SHANDS July/August 2004 at the University of Florida Drugs & Therapy B ◆ U ◆ L ◆ L ◆ E ◆ T ◆ I ◆ N

Volume 18, Number 7 SHANDS July/August 2004 at the University of Florida Drugs & Therapy B ◆ U ◆ L ◆ L ◆ E ◆ T ◆ I ◆ N

FORMULARY UPDATE DRUG INFORMATION FORUM The Pharmacy and Therapeutics NSAIDS + ASA = CONFUSION Committee met June 15, 2004. 3 drugs were added in the Formu- atients are seeing advertisements on platelets and prevents the binding lary and 3 drugs were deleted and P promoting the use of acetamino- of aspirin to platelets.1 This led to the designated not available. phen instead of traditional nonsteroi- recommendation that aspirin should be dal anti-inflammatory drugs (NSAIDs), given before administering ibuprofen. like ibuprofen, when they are taking It also led to observational studies that ◆ ADDED low-dose aspirin for the prevention of suggest that chronic use of ibuprofen cardiovascular events. The premise of (and possibly other NSAIDs) may Extended-Release Divalproex ® these warnings is that traditional decrease the effectiveness of low-dose Sodium (Depakote ER by Abbott NSAIDs could negate the beneficial aspirin.2-3 However, a recently done Pharmaceuticals) cardiovascular effects of low dose case-control study showed that the Rimantadine (Flumadine® by aspirin. The advertisements suggest combination of aspirin and ibuprofen Forest Pharmaceuticals) that acetaminophen is the preferable did not increase the incidence of analgesic because it has fewer drug myocardial infarctions.4 Tiotropium (Spiriva® by interactions. Intermittent use of ibuprofen (and Boehringer Ingelheim/Pfizer) ◆ other NSAIDs) has not been shown to alter the cardiovascular protective ◆ DELETED Is acetaminophen effects of low-dose aspirin. Chronic use Bacitracin + Polymyxin B preferable to traditional of ibuprofen alone (without aspirin) may Topical Powder (Polysporin® NSAIDs in patients taking be cardioprotective compared with Topical Powder by Pfizer)* nothing. However, if there is concern aspirin? Are COX-2 that ibuprofen decreases aspirin’s Clotrimazole Vaginal Tablets inhibitors preferable to effectiveness, acetaminophen is a (Femcare® by Schering Plough)* traditional NSAIDs when good option for chronic pain. Salsalate (Disalcid®)* Acetaminophen at doses of less than acetaminophen does not or equal to 4 grams per day (eg, 500 mg 4 times a day) is a first-line agent for *Nonformulary and Not Available work? Does low-dose mild to moderate joint pain associated aspirin cancel the lower with osteoarthritis. It is a first-line Tiotropium is a quaternary gastrointestinal effects of therapy because it is inexpensive, has ammonium derivative that is few adverse effects, and does not have structurally related to ipratropium. COX-2 inhibitors? many drug interactions. Patients treated It acts as an anticholinergic bron- with acetaminophen do not have to chodilator and is indicated for the What is the science behind these worry about mitigating the cardio- maintenance treatment of chronic warnings? Is acetaminophen prefer- protective benefits of low-dose aspirin. obstructive pulmonary disease able to traditional NSAIDs in patients Unfortunately, acetaminophen may (COPD). Although similar to taking aspirin? Are COX-2 inhibitors not provide sufficient pain relief. Many ipratropium, tiotropium possesses preferable to traditional NSAIDs when patients have already tried over-the- a unique pharmacodynamic profile acetaminophen does not work? Does counter acetaminophen before seeking allowing for once daily administra- low-dose aspirin cancel the lower gastro- medical attention and it did not pro- tion. The improved dosing schedule intestinal effects of COX-2 inhibitors? vide adequate relief. Also, many is a major advantage over ipratro- These are all related questions received patients find it difficult to adhere pium, which requires dosing up to 6 by the Drug Information & Pharmacy to the 4-times-a-day dosage. times daily. Tiotropium is the first Resource Center. This article will (continued on page 4) anticholinergic drug approved for summarize what we know about these COPD-associated bronchospasm issues…and what we do not know. ◆ since the approval of ipratropium ASA and Traditional NSAIDs INSIDE THIS ISSUE in 1986. Concern about the use of traditional In clinical trials, tiotropium ◆ Prescribing patterns NSAIDs with low-dose aspirin can demonstrated superior sustained be traced to a study that shows that ◆ Alcohol (continued on next page) ibuprofen binds to the COX-1 receptor Formulary update, from page 1 by which valproic acid exerts its Rimantadine has shown superior effects on pulmonary function tests anticonvulsant activity is unclear. It is efficacy to placebo and comparable compared to ipratropium. Tiotro- believed that its anticonvulsant efficacy to amantadine. Symptomatic pium reduced beta-agonist use, the activity results from inhibition of and virological improvements are number of COPD exacerbations, the GABA (gamma-amino-butyric acid), an the efficacy markers used in trials. time to exacerbation, the overall inhibitory neurotransmitter. Treatment appears to reduce the number of hospitalizations, and Depakote® ER has labeled indica- duration of symptoms by approxi- number of days spent in the hospital tions for the treatment of seizures in mately 1 day. when compared to ipratropium. adults and children at least 10 years Rimantadine has a significantly Significant increases in broncho- old and for the prophylaxis of migraine better adverse effect profile than dilation, dyspnea, and health-related headaches. The advantage of Depa- amantadine. Amantadine is associ- quality of life scores were seen with kote® ER is a simplified dosing ated with severe gastrointestinal tiotropium versus twice-daily sal- regimen. The manufacturer’s claims and central nervous system adverse meterol use. However, tiotropium of more stable serum concentrations effects, especially in the elderly. has not been shown to reduce the have not been shown to translate into These effects occur less frequently number of exacerbations or hospital- meaningful differences in clinical with the use of rimantadine. izations compared with salmeterol. outcomes. Salsalate is a traditional nonste- The recommended dosage of Conversion from the regular release roidal anti-inflammatory drug tiotropium is the inhalation of one Depakote® to Depakote® ER requires (NSAID) that lacks antipyretic 18-mcg capsule once daily using the approximately a 20% increase in dose. properties. Salsalate has not been HandiHaler® device. The most For example, 1750 mg of regular dispensed in over a year and, commonly reported adverse effect release Depakote® is equivalent to therefore, was deleted from the with tiotropium use in clinical trials 2000 mg of Depakote® ER. Formulary. Other available NSAIDS was dry mouth, followed by other Depakote® ER has a black box include: aspirin, ibuprofen, in- anticholinergic effects (ie, constipa- warning for hepatotoxicity, teratoge- domethacin, and naproxen. tion, increased heart rate, blurred nicity, and pancreatitis. Administra- The manufacturer of clotrimazole vision, glaucoma, urinary difficulty, tion of Depakote® ER is contraindi- vaginal tablets discontinued their and urinary retention). cated in patients with hepatic disease production in 1999. Thus, it was Depakote® ER is a once-daily or significant hepatic dysfunction. deleted from the Formulary. version of valproic acid. Valproic Rimantadine belongs to the Clotrimazole vaginal cream (eg, acid is available in several different adamantane class of antiviral agents. Mycelex®-G) is an alternative formulations. Divalproex sodium It has activity against influenza A therapy. (Depakote®) was introduced as a viruses but not influenza B viruses. Bacitracin and Polymyxin B sustained-release formulation of Rimantadine is FDA approved for Topical Powder (Polysporin®) is a valproic acid that allowed for twice- the treatment of influenza A in adults topical anti-infective. It has been daily dosing. The extended-release and for the prophylaxis of influenza A removed from the Formulary version of divalproex (Depakote® ER) in children at least 1 year of age. because of low utilization. Alterna- was developed to permit once-daily However, the American Academy of tives to this product include neomy- administration. Valproic acid is also Pediatrics recommends rimantadine be cin-bacitracin-polymyxin (Neo- available as a liquid, as Depakote used in the treatment of influenza A in sporin®) ointment, mupirocin Sprinkles®, and for intravenous children. Rimantadine is dosed at 100 (Bactroban®) cream or ointment, administration. mg twice a day for adults and children and bacitracin ointment. Similar to other antiepileptic over 10 years of age. by Wendy D. Smith, PharmD medications, the exact mechanism

PRESCRIBING Tracking physicians’ prescribing patterns: If HIPAA protects patients, then who protects physicians? hen prescriptions are dispensed the quantity, the location where the environment. Prescription databases Win community pharmacies, an prescription was filled, and most are extremely useful in analyzing enormous database is created. When surprisingly, the identity of the patterns of utilization. a patient brings a prescription to be physician writing the prescription. The pharmaceutical industry uses filled, the pharmacist attempts to This process leaves the switch the IMS prescription information to submit an electronic claim for payment companies in possession of a huge define marketing targets for their sales by the patient’s insurer. The informa- amount of data. Unknown to most force, a practice known as “detailing.” tion is transmitted online by commu- pharmacists, these data are then sold The pharmaceutical companies use nity pharmacies to independent com- to an information company known the IMS data to identify physicians in panies, known as “switch” companies. as IMS America (IMS). IMS, in turn, specific practice areas prescribing the The switch companies provide infor- organizes the prescription information drugs they are interested in. The mation about the patient’s third-party and these data are sold to pharmaceu- reports contain information for all prescription coverage and required co- tical companies. drugs, not just those manufactured by payments back to the pharmacy at the Data and information are essentials that particular company. They contain time of dispensing. Each transaction of decision-making in any industry. prescription-writing information for all submitted to the switch company The large amount of documentation drugs within a class. This educates 2 contains the drug dispensed, the date, used in health care creates a data-rich (continued on next page) Prescribing, from page 2 ceutical industry to focus their market- telemarketers. It would prohibit switch the industry on which physicians are ing efforts to receive the largest companies from selling prescription prescribing what drugs. This would capital return. It also allows compa- data for physicians who ask that their also provide insight to determine if nies to “research” the success of new information not be used for marketing. another company is outselling them or innovative marketing strategies. The bill would not block the informa- on a particular drug. Determining However, in order for “research” to tion for public health research. prescription-writing patterns allows occur, consent from the “subject” is The pharmaceutical industry companies to monitor the success of required, right? Not in the case of contends that IMS data are helpful to their sales force. prescribing data. patients because it directs the indus- Pharmaceutical sales jobs are unlike Under current federal law, physi- try to physicians that can be contacted many occupations because the repre- cians, unlike patients, have no specific for clinical trials and physicians to sentatives do not report to their right to privacy. Neither the switch notify when a drug is recalled or to “office” for work. Most of their time companies selling the information nor distribute important safety informa- is spent in the community. Therefore, the company buying the information tion. market share data provide a tool for ◆ Most physicians and pharmacists the industry to monitor the activities are unaware this process even occurs. and success of their sales representa- Prescription-tracking There is no official documentation or tives. If IMS data contained only information provides a very reference describing the process of information about individual drug clear picture of prescribing prescription tracking. One of the utilization, it would be impossible to services offered by IMS is “Brand measure the success of a sales force patterns of physicians. Management.” The IMS website in relative terms. For example, if the This information is not (http://www.imshealth.com/ims/ pharmaceutical company only knew portal/front/indexC/0,2773,6599_ that sales for their new ACE inhibitor considered privileged and, 43089764_0,00.html) states that in the Gainesville area generated therefore, consent is “Brand Management contributes to $50,000 per month, it might think the not required for the our customers’ [the pharmaceutical marketing of the drug was successful. industry] success by providing tools, However, if the data showed the total information to be sold in an business intelligence, services and market share for all ACE inhibitors in effort to target marketing. expertise at every phase of a product’s Gainesville was $500,000 per month, lifecycle. Our goal is to ensure maxi- it would stimulate the company to mum market share while minimizing are required to obtain consent from increase its marketing efforts. Deter- the effects of product maturity, generic physicians or patients. They are not mining the percentage of the total erosion and other factors contributing required to obtain consent from market share a drug has provides a to a decline in market share.” Provid- patients because the information in measuring tool to monitor improve- ing the pharmaceutical industry with the database does not identify the ment and failure of sales efforts. prescription-tracking information patient. Even though the physicians’ IMS data are also used to help sales earned the IMS company $1.4 billion in identities are contained in the data, teams target physicians who have the revenue in 2003.1 the data are not considered protected. largest potential to affect their market Prescription-tracking information This practice may change in the share. Physicians who prescribe large provides a very clear picture of pre- future. quantities of the class of medication scribing patterns of physicians. This The California Medical Association they are interested in are identified and information is not considered privi- has proposed a bill to the state Senate targeting for marketing. This allows leged and, therefore, consent is not granting physicians the ability to stop streamlining of the marketing efforts required for the information to be sold companies from using information in order to gain the largest increase in in an effort to target marketing. This about their prescription-writing habits market share. Representatives of the may change in the future as more in marketing campaigns. The group pharmaceutical industry are often physicians become aware of this states that detailing is harmful to rewarded for increasing their market practice. For more information on IMS, patients because it encourages share above a predetermined quota. visit http://www.imshealth.com. physicians to use expensive brand- The data provided by IMS are very by Wendy D. Smith, PharmD name drugs when cheaper, generic specific. They identify physicians by equivalents exist. The bill, AB 262, REFERENCE DEA numbers writing prescriptions for would create a “do-not-sell list” 1. http://www.ims-america.com/ims/portal/front/ the drug of interest. Approximately 10 articleC/0,2777,6599_18731_40198214,00.html modeled after “do-not-call lists” for (accessed June 23, 2004). years ago, the information could only be drilled down to the zip code for the area where the drug was being pre- POLICIES AND PROCEDURES scribed. During this time, drug rep- resentatives visited community Alcoholic beverages and patients pharmacies and asked the pharmacists about the prescribing habits of local lcoholic beverages (beer, whis- holic beverages from the Formulary physicians. Technology has allowed A key, and wine) were deleted was because the effectiveness of the IMS information to become much from the Formulary in March of 2003. using alcohol to prevent alcohol more precise by identifying the DEA Since that time, there have been withdrawal is uncertain. Appropriate number of the physician. requests to allow patients to bring therapeutic uses of alcohol in the Within the institutional setting, a their own alcohol into the hospital hospital setting are for the treatment similar database is created describing similar to patients bringing their of ethylene glycol and methanol the usage patterns for the entire home medications to use while they poisonings. A review on the treat- hospital. The difference here is that are in the hospital. It is against ment of alcohol withdrawal may be the data cannot identify individual hospital and university policy to found at http://www.shands.org/ physicians. bring alcoholic beverages to campus. professional/drugs/bulletins/0204.pdf. Detailed reports of physicians’ pre- The rationale for eliminating alco- by Wendy D. Smith, PharmD 3 scribing-patterns allow the pharma- Drugs & Therapy SHANDS NON-PROFIT ORG. U.S. POSTAGE B ◆ U ◆ L ◆ L ◆ E ◆ T ◆ I ◆ N Shands at the University of Florida DRUG INFORMATION SERVICE PAID GAINESVILLE, FL Volume 18, No. 7 July/August 2004 PO Box 100316 PERMIT NO. 94 Gainesville, FL 32610-0316 This publication is produced by the Drug Information and Pharmacy Resource Center under the direction of the Department of Pharmacy Services and the Pharmacy and Therapeutics Committee. EDITOR, DRUGS & THERAPY BULLETIN Randy C. Hatton, PharmD DIRECTOR, PHARMACY SERVICES Alan Knudsen, MS, RPh CHAIRMAN, PHARMACY & THERAPEUTICS COMMITTEE Ricardo Gonzalez-Rothi, MD EDITING, DESIGN, & PRODUCTION Shands HealthCare’s Publication Svcs.  Copyright 2004. All rights reserved. No portion of the Drugs & Therapy Bulletin may be reproduced without the written consent of its editor. FOR MORE INFORMATION, VISIT US ONLINE http://shands.org/professional/drugs/ bulletin.htm

Drug information forum, from page 1 favorable gastrointestinal profile of aspirin first and wait a period (eg, 2 This leaves prescribers and patients COX-2 inhibitors.5 Rates of GI events hours) before administering a tradi- wondering whether a traditional NSAID in patients on a COX-2 inhibitor and tional NSAID (eg, ibuprofen). and low dose aspirin is acceptable. Of low-dose aspirin approach rates If a patient requires chronic therapy course, both aspirin and the NSAID expected with a traditional NSAID. with a traditional NSAID and low-dose can cause gastrointestinal effects. A traditional NSAID plus a gastro- aspirin, an alternative to ibuprofen Ideally, they would not be used intestinal protective agent (eg, miso- could be considered. A gastrointestinal together. If the NSAID cancels part of prostol) would be another reasonable protective agent, like misoprostol or a the therapeutic benefit of aspirin, the alternative in a patient on low dose proton-pump inhibitor could be added additive toxicity would result in an aspirin. Of course, this assumes that to the regimen. even worse benefit versus risk ratio. the patient has failed acetaminophen. Data suggest that chronic use of low- There is some evidence that not all If low-dose aspirin is avoided in dose aspirin with a COX-2 inhibitor traditional NSAIDs have the same patients on a COX-2 inhibitor, there is increases the risk of gastrointestinal blocking effects with low dose aspirin. some evidence that the rate of cardio- adverse effects. A COX-2 inhibitor alone Therefore, if a traditional NSAID is vascular events may be higher than appears to have inferior cardioprotec- chosen to treat chronic pain (ie, with a traditional NSAID.6 This is not tive effects compared with a traditional because of the low cost of the generic surprising, since traditional NSAIDs NSAID. How these risks and benefits of versions of these products), a tradi- do bind to the COX-1 receptor on a COX-2 inhibitor balance is not clear. tional NSAID other than ibuprofen (eg, platelets and have been shown to REFERENCES 7 naproxen, diclofenac) could be con- confer cardioprotective effects. Unlike 1. Catella-Lawson F, Reilly MP, Kapoor SC, et al. sidered. Also, aspirin should be given aspirin, however, this inhibition is Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809-17. 2 hours before the dose of the NSAID. reversible and does not appear to be 2. MacDonald TM, Wei L. Effect of ibuprofen on equally effective. cardioprotective effect of aspirin. Lancet 2003;361:573-4. ASA and COX-2 Inhibitors 3. Kurth K, Glynn R, Walker A, et al. Inhibition of clinical Another alternative is to use a COX- Summary benefits of aspirin on first myocardial infarction by non- 2 specific inhibitor (eg, celecoxib) for If acetaminophen is effective, it steroidal antiiinflammatory drugs. Circulation 2003;108:1191-5. 4. Patel TN, Goldberg KC. Use of aspirin and ibuprofen patients with chronic pain receiving should be considered a first-line agent compared with aspiring alone and the risk of myocardial low-dose aspirin. This appears to make for patients on low-dose aspirin being infarction. Arch Intern Med 2004;164:852-6. 5. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointesti- sense because COX-2 inhibitors are treated for mild to moderate chronic nal toxicity with celecoxib vs nonsteroidal anti-inflammatory associated with less gastrointestinal pain (eg, osteoarthritis). drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term effects and they do not block the COX- If acetaminophen is ineffective and Arthritis Safety Study. JAMA. 2000;284:1247-55. 1 receptor on platelets. COX-2 inhibi- traditional NSAIDs are used for inter- 6. Bombardier C, Laine L, Reicin A, et al. Comparison of tors should not mitigate the cardio- mittent pain, the interaction between upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N protective effects of low-dose aspirin. low-dose aspirin and traditional NSAIDs Engl J Med. 2000 Nov 23;343(21):1520-8. Unfortunately, there is some has not been shown to be clinically 7. Kimmel SE, Berlin JA, Reilly M, et al. The effects of 3 nonselective non-apirin non-steroidal anti-inflammatory 4 evidence that the gastrointestinal significant. However, it would be medications on the risk of nonfatal myocardial infarction effect of low-dose aspirin cancels the prudent to administer the low dose and their interaction with aspirin. J Am Coll Cardiol 2004;43:985-90.