Volume 22, Number 1 January 2008 Drugs & Therapy B � U � L � L � E � T � I � N

FORMULARY UPDATE PRESCRIBING The Pharmacy and Therapeutics Committee met November 20, 2007. Discontinue stress, discontinue 2 drugs were added in the Formu- lary, and 4 drugs or dosage forms prophylaxis were deleted. 5 drugs or dosage tress ulcers are superficial lesions should be discontinued in patients with- forms were designated nonformulary involving the mucosal layer of the out an additional indication for use (eg, and not available. Criteria for use S that appear after major stressful gastrointestinal reflux disease [GERD] or were changed for 3 drugs. events.1 Critically ill patients admitted history of GI bleed). When a patient trans- ◆ ADDED to intensive care units (ICUs) are at an fers or is discharged from an ICU, there is increased risk for suffering from compli- an opportunity to discontinue SUP. Ambrisentan cations related to stress ulceration.2 As An audit of SUP use in the ICUs at (Letairis® by Gilead Sciences)* such, stress ulcer prophylaxis (SUP) is Shands at UF was recently conducted. *Restricted to patients approved for the appropriate for many critically ill patients. Thirty adult patients receiving SUP were Letairis Education and Access Program SUP is defined as any medication used followed during their hospital admis- to prevent formation of stress ulcers and sion, beginning upon admission to the Anidulafungin includes , , prostaglan- surgical (SICU). When (Eraxis® by Pfizer)† din analogues, histamine H2-receptor and †Restricted to approval by the ID antagonists, and proton-pump inhibitors were no longer present, SUP was no lon- Consult Service, Dr. Wingard, or the (PPIs). Although these therapies are con- ger considered necessary. Other reasons Antimicrobial Management Program sidered effective, there are disadvantages to continue SUP included acid suppres- associated with their use. A higher gas- sion therapy prior to admission, or a past ◆ DELETED tric pH is associated with gastric microbi- medical history of GERD or a GI bleed. Aprotinin (Trasylol® by Bayer)‡ al growth, tracheobronchial colonization, Upon transfer from the SICU, 73% of 3 patients were continued inappropriately, ® ‡ and nosocomial . Unnecessary Caspofungin (Cancidas by Merck) use of acid suppression therapy has been 16% continued appropriately, and only Itraconazole, Intravenous associated with the development of com- 11% discontinued appropriately. A similar (Sporanox® by Ortho Biotech)‡ munity-acquired pneumonia, as well as evaluation was conducted for 30 patients community-acquired Clostridium difficile in the medical intensive care unit (MICU). Effervescent Tablets infections.4,5 Both studies were conducted Upon transfer from the MICU, 36% were (Zantac® Efferdose by Glaxo- in outpatients and found an association continued inappropriately and 64% con- SmithKline)‡ between the use of acid suppression tinued appropriately. SUP was discontin- ‡Nonformulary and Not Available therapy and infection.4,5 In addition, long- ued appropriately in none of the patients. term PPI use, particularly at high-doses, The evaluation also indicated that some ◆ NONFORMULARY AND has been associated with an increased patients (ie, 15% from the SICU and 5% NOT AVAILABLE risk of hip fracture (ie, osteoporosis).5 SUP from the MICU) were discharged from the Ramelteon (Rozerem® by Takeda also increases the number of medications hospital on acid suppression therapy with Pharmaceuticals) a patient receives, as well as the cost of no indication for continued use. their treatment.3 The results of this audit show that ◆ CRITERIA-FOR-USE CHANGES Several risk factors have been identi- some critically ill patients are unneces- fied for the development of stress ulcers, sarily continued on SUP upon discharge Altretamine (Hexalen® by MGI including , coagulopa- from the ICUs. SUP should be discontin- Pharma)§ thy, , , hepatic failure, ued upon elimination of risk factors. §Requires a Chemotherapy Order renal failure, , burns, and major Appropriate use of SUP may translate Form; Nonformulary. trauma.2 A prospective, multi-center to a reduction in adverse events and Ceftriaxone (Rocephin® & generics)** cohort study conducted by Cook and healthcare expenditures. By Sarah Bush, PharmD ** colleagues identified 2 independent risk Resticted:Cannot be used in infants factors for bleeding. The strongest risk (References listed on page 4) 28 days old or less factors are mechanical ventilation for Meningococcal Polysaccharide more than 48 hours and coagulopathy, Diphtheria Toxoid Conjugate Vac- defined as a platelet count less than ◆ ® †† 3 cine (Menactra by Sanofi Pasteur) 50,000 mm , an International Normalized INSIDE THIS ISSUE ††Can be used in patients from 2–55 Ratio (INR) of greater than 1.5, or a partial thromboplastin time of greater than 2 years of age ◆ P&T 2007 times the control value.2 (continued on next page) When risk factors no longer exist, SUP Formulary update, from page 1 Anidulafungin was added in the For- significant higher rate compared with Ambrisentan was approved by the mulary as the sole representative of the either of the other treatment arms. FDA in June 2007 with a labeled indi- echinocandin antifungal agents. Caspo- This trend of higher mortality with cation for the treatment of pulmonary fungin was deleted from the Formulary aprotinin was observed throughout arterial (WHO Group 1) and designated nonformulary and not the study. Although less blood was in patients with WHO class II or III available. Micafungin (Mycamine®) re- used in the aprotinin arm compared symptoms to improve exercise capac- mains nonformulary and not available. with either of the other treatments, ity and delay clinical worsening. It is The echinocandins were originally more deaths due to hemorrhage were an alternative to bosentan (Tracleer®), reviewed in November 2006. At that observed in the aprotinin arm. The which is listed in the Formulary but time, caspofungin, micafungin, and data safety board con- restricted to patients who have been anidulafungin were deemed equiva- cluded that continued enrollment of approved for bosentan’s restricted lent. Caspofungin was selected as the patients was unlikely to change these drug distribution program. formulary agent, and micafungin and findings. Due to the risk of hepatic injury anidulafungin were designated nonfor- The FDA is currently evaluating and birth defects, ambrisentan also is mulary and not available. these results and determining what only distributed through a restricted The echinocandins were re-evalu- additional actions are needed (eg, drug distribution program (ie, the Le- ated because increased competition further modification of the product tairis Education and Access Program among these products has resulted in labeling or permanently pulling the [LEAP]). Prescribers and pharma- cost reductions. Little new evidence drug from the market). These data cists must call 866-663-LEAP (5327) has been published in the last year. from a randomized controlled trial to enroll patients. In order to stock There is a study showing equivalency are consistent with an observational ambrisentan, hospitals must sign an of micafungin at doses of 100 mg and study published approximately a year agreement that it will be dispensed 150 mg once daily with standard doses ago that also found a higher rate of only to patients who are already en- of caspofungin for the management of mortality with aprotinin. The Director rolled in the restricted drug distribu- candidemia and invasive candidiasis. In of the Office of New Drugs was quot- tion program (ie, LEAP). addition, results from a study compar- ed as saying, “FDA cannot identify a Compared with bosentan, ambrisen- ing anidulafungin to fluconazole in the specific patient population where we tan costs roughly the same (ie, approxi- management of invasive candidiasis believe the benefits of using Trasylol® mately $50,000 per year). Bosentan is were published, and anidulafungin was [aprotinin] outweigh the risks.” given twice a day, while ambrisentan found to be noninferior to fluconazole. The FDA’s decision not to recall is given once a day. Anidulafungin was selected for the aprotinin was intended to prevent There is limited information pub- Formulary because it results in the a shortage of alternatives (ie, amin- lished on the efficacy of ambrisentan; most potential cost savings. ocaproic acid and tranexamic acid). but there is a theoretical pharmaco- Aprotinin is a proteolytic enzyme Shands at UF has been able to get an logic advantage for ambrisentan; it is from bovine lung that has a labeled ample supply of aminocaproic acid more specific for blocking endothelin indication for the prevention of blood and tranexamic acid to be used as an A, which is responsible for vasocon- loss and transfusion in patients under- alternative. Based on the new warn- striction and tissue damage in the going surgery requiring cardiopulmo- ings and the availability of alterna- pulmonary vasculature. nary bypass. It was deleted from the tives agents, the P&T Committee Both bosentan and ambrisentan are Formulary and designated nonformu- determined that the continued use pregnancy risk category X because of lary and not available after marketing of aprotinin is not warranted at this their teratogenic potential. Both also was suspended based on recent safety time. are associated with liver dysfunction; concerns. Itraconazole IV is an intrave- however, noncomparative incidence The FDA recently released safety nous triazole antifungal agent that data suggest that the rate of hepato- information from the study, Blood has been used for the treatment of toxicity may be lower with ambrisen- Conservation Using Antifibrinolyt- susceptible fungal infections. Ortho tan. Also, a small case series, which ics: a Randomized Trial in a Cardiac Biotech is discontinuing the sale and has been reported as an abstract, Surgery Population or BART. This study distribution of Sporanox® injection, suggests that patients intolerant to was done to determine if aprotinin but itraconazole capsules and oral bosentan (ie, elevated LFTs) may is superior to aminocaproic acid and solution will continue to be available. tolerate ambrisentan. These limited tranexamic acid in terms of decreasing Currently there are other antifungal benefits for ambrisentan are balanced massive postoperative bleeding, mini- options for the treatment of these by the fact that there is considerably mizing exposure to blood products, and infections. Itraconazole was deleted more efficacy data on bosentan, and, decreasing both fatal/life-threatening from the Formulary and designated because bosentan has been used more or serious post-operative complications. nonformulary and not available. extensively, there is a greater under- It was a 25-center study in Canada. Ranitidine effervescent tablets standing of its safety profile. If aprotinin was found to decrease al- were deleted from the Formulary and The current American College of logenic exposure and decrease clinical designated nonformulary and not Chest Physician guidelines do not complications, then its use would be available. GlaxoSmithKline no longer specify when or if ambrisentan would endorsed. If aprotinin only decreased makes these effervescent tablets, be preferred over bosentan. However, exposure to allogenic blood products, which were rarely used. the limited data available suggest then an economic evaluation was The only alternative to ranitidine that ambrisentan may be an alterna- planned. If the therapies were found effervescent tablets is ranitidine tive in patients who do not tolerate to be equally effective, the researchers syrup 15 mg/mL, which uses sorbitol bosentan. Bosentan is currently felt that the preferential use of amin- as a vehicle and sweetener. In larger recommended in patients with early ocaproic acid would be justified. doses, the amount of sorbitol in raniti- functional class III PAH, especially in The data safety monitoring board for dine syrup has been associated with patients who are not good candidates the BART suspended the study when an increased incidence of diarrhea. for sildenafil (eg, patients with ocular the 30-day mortality in the aprotinin The sweet taste of this syrup has not disease or recurrent epistaxis). group nearly reached a statistically (continued on next page) 2 Formulary update, from page 2 Altretamine, also known as hexa- ent infusion lines and that calcium- been tolerated by some adult methylmelamine, is a synthetic anti- containing solutions or products must patients. neoplastic agent effective in the treat- not be administered within 48 hours Ramelteon is a unique hypnotic ment of some ovarian tumors resistant of the last administration of ceftriax- that does not work at GABA recep- to alkylating agents. Its mechanism of one. These warning are based on 5 tors; it is not a controlled substance action is not related to any other avail- neonatal deaths reported between because it has limited abuse poten- able antineoplastic. This capsule is not 1992 and 2002 by post-marketing tial. It is the first in a new class of listed in the Formulary. surveillance where there was an agents known as melatonin recep- Altretamine must be metabolized association between ceftriaxone and tor agonists. Ramelteon selectively to be active. Altretamine is associated calcium-containing products and targets the MT1 and MT2 melatonin with dose-related myelosuppression crystalline material found in the kid- receptors, which are believed to be (ie, leukopenia and thrombocytopenia), ney and lungs upon autopsy. involved in the promotion of sleep which occurs 3-4 weeks after begin- The P&T Committee found no and the maintenance of the normal ning altretamine therapy. conclusive evidence to support a circadian rhythm. Ramelteon has a Since altretamine is a cytotoxic che- significant safety risk of ceftriaxone 3- to 16-times higher affinity for the motherapy agent associated with dose- in non-neonate patients. Ceftriax- receptors than melatonin. dependent myelosuppression, it was one use in children 28 days old or Ramelteon is rapidly absorbed, but added in the list of medications that younger will be prohibited based on has poor bioavailability (1.8%) due to must be ordered via a Chemotherapy the contraindication language in the high hepatic first-pass metabolism. Order Form. labeling. The half-life is short and ranges from Ceftriaxone is an injectable third- Menactra® is 1 of 2 meningococcal 1-2.6 hrs. Metabolism is primarily generation cephalosporin with activity vaccines currently listed in the For- oxidation via CYP1A2 isoenzymes. against gram-positive and gram-neg- mulary. It was initially reviewed and Serum concentrations of ramelteon ative bacteria. Its penetration into the added in the Formulary in January and the major active metabolite are central nervous system has made it a 2007. It is the first and only quadri- essentially undetectable at 24 hours. valuable agent in the treatment of men- valent conjugate vaccine licensed in Rozerem® only has an FDA-labeled ingitis. Its long half-life has allowed for the US for the prevention of menin- indication for the treatment of insom- once-daily dosing. gococcal disease and offers protec- nia characterized by difficulty with The criteria for ceftriaxone use were tion against 4 of the 5 most common sleep onset. The recommended dos- reviewed based on recent changes to serogroups that cause meningococcal age is 8 mg taken within 30 minutes the product’s labeling. These changes infection. of going to bed. Dosage adjustments include a contraindication for the At the time of its initial review, are not needed in patients with renal co-administration of ceftriaxone and Menactra® only had a labeled indica- impairment and caution is advised in calcium-containing intravenous solu- tion for patients aged 11–55 years patients with hepatic impairment. tions, including parenteral nutrient of age. However, the manufacturer Published clinical trials have shown preparations, in neonates age 28 days has recently been granted approval a small (ie, approximately 10-15 or younger. Ceftriaxone was already to expand the indication to include minutes) but statistically significant contraindicated in hyperbilirubinemic patients 2–10 years of age based on decrease in sleep latency when newborn infants. recent studies. These studies dem- compared to placebo. Effects on total Cefotaxime is an alternative third onstrated that seroconversion rates sleep time and sleep efficiency are generation cephalosporin that was were similar between Menactra® and even less pronounced and are not added in the Formulary specifically Menomune®. Therefore, both Menac- consistently observed in all trials. for use in neonates (ie, because of the tra® and Menomune® are available for Currently there are no clinical trials biliary sludging associated with ceftri- patients 2–10 years of age. Menac- comparing ramelteon with other hyp- axone use). tra® will still be available to those notic agents. New warnings were added in the patients aged 11–55 and Menomune® During clinical trials, 6% of patients labeling stating that ceftriaxone should for those patients older than 55 years exposed to ramelteon discontinued not be mixed or administered simul- that are identified as candidates for treatment, with the most common taneously with calcium-containing meningococcal vaccination. adverse effects being headache, diz- solutions or products, even via differ- ziness, and fatigue. In addition, long- term use has been associated with increased prolactin levels in women. Drug interactions are a concern with To Report an Adverse Drug Reaction ramelteon, especially for strong in- hibitors of CYP1A2. Co-administration Call the ADR Hotline: 5-ADRS (5-2377) with fluvoxamine results in a 190-fold increase in AUC and 70-fold increase PROVIDE: in Cmax of ramelteon. The clinical significance of increased levels has n Patient’s name n Whether the reaction was — probable, possible, or definite not been determined. n Patient’s location Although ramelteon may appear to n Your name and pager # or n Suspected drug(s) have several advantages over other extension hypnotic agents, data from clinical tri- n Type of reaction als show that it has minimal efficacy. Since ramelteon is not a controlled And we’ll do the rest! substance, patients will be allowed to use their own supply from home; ◆ however, it will not be obtained for nonformulary use. % ADR HOTLINE: 5-ADRS 3 Drugs & Therapy SHANDS NON-PROFIT ORG. B � U � L � L � E � T � I � N Shands at the University of Florida U.S. POSTAGE DRUG INFORMATION SERVICE PAID GAINESVILLE, FL Volume 22, No. 1 January 2008 PO Box 100316 PERMIT NO. 94 This publication is produced by the Gainesville, FL 32610-0316 Drug Information and Pharmacy Re- source 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 2008. 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/professionals/ druginfo/bulletin.asp

NEWS P&T Committee Actions 2007

nother year of Pharmacy and were requested; the rest of the additions take the time to read the changes that ATherapeutics (P&T) Committee were proactive actions taken by the P&T occur each month. Back issues of the activity was just completed. During Committee. 31 drugs were deleted from Bulletin are available on the Internet at this time, the Committee met 10 times. the Formulary. http://www.shands.org/professionals/ The goals of the Committee are to use 34 drugs were reviewed by the P&T drugInfo/bulletin.asp. evidence-based principles to Committee and designated nonformu- If you have questions or comments establish drug use policies and to estab- lary and not available. These medica- about the activities of the P&T Commit- lish a formulary. In addition, medication tions cannot be obtained through a tee, please contact us. Dr. Ricardo Gon- safety is promoted. nonformulary request. 16 of the prod- zalez-Rothi chairs the P&T Committee. The P&T Committee is a medical ucts designated “not available” were This is his 8th year leading this medical staff committee that is the formal line of removed from the market. staff committee. Dr. Gonzalez-Rothi can communications between the medical Several drug use policies were ap- be reached by e-mail at ricardo.gonzalez- staff and Shands at UF as it relates to all proved. For example, a policy was [email protected]. Correspondence drug-related matters. Currently, 16 medi- approved that prohibits a drug manu- regarding P&T procedures can be sent cal staff members help decide which facturer’s sales representative from by regular mail to Secretary, P&T Com- drugs are readily available for use, what promoting the off-label use of drugs at mittee, PO Box 100316, or by e-mail to limitations should be put on those drugs Shands at UF. Also, policies were passed [email protected]. that are available, and what can be done to continue to standardize IV concen- to improve medication safety. Members trations and establish ready-to-use References (from page 1) of the P&T Committee are appointed by doses (eg, for electrolytes like calcium, 1. American Society of Health-System Pharmacists. the Chief of Staff. magnesium, phosphate, and potassium) ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health-Syst Pharm 1999;56:347-79. The Formulary is a list of drugs that and to discontinue orders for drugs with 2. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for are readily available for use. Drugs automatic stop orders or unapproved re- gastrointestinal bleeding in critically ill patients. N Engl J Med 1994;330:377-81. listed in the Formulary can be found on stricted drugs. Therapeutic interchange 3. Dial S, Delaney JAC, Barkun AN, et al. Use of gastric the Shands intranet at http://tinyurl. changes, IV-to-oral conversions, physi- acid-suppressive agents and the risk of community- acquired clostridium difficile-associated disease. JAMA com/yw28td. This database of drugs cian approved protocols, and restriction 2005;294:2989-95. listed in the Formulary requires a portal changes were also approved. 4. Laheij RJF, Sturkenboom MCJM, Hassing RJ, et al. username and password, if you are not The Drugs & Therapy Bulletin (now Risk of community-acquired pneumonia and use of gas- tric acid-suppressive drugs. JAMA 2004;292:1955-60. nd already logged into the portal. beginning its 22 year of publication) 5. Yang YX, Lewis JD, Epstein S, et al. Long-term proton Last year, 21 new products were add- remains the primary method for commu- pump inhibitor therapy and risk of hip fracture. JAMA 2006;296:2947-53. 4 ed in the Formulary. Only 7 new drugs nicating P&T Committee actions. Please