste, nausea, vomiting; contraindicated
in first trimester of pregnancy; costs 3 times as much as metronidazole (Flagyl); effective against
some metronidazole-resistant trichomoniasis
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| Xifaxan: rifaximin; another new antibiotic; derived from rifampin; available in Europe for almost 20 yr; inhibits
bacterial RNA synthesis; <0.4% absorbed from GI tract; “what you put in at the top comes out at
the bottom unchanged, but along the way, it kills all the bacteria”; identical to ciprofloxacin in time-to-
last-unformed-stool (TLUS), symptom resolution, and cost; good choice for standard traveler’s diarrhea;
gastroenterologists have used it off-label for hepatic encephalopathy, Crohn’s disease, diverticulitis, pouchitis,
bacterial overgrowth syndromes in diabetic patients, and many other diseases
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| Zyprexa: intramuscular (IM) olanzapine; approved for use in patients with bipolar disorder and schizophrenia;
speaker prefers sedation (eg, with haloperidol) to physical restraints; representatives for new drug argue
haloperidol’s side effects make its use malpractice; IM olanzapine—peak plasma concentration in 15
to 30 min; half-life 34 to 38 hr; no QT interval prolongation; study showed olanzapine better than placebo
and equivalent to haloperidol; alters blood glucose in small subset of patients; manufacturer has
withdrawn request that drug be used in dementia-related psychosis because of significantly increased
death rate; maintenance 6 cents/day for haloperidol compared to $8/day for Zyprexa; studies used defined
patient populations with known diagnoses (not real world in ED); need studies in undifferentiated
populations; in some locations, psychiatrists have required Zyprexa to be drug of choice for restraining
psychotic patients in ED, and emergency physicians say it does not work
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| Nesiritide: now shown in 6 studies to worsen renal insufficiency and increase number of patients who end up
on dialysis
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Educational Objectives
| The goal of this program is to educate the listener about new drugs. After hearing and assimilating this program, the clinician
will be better able to:
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| 1. Name a new combination drug used for treating hypertension and hypercholesterolemia and discuss the evidence for its
efficacy.
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| 2. Describe the off-label use of coagulation factor VIIa (NovoSeven) and describe the evidence for its efficacy.
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| 3. Discuss the characteristics and uses of modafinil (Provigil).
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| 4. Describe the effects of tiotropium (Spiriva).
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| 5. List 2 new antibiotics available on the market and describe their indications and efficacy.
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Discussed on This Program
Acetaminophen (N -acetyl-P -aminophenol; APAP) [many trade names]
Acetylcysteine (N -acetylcysteine) [Acetadote, Mucomyst, Mucosil]
Amlodipine [AmVaz, Norvasc]
Atorvastatin calcium [Lipitor]
Azithromycin [Zithromax]
Carbamazepine [Tegretol, others]
Cisapride [Propulsid]
Clarithromycin [Biaxin]
Coagulation factor VIIa (recombinant) [NovoSeven]
Doxazosin mesylate [Cardura]
Erythromycin (many trade names)
Haloperidol [Haldol]
Hydrocodone bitartrate and acetaminophen [Vicodin, others]
Ipratropium bromide [Atrovent]
Itraconazole [Sporanox]
Lisinopril [Prinivil, Zestril]
Metronidazole [Flagyl, others]
Modafinil [Provigil]
Acetylcysteine (N-acetylcysteine) [Acetadote, Mucomyst, Mucosil-10, -20]
Nesiritide [Natrecor]
Nitazoxanide [Alinia]
Olanzapine [Zyprexa]
Oxycodone and acetaminophen [Percocet, others]
Phenytoin [Dilantin Infatab, Dilantin -125]
Rifampin (rifampicin) [Rifadin, Rimactane]
Rifaximin [Lumenax, Normix, Xifaxan]
Sertaconazole nitrate [Ertaczo]
Sotalol HCl [Betapace, Betapace AF]
Telithromycin [Ketek]
Theophylline (many trade names)
Tinidazole [Tindamax] (sold in Europe as Fasigyn)
Tiotropium bromide [Spiriva, Spiriva HandiHaler]
Programs of Related Interest
Lex JR, Otten EJ: Drugs: healing or harmful? Audio-Digest Emergency Medicine 20:10(May 21), 2003; Lieberman
JM: Tough bugs and new drugs. Audio-Digest Pediatrics 49:13(Jul 7), 2003.
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Suggested Reading
Acetylcysteine (Acetadote) for acetaminophen overdosage. Med Lett Drugs Ther 47:70, 2005; Aldouri M: The use of recombinant
factor VIIa in controlling surgical bleeding in non-haemophiliac patients. Pathophysiol Haemost Thromb 32
Suppl 1:41, 2002; ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized
to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-
Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 288:2981, 2002 (Erratum in 289:178, 2003, and
291:2196, 2004); American College of Emergency Physicians: Clinical policy for the management and risk stratification
of community-acquired pneumonia in adults in the emergency department. Ann Emerg Med 38:107, 2001; Amlodipine/atorvastatin
(Caduet). Med Lett Drugs Ther 46:56, 2004; Blatt J et al: Off-label use of recombinant factor VIIa in patients following
bone marrow transplantation. Bone Marrow Transplant 28:405, 2001; Carbon C: A pooled analysis of
telithromycin in the treatment of community-acquired respiratory tract infections in adults. Infection 31:308, 2003; Casaburi
R et al: A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J
19:217, 2002; Czeisler CA et al: Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J
Med 353:476, 2005; Dossenbach M et al: Effectiveness of antipsychotic treatments for schizophrenia: interim 6-month
analysis from a prospective observational study (IC-SOHO) comparing olanzapine, quetiapine, risperidone, and haloperidol. J
Clin Psychiatry 65:312, 2004; Keating GM et al: Modafinil: a review of its use in excessive sleepiness associated with obstructive
sleep apnoea/hypopnoea syndrome and shift work sleep disorder. CNS Drugs 19:785, 2005; Mandell LA et al:
Summary of Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by
the Canadian Infectious Disease Society and the Canadian Thoracic Society. Can Respir J 7:371, 2000; Mandell LA et al:
Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect
Dis 37:1405, 2003; Mayo A et al: Recombinant activated factor VII (NovoSeven): addition to replacement therapy in
acute, uncontrolled and life-threatening bleeding. Vox Sang 87:34, 2004; Tinidazole (Tindamax)—a new anti-protozoal
drug. Med Lett Drugs Ther 46:70, 2004; Topical sertaconazole (Ertaczo)--another azole for tinea pedis. Med Lett Drugs
Ther 46:50, 2004; Trespi E et al: Intestinal bacterial overgrowth during chronic pancreatitis. Curr Med Res Opin 15:47,
1999; Westcott KJ: Modafinil, sleep deprivation, and cognitive function in military and medical settings. Mil Med 170:333,
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 speaker
reported no conflict.
Dr. Lex was recorded April 14, 2005, in Riverside, California, at the 2005 CEP Emergency Medicine Symposium, sponsored
by the California Emergency Physicians Medical Group. The Audio-Digest Foundation thanks the speaker and the
sponsor for their cooperation in the production of this program.
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