Controlled substance diver-sion is a major challenge for

hospitals across the country. The problem is being fueled, in part, by the power of addiction: It is esti-mated that 10% to 15% of health professionals will develop serious substance abuse/addiction prob-lems during their career (Crit Care Med 2007;35:S106-S116). Experts warned during a recent webinar

Addiction Cited As Powerful Diversion Driver

After four years, the effectiveness of the FDA’s mandatory Risk

Evaluation and Mitigation Strate-gies (REMS) program remains open to question because drug companies have failed to comply with key report-ing requirements and the agency lacks adequate enforcement authority to take action against them, accord-ing to a report by the Department of Health and Human Services’ Office of Inspector General (OIG).

Nearly one-fourth of the drug com-panies with medications in the REMS program were found to be in violation of legislatively approved timetables for data reporting, according to the OIG report. Furthermore, less than 15% of the companies had met all of the safety goals stipulated in their products’ REMS.

As for the FDA, the agency has reviewed only one of 32 drugs whose REMS contain “elements to assure safe use” (ETASU)—usually reserved

OIG Says REMS Program Falling Short Of Goals

Hospital pharmacists face several challenges in helping manage antibiotic-resistant, gram-negative

superbugs that produce carbapenemases. One of the most worrisome is carba- penemase-producing Klebsiella pneumoniae (KPC).

A report in the March issue of Infection Control and Hospital Epi-demiology (2013;34:259-268) found that the proportion of K. pneumoniae cases resistant to carbapenems increased from 0.1% in 2001 to 4.5% in 2010. “That is huge,” said Robert Rapp, PharmD, a professor of pharmacy and sur-gery emeritus at the University of Kentucky Medical Center in Lexington, who is one of many pharmacists concerned about KPC.

Those concerns were compounded by a Centers for Disease Control and Prevention’s report on the rising preva-lence of carbapenem-resistant entero-bacteriaceae (CRE). According to the report, in the last decade, hospitals have seen a four-fold increase in CRE, with most of the increase attrib-utable to Klebsiella species (MMWR 2013;62:1-6).

In Ranking of Superbugs, Klebsiella Takes the Lead

Las Vegas—A San Antonio health care sys-tem markedly reduced unnecessary use of proton pump inhibitors (PPIs) for stress ulcer prophylaxis (SUP) in the ICU and ended up saving $80,000 annually. At a Boston-area hospital, research-ers determined that reducing inappropriate PPI use among general medicine patients could lead to yearly cost avoidance in the neighborhood of $1 million.

Both initiatives, presented at the Decem-

ber 2012 Midyear Clinical Meeting of the American Society of Health-System

Pharmacists (ASHP), were under-taken to address persistent inap-

propriate use of PPIs, which has been linked to higher hospital costs and an increased risk for Clostridium difficile infections (sidebar, page 30). “Many of our general medicine

patients were on PPIs or H2-recep-tor agonists constantly, and no one

Shifting the Main Focus of Acid Suppression to the Critically Ill

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Las Vegas—Pharmacists can more easily help make improvements in their health care settings by working in multidisciplinary teams, according to a session on safety and quality pearls presented at the American Society of Health-System Pharmacists 2012 Midyear Clinical Meeting.

“We [as pharmacists] sometimes have tunnel vision,” said Lt. Col. Jorge Car-rillo, PharmD, the deputy director of the Military Vaccine Agency, in Falls Church, Va., who organized the pearls session. It’s important to work in mul-tidisciplinary teams, and consider sev-eral strategies to solve a problem, he told Pharmacy Practice News.

During the session, pharmacists detailed efforts to improve medica-tion and patient safety, ranging from reducing distractions during medica-tion administration and optimizing the delivery of high-risk medications via infusion pumps, to better educat-ing staff on storage requirements for replacement drugs during shortages. For many of the improvement projects described below, pharmacists worked in conjunction with nurses, informa-tion technology specialists or other health care workers to effect change.

Less Distractions Equals Fewer Med Errors

Giving nurses protected time to administer medications without inter-ruptions reduced the number of medi-cation administration errors linked to disruptions by half, pharmacists at the Cleveland Clinic have found.

From January to June 2011, research-ers observed that 47% of medication administration errors reported through the Cleveland Clinic’s voluntary report-ing system for two nursing units were caused, at least in part, by workflow disruptions, according to Alina Bulgar, PharmD, PhD, the hospital’s coordinator of medication regulatory and accredita-tion services. Each medication adminis-tration had an average 4.1 interruptions or distractions such as phone calls, con-versations with patients or staff, missing medications or noise.

Dr. Bulgar and her colleagues cre-ated a set of interventions to reduce distractions and raise staff awareness that medication administration was in progress. The measures, tested in two nursing units, included 45-minute “medication pass time-outs” at com-mon medication administration times (9 a.m., 1 p.m. and 9 p.m.), during which nurses could turn off their wireless phones and have calls triaged by the health unit coordinator and an assis-tant nurse manager or charge nurse; red badges with the words “medication pass” on red lanyards on the comput-ers on wheels that nurses used during medication delivery; and “do not dis-turb” signs to be put on patient room doors when nurses were administer-ing medications. The pharmacy team used tape to mark off a “quiet zone” on the floor surrounding automated dis-pensing cabinets. The team also devel-oped educational resources, including an information sheet for patients and families that explained the medication administration process and asked them to refrain from asking nurses social and personal questions during that time. They also created a medication admin-istration checklist for nurses.

After the intervention, data from

January to June 2012 showed that only 20% of medication errors had work-flow disruptions as a cause or con-tributing factor, and each medication administration averaged two interrup-tions or distractions. The biggest suc-cess has been a decrease in “significant interruptions from other personnel,” Dr. Bulgar said. She added that the overall number of medication errors has decreased since implementing the interventions, “although more research is needed to determine if there is a direct correlation.”

Five additional units now follow that process, she said, and the pharmacy-nursing team is rolling it out through-out the main hospital and affiliated regional hospitals.

The work was funded by the Cardinal Health Foundation.

Education, Formulary Changes Decrease Naloxone Overuse

A pharmacy-led multidisciplinary team at a small Massachusetts health system has reduced the frequency of nar-cotic oversedation requiring naloxone administration.

Nicole Clark, PharmD, BCPS, the phar-macy clinical manager for Hallmark Health Systems, Inc., in Medford, a two-community hospital system comprising 340 inpatient beds, and her colleagues

Process Improvement Requires Collaboration

TheClevelandClinichascutmedicationdis-tractionsinhalfviatheuseofsignsandbadgesthatsignalthatdrugadministrationisoccurring.

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ANESTHESIOLOGy/PAIN

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BIOTECHNOLOGy

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CRITICAL CARE

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Robert P. Rapp, PharmD, Lexington, KY

INTERNAL MEDICINE

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Pharmacy Practice News • April 2013

Safety and Quality Pearls

Clinical 3

noticed an uptick in naloxone usage, from two to five instances per quarter, to 10 instances. In all 10 cases, patients had been receiving hydromorphone for pain.

A pharmacy-led multidisciplinary medication safety subcommittee that was formed to look into the issue realized that they had “one-size-fits–all” dosing recommendations for patient-controlled analgesia (PCA). The committee’s fix was to establish three dosing groups for morphine, hydromorphone and fentanyl PCAs: patients who were over the age of 64 years, had sleep apnea or weighed less than 50 kg; patients who were opioid-tolerant; and patients not in one of these other groups (the majority of patients). They also created a series of six online education sessions on pain management, with narrated slides, interactive case studies and a podcast. They held a “Pain Day,” offering a half hour of continu-ing education credit for participation, including games and activities related to pain management. The group also orga-nized a physician grand rounds educa-tion session on acute pain management.

The team also recommended a change to the formulary, eliminating 4-mg

injections of hydromorphone and add-ing 1-mg injections of the drug to allow for more incremental dosing. They rec-ommended changing the hydromor-phone order strings for physicians to include only the most appropriate doses and frequencies, and posted a visual medication safety alert in each unit that compares dosing of hydromorphone with that of other medications, includ-ing morphine, to illustrate the potency differences of the medications. All rec-ommendations were approved by the Pharmacy & Therapeutics Committee before implementation, Dr. Clark noted.

Post-intervention, the health system is averaging seven naloxone events per quarter, and the team is still in the pro-cess of making improvements.

Dr. Clark said, “What we thought was going to be a temporary multi-disciplinary team has now become a very important group in our health sys-tem working toward improving safety

and quality.” She added that the team is updating PCA nursing documenta-tion to improve methods of assessing sedation, including utilizing the Pasero Opioid-Induced Sedation Scale (POSS). Once this is completed, the group will incorporate POSS into all pain assess-ments. The team also is looking at appropriate use of fentanyl patches.

Replacement Drug Log Alerts Staff to Substitutions During Drug Shortages

The pharmacy team at Connecti-cut’s Bristol Hospital has streamlined their process of ordering and storing replacement drugs during shortages.

The work started following a recent shortage of gemcitabine, when the team found their usual powdered vials of the drug in short supply and ordered a vial in solution as an alternative. Although the product was shipped to the pharma-cy on ice, whoever opened the package placed the medication at room tempera-ture. A keen-eyed pharmacy technician caught the error and brought it to clinical manager Brenda Egan, PharmD, BCPS. Unfortunately, the integrity of the prod-uct was compromised because of the incorrect storage, so it was thrown out. When Dr. Egan looked at the product, she noticed that the vial in solution had “store in refrigerator” in small letters on the package, whereas their powdered vials had “store at room temperature” in large letters.

Monitoring replacement drugs can be tricky, Dr. Egan noted. Not only might they have different storage requirements, but they also may come in different vial sizes or formulations (powdered vials vs. solutions) or in ampules instead of syring-es, or vice versa. Inconsistencies in drug labeling, as evidenced by the gemcitabine issue, also can be problematic.

To address these potential causes of errors, Dr. Egan and her colleagues assigned a purchaser to identify all sub-stitute drugs and signal when they are coming in for delivery, and a pharma-cist to take charge of the final verifica-tion process. They also created a drug replacement log of the usual drugs and their substitutes, with the substitutes’ concentrations, storage requirements, clinical considerations, caregiver noti-fications and bar-code information, as well as the need for any education.

Using the chart has become “hard-wired into our routine,” Dr. Egan said. “It’s a very low-tech regimen that has helped us tremendously.”

Near-Miss Tracking Promotes Patient Safety

Tracking near misses that could have resulted in medication errors is helping one hospital pharmacy in Massachu-setts fine-tune its operations.

The pharmacy team at Saint Vincent

Hospital, in Worcester, wanted to cre-ate an environment where pharmacists would feel comfortable reporting near misses and speaking up about safety concerns without fear of being pun-ished, said Jules Trahan, PharmD, a medication safety fellow at the hospital.

Near misses caught on patient floors generally result in a call from the nurs-es, Dr. Trahan said, but “we hear very little about” issues happening in the pharmacy. She noted that staff mem-bers “feel like they will get themselves or their co-workers in trouble. They don’t want to tattle, so they tend to hide those events.”

The pharmacy created a paper near-miss tracker chart, with spaces for days and two- to four-hour time blocks during the week. Pharmacy staff was asked to put a tally mark in the chart each time they caught a near-miss event. Trackers were placed in four areas of the pharmacy: the inventory/medication storage area, the pharma-cist workstation, the IV room and the verification area.

To promote the trackers’ importance to staff, leaders used a “Swiss cheese” analogy, demonstrating how each event reported provides an opportunity to study a hole in the pharmacy process and make staff workloads easier. Phar-macy staff members were compliant in using the anonymous charts, Dr. Trahan said, but they expressed frustration at not being able to report what types of errors they caught, so the grids were revised to include check-off boxes for six to eight types of common near-miss events, including inventory/medication storage (medication stocked in wrong bin (look-alike sound-alike drugs), pharma-cist workstation (medication ordered for wrong patient), verification area (incor-rect strength of correct medication), etc.

The trackers report about 30 near misses a week, Dr. Trahan said. Because they showed more near misses during the evening shift and Mondays and Tuesdays, the pharmacy scheduled additional staff to work those shifts.

Mining Error Data Improves Administration Accuracy

Investigating medication administra-tion errors led leaders at Novant Health to make significant changes in its infu-sion pump procedures.

Novant Health data from 2010 showed that 20% of medication administration errors were related to infusion pumps, said Elizabeth McGowan Rebo, PharmD, a medication safety manager for Novant, a group of 13 hospitals, 100 outpatient facilities and 364 physician practices in Virginia, North Carolina, South Carolina and Georgia. The pumps did not have wireless upgrade options, had limited drug libraries and dubious dose-range guardrails, were not integrated with

medication administration systems, and lacked reporting capabilities. Addition-ally, there were dosing errors because staff members were recording incorrect patient weights (sometimes because of pound/kilogram mix-ups) or recording height as whatever patients told them rather than verifying it.

Novant’s corporate medication team set out to improve two parameters: the rate that high-risk medications delivered via infusion pumps are given in the correct dose at the correct rate of administration with providers using proper safety guidelines, and the rate that patients in acute care facilities and group practices have an accu-rate height and weight recorded if the information is relevant to medica-tion administration.

To improve these parameters, the team updated the health system’s drug libraries, standardized drug concentra-tions corporation-wide, implemented a nursing-pharmacy double-check for high-risk infusions and conducted bedside education for nurses on the use of pumps. Team members also added a mandatory hard stop to records to indicate how height/weight was measured, and obtained additional tools to record patients’ height and weight accurately.

From August to October 2012, the sys-tem improved both parameters (Table). Dr. Rebo noted that the team is still tracking data and is looking to upgrade to wireless pumps.

—Karen Blum

Table. Improvements with New Infusion Pump Procedures at Novant Health

ParameterBefore Changes

After Changes

Ratethathigh-riskmedicationsdeliveredviainfusionpumpsweregiveninthecorrectdoseatthecorrectrateunderpropersafetyguidelines

83% 98%

Rateofaccurateheightandweightmeasurements

45% 61%

“One-size-fits–all”dosingregimenspro-grammedinpatient-controlledanalgesiaunitscanleadtooveruseofnarcoticsforpain.

COLLABORATIONcontinued from page 3

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Pharmacy Practice News • April 2013

Safety and Quality Pearls

4 Clinical

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The fact that these superbugs are mak-ing their presence most felt in hospi-tals is not surprising: In healthy patients, KPC may colonize the intestines without causing disease, but in patients whose immune system is impaired, it can turn deadly. KPC can spread through human-to-human contact and has been found to live on equipment such as catheters. In the past, K. pneumoniae typically had been treated with cephalosporins or car-

bapenem antibiotics, but the bacteria are becoming increasingly resistant. Thus, drugs such as colistin, polymyxin B and tigecyline are not always effective alone, so they have to be combined. “But there’s no real, solid data on the drugs of choice,” Dr. Rapp noted, and medical staff “are just kind of flying by the seat of their pants.”

With no new antibiotics in the pipeline, “we really have a problem,” he stressed. “If you come down with one of these [superbug infections], your chances of dying are high—probably 40% to 50%,” a figure echoed in the March CDC report.

KPC is “definitely something that’s on our radar,” said Claudine El-Beyrouty, PharmD, BCPS, an infectious disease pharmacist at Thomas Jefferson Uni-versity Hospital in Philadelphia. KPC most often is found among critically ill patients hospitalized for extended stays or in patients who go in and out of the hospital frequently, she said. At this point, most hospitals in the Northeast region of the country have encountered it, according to Dr. El-Beyrouty. At Jef-ferson, several patients per quarter carry the organism or show signs of being infected, she noted.

The hospital manages the infections through a multitiered approach, Dr. El-Beyrouty said. Infection control person-nel track cases; once the organism is detected in a patient, the person is isolat-ed and the chart is flagged. If the patient is discharged and later returns, the flag is reactivated and the person is isolated again. Caregivers treating these patients wear gowns and gloves and employ handwashing techniques. Pharmacists participating in the hospital’s antibiot-ic stewardship program try to reserve agents like colistin, tigecycline and ami-kacin specifically for KPC patients.

A Deadly Outbreak

One of the most difficult Klebsiella outbreaks to control occurred in 2011, at the National Institutes of Health (NIH) Clinical Center in Bethesda, Md., where the organism infected 19 patients, seven of whom died. That June, a 43-year-old woman with lung disease was trans-ferred to the medical center from a New York hospital. Medical staff knew the patient was colonized with KPC, so they isolated her and wore gowns, gloves and masks while treating her. Three weeks after that patient left the hospital, a cancer patient who had no contact with the infected patient developed KPC. Ten days later, a patient with an immune dis-ease also became infected.

NIH epidemiologists and infection con-trol specialists scrutinizing the problem

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Infectious Disease

6 Clinical

found that the organism had been trans-mitted from the first patient despite the fact that the health care team followed all infection control protocols. They imple-mented additional procedures to prevent further transmission, including more invasive testing of ICU patients; using rectal swabs to check for KPC carriers; building a wall to cre-

ate a specific unit to care for and isolate KPC patients; pay-ing monitors to ensure every-one followed infection con-trol procedures; and spraying hydrogen peroxide in rooms

and on equipment. They report-

ed their efforts in the journal Science Translational Medicine (2012;4:148ra116). The last carrier was identified in Decem-ber 2011, but patients still are swabbed to check for KPC when they arrive and before they leave the facility.

Klebsiella ResourcesHow can your pharmacy prepare for and manage carbapenemase-producing Klebsiella pneumoniae (KPC)?

Follow the literature. Emerging studies are sheddinng light on KPC and potential drug combina-tions to manage it, said Claudine El-Beyrouty, PharmD, BCPS, an advanced practice pharmacist in infectious diseases at Thomas Jefferson University Hospital, in Philadelphia. In addition, “try to reserve broad-spectrum antibiotics or ‘big guns’ for KPC rather than use them on anybody.”

Keep an open line of communi-cation with infection control, the infectious diseases division and hospital epidemiology, advised Timothy Jancel, PharmD, BCPS, a clinical pharmacy specialist in infectious diseases at the NIH Clinical Center, in Bethesda, Md.

Create a plan. Will patients be isolated? What does the pharmacy need to do? Educate pharmacy and medical staff about how antibiotics will be used, dosed and monitored, Dr. Jancel said. Educate pharmacy staff on proper hand hygiene and how to follow isolation protocols. Ideally, a clinical pharmacist should monitor each patient, he noted.

Use the Internet. The American College of Clinical Pharmacy has a message board that can be used to share information on KPC man-agement. For more information, see the Infectious Diseases PRN at http://www.accp.com/index.aspx. The Centers for Disease Con-trol and Prevention offers informa-tion on K. pneumoniae in health care settings: http://www.cdc.gov/HAI/organisms/klebsiella/klebsi-ella.html. Documents discussing dosing confusion with colistimeth-ate, the prodrug for colistin, can be accessed at http://www.ismp.org/pressroom/PR20110629.pdf and http://www.ashp.org/DocLibrary/Policy/PatientSafety/NANAlert-Colistimethatesodium.aspx.

—K.B.

‘Ifyoucomedownwithoneofthese[superbug

infections],yourchancesofdyingarehigh—

probably40%to50%.’—Robert Rapp, PharmD, FCCP

• see SUPERBUGS, page 8

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Pharmacy Practice News • April 2013

Infectious Disease

Clinical 7

The pharmacy faced several challeng-es during its KPC outbreak, according to Timothy Jancel, PharmD, BCPS, a clini-cal pharmacy specialist in infectious diseases at the hospital. The isolation unit was created overnight, he said, so pharmacists had to quickly install a new drug-dispensing unit and decide how emergency medicines would be deliv-ered. They educated pharmacy staff on handwashing and isolation protocols.

Because some isolated patients took their own medicines, pillboxes leaving the unit had to be sterilized.

Pharmacists also worked with infec-tious disease experts to come up with antibiotic regimens to treat KPC as well as protocols to monitor those treatments, which involved educating a lot of people, Dr. Jancel said. Medications like colistin have “been around for decades, but we never had to use it because we always had other options.” Devising accurate dosing was challenging because labeling require-ments were less stringent when colistin

was approved, and the pharmacokinetics of the antibiotic still are not well under-stood, he added. They had to combine colistin with gentamicin and tigecycline for some patients, and then monitor them for side effects including renal toxicity, pancreatitis, nausea and vomiting. “We were using drug combinations typically not used on a daily basis.”

The pharmacy also pursued investi-gational antibiotics. One such agent was acquired and administered to a patient, but it was too late. The patient died a few days after starting therapy.

Dr. Jancel said he has helped thwart other types of antibiotic-resistant bacte-ria, such as methicillin-resistant Staphy-lococcus aureus (MRSA), but MRSA still had treatment options such as linezolid (Zyvox, Pfizer), trimethoprim/sulfa-methoxazole and clindamycin. “With gram-negative bacteria [like KPC], we’re getting to the point where we don’t have other options.”

More From the CDC ReportAs daunting as Klebsiella is to eradicate

in the nation’s hospitals, it isn’t the only superbug that poses a public health threat, the CDC report stressed; the authors also cited the emergence of resistant Entero-bacter and Escherichia species. By releas-ing these findings, the agency succeeded in getting a long-standing problem quite a bit of media attention. News articles in The Wall Street Journal, The New York Times and television news outlets covered the report in seemingly alarmist terms. Most quoted one health official who termed these resistant organisms “nightmare bacteria,” and the CDC’s Arjun Srinivasan, MD, got a lot of cover-age when he called these superbugs “a major threat emerging in our hospitals.”

That statement is not surprising, giv-en the 40% mortality associated with some of the superbug infections. More-over, many of the bacteria have a kind of “panresistance” that renders them, in some cases, unresponsive to most avail-able antimicrobials, which makes even combination treatments problematic, the CDC researchers reported.

“Make no mistake, this is a public health crisis,” Dr. Rapp said. With the pipeline for new drugs looking dismal right now, “I don’t see much hope for a savior coming from Pharma.”

Dr. Rapp thus urged hospitals to take the same types of proactive approach-es detailed in the Science Translational Medicine report. “We have several tools to prevent transmission and improve patient outcomes, including better infec-tion control practices, strong antimicro-bial stewardship programs and optimiza-tion of the pharmacokinetics/pharma-codynamics of our presently available agents to enhance the killing of these bacteria,” he said. “So we are certainly not powerless in this fight. But it’s going to be a long battle.”

—Karen Blum

SUPERBUGScontinued from page 7

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Pharmacy Practice News • April 2013

Infectious Disease

8 Clinical

Las Vegas—During a “bloody debate” at the American Society of Health-System Pharmacists 2012 Midyear Clinical Meeting, four experts argued fervently in favor of one of four oral anticoagulants for stroke prevention in treatment-naive patients with atrial fibrillation (AF). In this issue, Pharmacy Practice News presents a summary of the debate.

Dabigatran Etexilate Is Preferred

Michael Gulseth, PharmDProgram Director for Anticoagulation Services Sanford USD Medical CenterSioux Falls, South Dakota

There are several advantages to using dabigatran (Pradaxa, Boehringer Ingel-heim) over the other anticoagulants for patients with AF. Because of its 12- to 17-hour half-life, if one of the two daily doses of dabigatran is missed, patients are still covered for a significant part of the day. Furthermore, unlike the other novel oral anticoagulants, only 35% of metabolized dabigatran binds to pro-tein, making it dialyzable in cases of emergent or life-threatening bleeding.

Dabigatran was approved in October 2010; rivaroxaban (Xarelto, Janssen) entered the market nearly one year lat-er; and apixaban (Eliquis, Bristol-Myers Squibb) only recently received approval. I would argue we have more valuable experience using dabigatran and don’t yet know what skeletons are in the closet for the other agents.

Dabigatran is the only agent that, based on trial results, can be said to be superior to warfarin for prevention of ischemic strokes. Findings from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial showed that only 1.11% of the large group of individuals receiving 150 mg of dabi-gatran twice daily suffered a stroke or systemic embolism compared with 1.69% of warfarin recipients (P<0.001) (N Engl J Med 2010;363:1875-1876). Furthermore, the annual mortality rate with 150 mg of dabigatran was 3.64%, compared with 4.13% with warfarin (P=0.051).

With dabigatran, most of the time there is no need to use a bridging agent in patients scheduled to undergo sur-gery. In RE-LY, dabigatran was admin-istered an average of 49 hours prior to surgery, compared with an average 114 hours (87-144 hours) with warfarin (P=0.001). Finally, the American Heart Association (AHA)/American Stroke Association (ASA) guidelines recom-mend dabigatran 150 mg twice daily as an effective alternative to warfarin for the prevention of first and recurrent stroke in patients with nonvalvular AF, at least one additional risk factor, and

a creatinine clearance (CrCl) greater than 30 mL per minute. The Ameri-can College of Chest Physicians (ACCP) guidelines also state that dabigatran 150 mg twice daily can be used “rather than adjusted-dose vitamin K antagonist therapy” for patients with AF.

Dr. Gulseth on warfarin: The infra-structure and training needed to use warfarin is quite extensive. In fact, many health systems have an anticoagulation service in large part because warfarin is a challenge to dose and manage.

Dr. Gulseth on rivaroxaban: Rivar-oxaban is associated with a 3.15% rate of gastrointestinal (GI) bleeding, com-pared with 2.16% for warfarin (N Engl J Med 2011;365:883-889). Further-more, although it was not statistically significant, data from ROCKET-AF (Rivaroxa ban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) suggest that the overall bleeding rate could be even higher in the elderly, even when dose adjust-ments are made.

Dr. Gulseth on apixaban: The apixa-ban data are quite strong. We will have to watch for new data with this drug and see what is learned as experience accumulates.

Rivaroxaban Gets the Nod for Atrial Fibrillation

Nathan Clark, PharmDClinical Pharmacist Anticoagulation and Anemia ServiceKaiser PermanenteAurora, Colorado

Rivaroxaban has a rapid onset of action, once-daily dosing for stroke prevention in AF and few drug inter-actions, and it is approved for a wide range of indications.

Importantly, the ROCKET-AF trial of rivaroxaban included high-risk patients with a history of stroke, transient isch-emic attack (TIA) or systemic embo-lism, or two or more of the following: heart failure, hypertension, age above 75 years and diabetes mellitus. The mean CHADS2 (Congestive heart failure, Hypertension, Age>75, Diabetes, Stroke or TIA [2]) score of 3.48 in the trial was a full point higher than the mean score in trials of dabigatran and apixaban (N

Engl J Med 2011;365:883-891; N Engl J Med 2011;365:981-992).

The per-protocol analysis of ROCK-ET-AF data found that rivaroxaban reduced the cumulative incidence of stroke or systemic embolism by 21% compared with warfarin (P<0.001). Rates of major and clinically relevant bleeding events were similar between the two groups, but the number of bleeding-related deaths and intracra-nial hemorrhages were 50% and 33% lower, respectively, than the rates of these complications in the warfarin arm (P≤0.02 for both).

A small, double-blind, crossover study showed that rivaroxaban’s effects can be reversed using prothrombin complex concentrates (PCCs) (Circu-lation 2011;124:1573-1579). That study included 12 healthy participants ran-domized to receive either rivaroxaban 20 mg or dabigatran 150 mg, both twice daily, followed by randomization to infusion of either placebo or PCC. PCC reversed the prothrombin time in riva-roxaban recipients but did not reverse the effects of dabigatran.

Finally, the novel once-daily formu-lation of rivaroxaban promises greater adherence and better disease control. To quote the late C. Everett Koop, MD, “drugs don’t work in patients who don’t take them.”

Dr. Clark on dabigatran: The open-label design of RE-LY weakens the strength of the evidence in support of dabigatran. Moreover, the risk for myo-cardial infarction is 28% higher with dabigatran than with warfarin (Am J Med 2010;123:785-789). Another issue I’ve seen is that many warfarin patients who switch to dabigatran pop these pills into their pill boxes, unaware that the medication needs to be kept in the original packaging to maintain short-term stability.

Dr. Clark on warfarin: To be used effectively, warfarin requires a high time-in-the-therapeutic range (TTR). However, most centers still do not know their own TTR and tend to overestimate it. Even with optimal warfarin manage-ment, the risk for intracranial hemor-rhage remains significant.

Dr. Clark on apixaban: Results from the ARISTOTLE (Apixaban for Reduc-tion In STroke and Other Thromboem-boLic Events in atrial fibrillation) trial are impressive [See next section for a summary of the ARISTOTLE data].

Apixaban Is the Best Option

Edith Nutescu, PharmDClinical ProfessorUniversity of Illinois at Chicago College of PharmacyChicago, Illinois

Of the pivotal trials for the three novel oral anticoagulants, apixaban’s ARISTO-TLE trial was the largest, with 18,201 participants (N Engl J Med 2011;365:981-992). ARISTOTLE found 1.27% and 2.13% annual rates of stroke or systemic embolism, and major bleeding, respec-tively, with apixaban 5 mg twice dai-ly (2.5 mg twice daily for participants above 80 years of age, below 60 kg or with creatinine >1.5 mg/dL). The rates of both outcome measures were signifi-cantly lower in the apixaban arm than in the warfarin arm (P<0.05). Apixaban is the only novel oral anticoagulant that has been shown to significantly reduce annual all-cause mortality compared with warfarin (3.52% vs. 3.94%; P=0.047).

Indirect comparisons show that apix-aban is associated with lower rates of stroke, systemic embolism and major bleeding compared with rivaroxaban, and less major bleeding compared with dabigatran 150 mg twice daily. Further-more, 0.75% of patients in ARISTOTLE had GI bleeding, compared with 1.5% of those treated with dabigatran 150 mg and 3% of those treated with rivaroxa-ban in trials of those agents.

With a 25% renal excretion rate, apix-aban is the best option in patients with renal impairment. The renal excretion rate for unmetabolized drug is 92% with warfarin, 80% with dabigatran and 33% with rivaroxaban. Apixaban is effec-tive regardless of renal function or the method used to determine CrCl (Eur Heart J 2012;33:2821-2830). In fact, the greatest risk reduction in major bleed-ing in ARISTOTLE was seen in renally impaired patients.

Finally, apixaban is the most cost-effective of all the oral anticoagulants. The estimated annual cost of treating a patient receiving apixaban, not includ-ing the price of the drug itself, is $1,599 (J Med Econ 2012;15:776-785). Cost data for other anticoagulants were as follows: warfarin, $2,084; dabigatran, $1,905; rivaroxaban, $1,995.

Anticoagulation Experts Argue a Bloody Debate

• see ANTICOAGULATION, page 10

Spotlight on Bleeding Management 9Pharmacy Practice News • April 2013

Dr. Nutescu on dabigatran: All of the data on dabigatran show an increased incidence of acute coronary events with the drug (Arch Intern Med 2012;172:397-402). Furthermore, real-world data show a 9% rate of major bleeding that is nearly three times the rate reported in clinical trials (J Am Coll Cardiol 2012;59:E602).

Dr. Nutescu on rivaroxaban: In ROCKET-AF, rates of stroke were higher following rivaroxaban discontinuation during transition to warfarin (N Engl J Med 2011;365:883-891). Therefore, if rivaroxaban is discontinued in anticipa-tion of surgery or invasive procedures, the interim period should be minimized and shorter-acting anticoagulants, such as unfractionated heparin, should be considered to bridge the gap.

Dr. Nutescu on warfarin: Warfarin is a poor option in patients with renal impairment. It also is associated with a high risk for bleeding complications. Whether these risks are offset by the lower rates of stroke and systemic throm-boembolic events is up for debate.

warfarin: Best Show And Odds in Town

william Dager, PharmD, BCPS Anticoagulation Specialist University of California, Davis Clinical Professor University of California, San Francisco

Warfarin is an established therapy with a large body of evidence back-ing up its efficacy in reducing stroke risk in patients with nonvalvular AF. Data include results from five random-ized controlled studies including 3,691 patient-years of treatment. Cumulatively, these trials confirm that warfarin reduc-es the risk for stroke by nearly 70% (Arch Int Med 1994;154:1449-1457).

Unlike with the new agents, which still are not completely understood, with warfarin, clinicians have a wealth of experience in special subpopulations. For example, we know we can use it along with other antiplatelet agents. This is an important point, given that one-third of our nonvalvular AF patients have coronary artery disease.

We also know that the effects of war-farin can be reversed using a number of agents, including vitamin K, fresh frozen plasma, PCCs and recombinant activated factor VIIa. In contrast, the newer oral anticoagulants have effects that either cannot be reversed or require costly agents or longer hospital stays including hemodialysis for reversal.

We have a lot of experience with tests such as the international normalized ratio

to monitor warfarin and individualize the therapy. Tailoring treatment is particu-larly important in those who are receiv-ing multiple medications or have clini-cal conditions that may require dosing modifications. In contrast, the new agents have fixed doses. With a fixed dose, what do we do in unique patients, for example those with obesity or renal failure? We don’t know, partly because we do not have a good test or understanding of how to use test values to adjust therapy.

There may be some valid reasons to switch to one of the newer oral antico-

agulants, but many patients cannot tol-erate these newer medications. At our clinic, half of those who have switched to dabigatran returned to warfarin because of vomiting, bleeding or fatigue, among other issues.

Finally, warfarin is the only oral antico-agulant with level 1A support in guidelines for the prevention of stroke in nonvalvu-lar AF (Circulation 2011;123:e269-367). The strong recommendation based on high-quality evidence is a testament to warfarin’s superiority.

Dr. Dager on dabigatran: There are

significant safety concerns with dabi-gatran. In a summary of serious adverse events that occurred during the first quarter of 2011, the Institute for Safe Medication Practices pointed to 932 serious adverse events suspected to be related to dabigatran. These included 120 deaths, 65 of which were due to hemor-rhagic strokes, as well as 505 additional hemorrhages (www.ismp.org/quarter-watch/pdfs/2011Q1.pdf ).

Dr. Dager on rivaroxaban: The FDA has placed a little black cloud over riva-roxaban by stating that nonadherence

ANTICOAGULATIONcontinued from page 9

10 Spotlight on Bleeding Management Pharmacy Practice News • April 2013 Spotlight on Bleeding Management 11

to the medication can actually lead to a rebound phenomenon that could include hypercoagulability. There also is evi-dence the drug may not be as effective as it is claimed to be in the upper quartiles of TTR (FDA Draft Briefing Document for the Cardiovascular and Renal Drugs Advi-sory Committee [CRDAC]; Sept 8, 2011).

Dr. Dager on apixaban: Apixaban requires twice-daily dosing and there is limited knowledge about how to reverse, monitor and adjust dosing for unique patient populations. For all the new agents, the effect of reduced drug adher-

ence, use of a different dosing strategy for a particular indication and effects when used in populations not included in clini-cal trials need further clarification.

—David Wild

Dr. Gulseth is on the speakers’ bureaus for Boehringer Ingelheim and Janssen and also is a consultant for Janssen. Dr. Nutescu has

received research support from Janssen and serves as a consultant for

Daiichi-Sankyo and Janssen. Drs. Clark and Dager reported no relevant financial

conflicts of interest.

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Spotlight on Bleeding Management 11Pharmacy Practice News • April 2013

Las Vegas—Building an electronic alert into provider order sets can significantly improve rates of venous thromboembo-lism (VTE) prophylaxis, pharmacists at Mercy Hospital in Chicago have found.

Michael Mikrut, PharmD, a clini-cal pharmacist in internal medicine, reviewed the records from all August 2009 admissions to two nursing units of their community teaching hospital to determine if VTE prophylaxis was

ordered for medical-surgical patients by the end of their second hospital day. In a presentation at the American Society of Health-System Pharmacists 2012 Mid-year Clinical Meeting, he said that he found overall rates of VTE prophylaxis to be 77%, with a big gap between patients covered by medical residents (prophy-laxis rate of 89%) and those not covered by residents (prophylaxis rate of 65%).

Dr. Mikrut, Sonali Muzumdar, PharmD,

an informatics pharmacist, and others at the hospital formed a multidisciplinary committee to improve compliance in ordering VTE prophylaxis. In January 2011, Dr. Muzumdar created an electron-ic alert that fires for prescribers when they sign orders that do not include VTE prophylaxis. The alert allows physicians either to order prophylaxis or to explain why they felt it was inappropriate at that time. Pharmacy staff, nurses and

auditors can review the results easily. The reasons for forgoing prophylaxis are built as orders with an expiration of 24 to 48 hours. Once the order expires, the alert will fire for providers when they order anything for the patient and VTE prophylaxis is still absent. Provid-ers can bypass the alert in an emergency, but they will continue to receive the alert every time they place orders for the patient until they select a reason or order the prophylaxis.

“We get a lot of alerts,” Dr. Muzum-dar said, “so we had to make sure this was user-friendly.” Initially, many physicians were bypassing the alert, but with some education, compliance improved, she said.

The alert was made available in May 2011 to all units except for pediatrics, OB/GYN and hospice. Six months lat-er, the team again looked at prophylaxis rates for the initial two nursing units, finding the rates had increased to 94%. VTE prophylaxis compliance increased to 96% among patients with medical resi-dent coverage, and to 92% among patients not covered by residents (P<0.05).

A Similar Initiative

Edith Nutescu, PharmD, a clinical pro-fessor of pharmacy practice at the Uni-versity of Illinois at Chicago College of Pharmacy, said she and her colleagues employed a similar method in 2006 to improve VTE prophylaxis rates at the University of Illinois Medical Center. A task force created a VTE risk assessment form, which clinicians must complete when placing an order through the hos-pital’s CPOE system. In work published in the American Journal of Health-Sys-tem Pharmacy (2010;67:1265-1273), Dr. Nutescu and her colleagues showed that the rate of pharmacologic VTE prophy-laxis increased from 25.9% to 36.8% after implementation of the form (P<0.0001). The overall rate of VTE for the hospi-tal did not change significantly, but a significant reduction occurred among patients on medical units, from 0.55% to 0.33% (P=0.02). There was no increase in bleeding events.

“Obviously the goal is to treat every-one at moderate to high risk [for embo-lism], but ultimately we want to see that prophylaxis works,” said Dr. Nutescu, director of the medical center’s Anti-thrombosis Center. “Electronic alerts are an effective way of increasing pro-vider orders, increasing prophylaxis and decreasing patient events.”

—Karen Blum

Drs. Mikrut, Muzumdar and Nutescu reported no relevant financial

conflicts of interest.

e-Alert Helps Chicago Hospital Improve vTE Prophylaxis

12 Spotlight on Bleeding Management Pharmacy Practice News • April 2013

There was no difference between serum-derived and recombinant

factor VIII products, but there was a difference between third- and second-generation recombinant products with respect to the formation of antibodies, or inhibitors, that can make the prod-ucts ineffective, according to a study of previously untreated children with severe hemophilia A.

The content of von Willebrand factor in the various products and switching between products did not increase risk for inhibitor development, according to the study, which was published in The New England Journal of Medicine (2013:368:231-239).

The results of the observational study were unexpected, according to Asad Patanwala, PharmD, an assistant pro-fessor in the Department of Pharmacy Practice and Science at the University of Arizona, in Tucson. “The findings were important ones,” said Dr. Patan-wala. “It was surprising that there were differences in the outcome between second- and third-generation recom-binant products. The authors were unable to explain this using any bio-logical rationales.”

A multinational team evaluated 574 consecutive patients with severe hemo-philia A who were born between 2000 and 2010, and collected data on all clot-ting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibi-tor tests with decreased in vivo recov-ery of factor VIII levels.

Inhibitory antibodies developed in 177 of the 574 children (32.4%); 116 patients had a high-titer inhibitory anti-body, defined as a peak titer of at least 5 Bethesda units/mL (22.4%). Plasma-derived products conferred a risk for inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95%

confidence interval [CI], 0.62-1.49). Compared with third-generation full-length recombinant products—derived from the full-length complementary DNA sequence of human factor VIII, second-generation full-length products were associated with an increased risk for inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08-2.37).

Dr. Patanwala said that this well-designed study might change the way

hemophilia A is treated in the not-too-distant future. “When patients with hemophilia present with bleeding to an acute care setting, they are usually given the product they always use. In some cases it may not be available at that hospital. Perhaps hematologists would be more willing to use an alter-native product,” said Dr. Patanwala. “Also, perhaps the choice of product used can be based on other criteria

rather than inhibitor formation when patients are initiated on therapy.”

Author H. Marijke van den Berg, MD, declined to comment on the study on behalf of the study group. The study was funded by Bayer Healthcare and Baxter BioScience.

—Dana Hawkins-Simons

Dr. Patanwala reported no relevant financial conflicts of interest.

Factor vIII Products Comparable in Inhibitor Development

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Spotlight on Bleeding Management 13Pharmacy Practice News • April 2013

Las Vegas—When choosing the best treatment for trauma- or surgery-relat-ed bleeding, clinicians should know their pathophysiology and the pros and cons of each agent, according to a pre-sentation at the American Society of Health-System Pharmacists 2012 Mid-year Clinical Meeting.

“It amazes me how frequently I bring up the topic during rounds and find clinicians are unfamiliar with many of the causes, mechanisms and treatments for massive bleeding,” said presenter Rob MacLaren, PharmD, an associate professor at the University of Colorado School of Pharmacy, in Aurora.

The primary goal of treating trau-ma-related bleeding is to prevent the depletion of thrombin, Dr. MacLaren explained. “Trauma and shock lead to a release of large amounts of thrombin, which then binds to thrombomodulin, which is actually an anticoagulant,” he said. “On top of this, trauma patients often receive large volumes of resuscita-tive fluids that further dilute endogenous clotting factors and increase bleeding.”

Given this and other risks associ-ated with large volumes of resuscita-tive fluids, Dr. MacLaren recommended administering 2 L of crystalloid fluids “as soon as you can” and observing the patient’s response. If their vital signs do not quickly return to normal, he recom-mended adding more crystalloid fluid and considering the patient for transfu-sion and surgery.

Before administering blood prod-ucts or drugs, clinicians should ensure that other risk factors for mortality are under control. Most critically, minimize the risk for hypothermia, acidosis and dilution, he said. Because patients with this “lethal triad” have a 95% risk for death (Crit Care 2006;10:222), trying to control these should be a priority, Dr. MacLaren said.

Blood Products Are ‘Not Benign’

Once these risk factors are evaluated and, ideally, controlled, clinicians can consider transfusion of a blood product (Table 1). However, Dr. MacLaren said this decision should not be made lightly. “All blood products are associated with a risk of acute lung injury, infections and organ failure and are, therefore, not benign,” he said.

Bearing these complications in mind, each blood product has its advantag-es and limitations, Dr. MacLaren said. For example, cryoprecipitate increases fibrinogen levels but does not reduce a patient’s international normalized ratio (INR); platelets and red blood cells can worsen the immune response; and

The Tricky Business of Treating Massive HemorrhageTable 1. Blood Products Used in Patients with Hemorrhage

Product Contents Indication(s) and Dose(s) Concernsa

Platelets Thrombocytesinplasma Bleeding:Platelet<50x109/LPrevention: Platelet<20x109/L

•Storedat20°-24°C•Bacterialcontamination~1/2,000-1/3,000units

•Worsensimmunereactions

Freshfrozenplasma Coagulationfactorsandfibrinogeninvariableamounts

INR ≥1.5: 15mL/kg(~30%factorreplacement)

•Requiresthawing•Hypervolemia

Prothrombincomplexconcentrates(Bebulin,Baxter;Profilnine,Grifols)

FactorsII,VII,IX,Xandprothrombin,proteinsC,S,Zinvariableamounts

INR ≥1.5: 25-50IU/kg(basedonfactorIX)

•Variableamountsoffactors•Maycontainheparin•Numerousdonors•Costly

Cryoprecipitate FactorsVIII,XIII,vWF,fibrinogen,fibronectin

Fibrinogen <100 mg/dL:1unitwillfibrinogen~5-10mg/dLvWF deficiency

•Variableamountsoffibrinogen

•Costly

Cryosupernatant NotfactorVIII,vWF,andminimalfibrinogen

TTP •Costly

INR, International normalized ratio; TRALI, transfusion-related acute lung injury; TRIM, transfusion-related immunomodulation; TTP, thrombotic thrombocytopenia purpura; vwF, von Willebrand factor

a All products are associated with thrombotic events, TRALI, TRIM, infection transmission and febrile reactions.

Based on Pharmacotherapy 2007;27(9 Pt 2):57s-68s and Pharmacotherapy 2007;27(9 Pt 2):69s-84s.

Table 2. Pharmacologic Agents Used in Patients with Hemorrhage

Product Contents/Mechanism of Action Indications and Dose Concerns

Localhemostatics •Cellulose-based•Fibrin(humanorbovine)±fibrinolytic

inhibitor± aprotonin±thrombin•Thrombin(humanorbovine)•Zeolitecausesexothermicreaction•Chitason(chitin)activatesplatelets

andelectrophysiologicendothelialattractionofRBCs

To control or prevent oozing of blood at surgical site:Dosedependsonproduct

•Maynotadhere•Immunereaction,

infectiontransmission,aprotinin

•Immunereaction•Heat-inducedtissue

damage•Maynotadhere

VitaminK •CofactorforactivationoffactorsII,VII,IX,K

INR ≥1.5:0.5-20mg

•Slow-acting•VariableSQabsorption•IVrequiresslow

administration

RecombinantfactorVIIa(NovoSeven,NovoNordisk)

•Activatesplateletstoaugmentthrombinburst

Refractory hemorrhage (surgery, trauma):10-90mcg/kgIV

•Short-acting•Thrombosis(<10%)•Costly

RecombinantfactorVIIIa(Advate,Baxter;HelixateFS,CSLBehring;Kogenate,Bayer;Recombinate,Baxter;ReFacto,Wyeth)

•Promotesfibrincrosslinking Extremely refractory hemorrhage (surgery, trauma): 10-40units/kgIV

•Short-acting•Thrombosis•Costly•Requiresrefridgeration

Desmopressin •SelectiveV2agonisttoreleasefactorVIII,vWF,andtPA

Platelet dysfunction:0.3mcg/kgIV

•Short-acting•Tachyphylaxisandbleedingriskwithrepeatdoses

Conjugatedestrogen

•antithrombinandproteinS,factorsVII,VIII,IX,X,prothrombin

Platelet dysfunction:25-50mgIV

•Slow-acting•Slow-offset

Antifibrinolytics(EACA,TA)

•Inhibitplasminogenproteasesandplasmin(aprotonin)andsomeanti-inflammation

Prevention of surgical blood loss, refractory hemorrhage:EACA:150mg/kg(10,000mg),then15mg/kg/h(2,000mg/h)TA:10-30mg/kg,then1-16mg/kg/h(<400mg/h)

•Thrombosis,hypotension(TA)

EACA, ε-aminocaproic acid; INR, International normalized ratio; RBC, red blood cell; SQ, subcutaneous; TA, tranexamic acid; tPA, tissue plasminogen activator; vwF, von Willebrand factor

Based on N Engl J Med 2007;356(2):2301-2311, Pharmacotherapy 2007;27(9 Pt 2):93s-102s and Pharmacotherapy 2007;27(9Pt2):69s-84s.

• see STOP BLEEDING, page 16

14 Spotlight on Bleeding Management Pharmacy Practice News • April 2013

To contact an Abelcet representative call 1-800-447-0169Select option 1 and enter x572

or visit www.sigmatau.com/products/abelcet_rx.asp

ASK YOUR REPRESENTATIVE ABOUT ABELCET.

MCPPN2335.indd 1 3/14/13 3:54 PM

prothrombin complex concentrates and fresh frozen plasma (FFP) can lower INR levels but not below the goal of 1.5 prothrombin time. “Furthermore, large amounts of FFP may contribute to the development of encephalopathy and cerebral edema,” he noted.

Dr. MacLaren discussed the features of several of the newer pharmacologic agents that have joined the mainstays for treatment of hemorrhage (Table 2). “Recombinant factors VIIa [rFVI-Ia] and VIIIa [rFVIIIa] are appealing because they work downstream and cause a thrombin burst,” he explained.

“Therefore, they are more specific to the site of injury, and they don’t involve all the systemic activity of clotting fac-tors and platelets that the procoagulant blood products need.”

Although rFVIIa reduces the use of blood products and lowers the risk for acute respiratory distress syndrome, possibly a result of the reduced use of blood products, Dr. MacLaren noted, it does not actually reduce the inci-dence of mortality (Ann Intern Med 2011;154:529-540). Similarly, in the car-diac surgery setting, rFVIIa does not reduce mortality rates but increases the rate of thromboembolic events. “This agent should only be used for refractory bleeding,” he said.

Among the antifibrinolytics, tranexam-ic acid (TA) is a promising agent, he said, and data indicate that it signifi-cantly reduces the risk for trauma-relat-ed death (Lancet 2010;376:23-32; Lancet 2011;377:1096-1100). However, to prevent one death, 120 patients need to be treat-ed, Dr. MacLaren said. He noted that TA might have greater utility in the surgical setting, where it and ε-aminocaproic acid (EACA) can be used interchangeably to prevent and treat massive blood loss.

The myriad considerations involved in choosing a treatment for these types of bleeds make the task a tricky one, commented Asad Patanwala, PharmD, an assistant professor at the Universi-ty of Arizona’s College of Pharmacy, in

Tucson. However, he said advances in thromboelastography (TEG)—a method of testing clotting efficiency that is used primarily in the surgery setting—may yield better decision making. “TEG-directed therapy may allow for specific coagulation abnormalities to be tar-geted,” Dr. Patanwala told Pharmacy Practice News. “It could allow clinicians to tailor therapies, rather than using a one-size-fits-all approach, but better evi-dence is needed before it can be routinely used in settings such as trauma.”

—David Wild

Drs. MacLaren and Patanwala reported no relevant financial conflicts of interest.

Physicians treating unstable patients with pulmonary embolism (PE)

should, in most cases, administer throm-bolytic therapy regardless of a patient’s age or comorbidities, Michigan State University (MSU) researchers suggest.

Unfortunately, that message is not getting across to clinicians, according to the investigators. In their database study of 72,230 unstable patients with PE—a blockage of arteries in the lungs caused by clots moving from the legs—only one-third of the patients in shock or on a ventilator received thrombo-lytic therapy.

The hesitancy to use thrombolytics in these patients was presumably due to concerns that the medications would boost a patient’s risk for severe bleeds, especially in those with comorbid condi-tions, according to Paul Stein, MD, a pro-fessor of osteopathic medical specialties at MSU and a co-author of the study. But the results showed a benefit in terms of decreased mortality. Patients who were treated with thrombolytics had half the in-hospital death rate of those who did not receive the therapy, regardless of age or comorbid conditions.

“The cautious approach of withhold-ing thrombolytic therapy in those who might have major bleeding [thus] might not be the safest approach in terms of mortality, and needs to be prospectively evaluated,” Dr. Stein and Fadi Matta, MD, wrote in the American Journal of Medi-cine (doi: 10.1016/j.amjmed.2012.12.007 [Epub ahead of print]).

The researchers based their findings on a review of the Nationwide Inpa-tient Sample, a database of 5 million to 8 million hospital stays (1999 to 2008) from approximately 1,000 facilities. They found that overall, only 20% of unstable patients with PE and associated chronic conditions received thrombolyt-ics compared with 80% of those without comorbidities (P<0.0001). Similar rates of underutilization were noted in sub-groups of patients who were aged 60 years or older.

Survival data from the study under-score the downside of that treatment

gap. Even in PE patients with associ-ated chronic conditions, the in-hospital death rate was 20% among those given thrombolytic therapy compared with 47% of those who did not get the clot-busting medications, the authors report-ed. The death rate also was lower among elderly patients who got the drug.

Based on these results, “physicians should give thrombolytic therapy in almost all cases of PE in unstable patients,” Dr. Stein told Pharmacy Prac-tice News. “Exceptions should be made only for patients with a demonstrated likelihood to bleed or those who have acute conditions such as bleeding ulcers.”

Previous studies estimate that the prevalence of fatal bleeding and intra-cerebral hemorrhage from thrombolytic therapy is 1.9% and 2.1%, respectively, Dr. Stein said. Yet the MSU study sug-gests that many more deaths occur in unstable patients in whom thrombolytic

therapy is withheld than the predict-ed number of episodes of intracerebral hemorrhage or deaths from bleeding.

A Pharmacist’s Take

John Fanikos, BSPharm, MBA, the director of pharmacy, business and finan-cial services at Brigham and Women’s Hospital in Boston, said the MSU research is “spot on.” Still, how best to treat patients with submassive PE remains to be deter-mined. “It’s quite obvious that in patients with massive pulmonary embolism with right ventricular dysfunction and hypo-tension, giving thrombolysis is lifesav-ing,” Mr. Fanikos said. “But in patients who aren’t critically ill, it’s unclear if thrombolysis offers benefit.”

Using risk stratification to determine which patients will have poor outcomes is a logical management strategy, “but it’s a challenge,” he said. “There are a couple of prognostic risk scoring systems, but they’re not universally employed. The issue is similar to stroke in that throm-bolytic agents scare people. You worry about intracranial hemorrhage.”

Late-breaking data from the PEITHO (Pulmonary Embolism Thrombosis) tri-al, which was presented at the American College of Cardiology 2013 Scientific Ses-sions in San Francisco, makes a good case for risk stratification, Dr. Fanikos noted. The combination of a thrombolytic agent, tenecteplase, with standard-treatment heparin in patients with submassive PE who had an abnormal right ventricle and positive troponin I or T significantly reduced the primary end point of death or hemodynamic collapse within seven days of randomization compared with heparin alone. That end point occurred in 13 (2.6%) of the 506 patients treated with tenecteplase and heparin versus 28 (5.6%) of the 499 patients in the hepa-rin-only group (P=0.0015), the investi-

gators reported. Major bleeding, how-ever, was significantly increased with tenecteplase: 6.3% versus 1.5% in the heparin-only group (P<0.001). Addition-ally, there were 10 hemorrhagic strokes in the tenecteplase group and one in the heparin-only group.

The subgroup analysis showed that in younger patients (aged <75 years), there was a 67% reduction in the primary end point and the risk for hemorrhagic stroke was 1.1%. In the older population, the reduction in the primary end point was 37%, but the risk for hemorrhagic stroke was almost 2%.

Overall, the study “strongly sup-ports” the concept of risk stratification in patients with submassive PE, “and that many, but not all patients, will need thrombolysis to prevent deterioration,” Dr. Fanikos said.

Other Interventions

Mr. Fanikos added that anticoagulation therapies, surgical procedures or cath-eter-related approaches might emerge as helpful management tools. Addition-ally, he said, there is a company that is devising a catheter to deliver low-dose thrombolytics in conjunction with ultrasound energy. The goal is to ensure faster and more complete embolus dis-solution in the pulmonary artery. The treatment regimen is being evaluated in a single-arm, multicenter trial of patients with PE (http://clinicaltrials.gov/show/NCT01513759), Dr. Fanikos noted.

In the meantime, he said, pharmacists seeing patients with PE “should keep thrombolytics readily available and on their list of possible therapies.”

—Karen Blum

Dr. Stein and Mr. Fanikos reported no relevant financial conflicts of interest.

Clot-Busting in Pulmonary Embolism: worth the Risk?

STOP BLEEDINGcontinued from page 14

‘Theissueissimilartostrokeinthatthrombolytic

agentsscarepeople.Youworryaboutintracranial

hemorrhage.’—John Fanikos, PharmD

16 Spotlight on Bleeding Management Pharmacy Practice News • April 2013

Las Vegas—Informatics pharmacists shared their strategies for using health care technology to reduce drug alert fatigue, set up remote pharmacies for rural locations, make smart pumps safer, and much more, during a session at the American Society of Health-System Pharmacists 2012 Midyear Clinical Meeting sponsored by ASHP’s Section of Pharmacy Informatics and Technology.

Cleveland Clinic Makes Its Smart Pumps Smarter

By standardizing smart pump set-tings and better managing alerts, phar-macists at the Cleveland Clinic Health System were able to improve the large-volume pump system that goes across all 10 of its hospitals and its 19 family health and ambulatory surgery centers, according to Silvana Balliu, PharmD, RPh, a smart pump pharmacist at the health system.

Noting that alert alarm management is a key factor in reducing health tech-nology hazards, Dr. Balliu described how Cleveland Clinic pharmacists focused on “decreasing the number of alerts received, to make them clinically significant to our caregivers.”

After reviewing continuous quality improvement (CQI) alarm report data and documenting the number of alerts received, a team at Cleveland Clinic tai-lored the audio alarm settings for alerts based on care areas and practice settings. The analysis revealed that many alerts received during infusion programming of pressors were caused by caregivers, who, when titrating doses downward ended up administering dosages lower than the lowest soft limits required by the smart pump’s settings. The health system significantly decreased alerts in this area by removing alerts for the low-est soft limits settings.

To reduce the risk for infusion pump

programming errors related to high-risk medications, Dr. Balliu said they programmed high-risk medications in the pump to be given as primary, not secondary, infusions. Also, they pro-hibited secondary medications from being programmed with high-risk medications.

Cleveland Clinic also standardized settings between the smart pump and the electronic medical record (EMR) to provide clinicians with consistent information regarding dosage, duration and concentration, Dr. Balliu noted.

For heparin infusions, the CQI analysis revealed that some alarm alerts were caused by caregivers attempting to enter the volume per hour versus the dosage. The team eliminated this practice by implementing the lowest hard dosage limit for heparin.

Pharmacy works closely with nurs-ing and anesthesia representatives dur-ing implementation and maintenance to “provide education and to make the library files transparent to them,” Dr. Balliu added. By making these types of improvements to the smart pumps, the number of alarm alerts decreased 50% from the fourth quarter of 2010 to the fourth quarter of 2011 (Figure). Today, Dr. Balliu added, Cleveland Clin-ic is working toward its goal of having a library compliance rate of 98%.

CPOE Helps with Timing Of Therapeutic Drug Levels

Before CPOE was implemented at the 173-bed Lawrence Memorial Hospital (LMH), in Lawrence, Kan-sas, pharmacists there discovered that many tests for drug levels were being timed inappropriately, contributing to multiple redraws and inappropriate adjustments of therapeutic drug dos-ages, and “increasing the cost of care,” said Gregory P. Burger, PharmD, a clini-cal pharmacist at LMH.

In March 2010, when LMH went live with CPOE, management made the decision that pharmacy would time all therapeutic drug levels for doctors.

To evaluate the effects of CPOE on timing of drug levels, pharmacists at LMH looked at phenytoin level tim-ing for the year before and after CPOE implementation. Dr. Burger said they

found that before CPOE, 73% of their orders were timed incorrectly compared with 17% after CPOE implementation.

After analyzing the post-CPOE data, Dr. Burger said they found that most of the errors occurred because pharma-cists “did not have all the information they needed to determine whether the doctor wanted a routine level or a stat level. We also had some confusion with laboratory not drawing the level at the correct time.”

In May 2012, LMH modified the CPOE system, putting in two different drug level orders, a “now” order (draw immediately) and “routine” order (draw based on best pharmacokinet-ic practices). The “now” order goes directly to the lab, but a communi-cation also is sent to pharmacists so they can monitor the lab result. The routine order goes to pharmacy, which sends an order to the laboratory to get an appropriate level. Pharmacy also sends a communication to the clinical pharmacist, so he or she can monitor the result, and sends a “dummy drug” order (pharmacy communication) to the EMR, so the nurses can coordinate with the lab to make sure the level is drawn on time relative to administra-tion of the dose.

In December, using the new pro-cess resulted in only two errors up to that point, Dr. Burger noted. “We have improved our processing to 92%, just

an 8% error rate. Currently, all narrow therapeutic drug levels are being pro-cessed this way.”

virtual Ambulatory Consult Is a Step Toward Collaborative Practice

To bridge the gap between pharmacy care for inpatients and outpatients in an affordable way, Roanoke, Va.-based Carilion Clinic, which owns and oper-ates eight hospitals and 160 ambula-tory practice sites in the western part of Virginia, is using its integrated EMR system to deliver post-discharge phar-macy consultations remotely.

Carilion started its remote program “very simply, with one pharmacist and one ambulatory practice site comprised of six health care providers,” said Kathy Yount, BS Pharm, RPh, a clinical phar-macist analyst at Carilion, in her pearl presentation.

Physicians work with an office refer-ral coordinator to send an electronic consult order through the hospital’s EMR to a remote pharmacist. Once the pharmacist receives the referral mes-sage, he or she uses the EMR to review the patient’s entire medical record, including such data as the patient’s medical history, current medications, pertinent laboratory information, insurance coverage, notes and so on.

On average, the pharmacist consults remotely with about two outpatients a week, mostly providing medication therapy recommendations. Treatment recommendations are sent directly to providers via the EMR.

The program, which so far has been expanded to a second hospital and a second ambulatory site, has the capabil-ity “to put standards in place that can be used with multiple patients, multiple locations and multiple pharmacists,” Ms. Yount said.

Carilion also is working on develop-ing an EMR medication management follow-up program to identify high-risk outpatients and flag their charts for follow-up consultations. Through that project, according to Ms. Yount, electronic health records will be shared among multiple hospitals, primary care practices and community pharmacies.

Better Timing of vancomycin Levels Improves Safety

Following the 2009 introduction of recommendations for vancomycin trough levels in the American Journal of Health-System Pharmacy, Gaines-ville-based Northeast Georgia Medical Center (NGMC), a 557-bed community hospital that typically has an average of 300 patients a month receiving van-comycin, changed its vancomycin dos-ing and monitoring guidelines.

To help prevent the development of

Pharmacy IT Strategies Can Prevent Errors and Help Streamline Operations

30

25

20

15

10

5

0

28

14

Fre

qu

en

cy o

f ala

rm a

lert

s (%

)

Q4 2010 Q4 2011

Figure. Cleveland Clinic pump alerts comparison.

• see IT STRATEGIES, page 28

Pharmacy Practice News • April 2013

Informatics Pearls

Technology 17

An analysis of Pennsylvania’s state-wide system for reporting patient-

safety incidents and serious events has yielded thousands of error reports that suggest electronic health records (EHRs) sometimes may cause drug mis-haps rather than prevent them.

“It’s the first time that I’m aware of that someone looked through a major reporting program to determine if the role of EHRs contributed to events,” said Matthew Grissinger, RPh, the director of error reporting programs at the Insti-tute for Safe Medication Practices, in Horsham, Pa., who was not involved in the study. “The biggest strength [of the study] is that [the investigators] rolled up their sleeves, got their hands dirty and read the reports.”

The researchers queried the Pennsyl-vania Patient Safety Reporting System (PA-PSRS) database using EHR-related search terms; the query returned 8,003 reports from June 2, 2004, through May 18, 2012. After the reports were winnow-ed, 3,099 were confirmed as relevant to EHRs. Of these, 2,763 (89%) were classi-fied as “event, no harm,” such as when an error occurred without an adverse out-come for the patient. An additional 320 reports (10%) were classified as “unsafe conditions,” which did not result in patient harm, according to the investiga-tors (Pa Patient Saf Advis 2012;9:113-121).

Fifteen reports (0.48%) involved tem-porary harm to the patient. In these cases, the harm was caused by “entering wrong medication data (n=6), administering the wrong medication (n=3), ignoring a documented allergy (n=2), failing to enter lab tests (n=2) and failing to docu-ment (n=2).” One event report involved significant harm, via failure to document an allergy to penicillin.

The proportion of health IT-related events that involved patient harm in the study is similar to the rates of harm seen with medication error reports, noted William M. Marella, MBA, the program director of the Pennsylvania Patient Safety Authority, in Harrisburg, and one of two authors of the study.

Digging a bit deeper into the findings of the report, most (81%) of the docu-

mented safety events involved medica-tion errors, such as those caused by

wrong drug, dose, time, patient or route (50%). Many of the events involved complica-tions of procedures, treat-

ments or tests (13%).Some reports were tagged with

more than one problem type (e.g., data entered into wrong fields), resulting

in a total of 3,946 problems identified

from the 3,099 reports. Many problems were related to wrong input (n=1,867), such as transposition or transcription errors, entry of incorrect patient param-eters (e.g., weight), and even entry of the wrong physician name.

Study weaknesses

Erin Sparnon, MEng, a senior patient safety analyst at the Pennsylvania Patient Safety Authority and the other

Pennsylvania Study Reveals Errors Associated with EHRs

‘Leadersmaynotrealize

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improved.Theriskisnot

knowingwhathastobe

done.’

—Matthew Grissinger, RPh

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Pharmacy Practice News • April 2013

Medication Safety

18 Technology

author of the study, said its major limi-tation was “lack of awareness on the part of reporting health caregivers that health IT could contribute to an event. Unless the reporter used specific que-ried health IT-related terms, we would have missed it. It suggests there may have been more health IT events.”

Mr. Grissinger said that the major limitation “is the data itself.” For exam-ple, “if you selected the wrong patient or the wrong drug, [that type of error report] doesn’t tell you the manufac-turer of the system, what did the screen

look like or other contributing factors. You don’t get a complete picture.”

The data in the study were not tagged by caregiver, so pharmacist-related events could not be isolated, Ms. Spar-non noted. However, Mr. Grissinger said selecting wrong patients and wrong drugs were common medication errors involving pharmacy order entry pro-grams. To reduce errors related to EHRs, he recommended the following: “Test the pharmacy order entry system. Test it to know what it can and cannot do. Pharmacists get a lot of drug interac-

tion alerts; as a result, you can get alert fatigue. Consider a process of reviewing alerts over a month for orders that have been overridden. Clean house by review-ing the drug dictionary in the pharmacy order entry system to remove unneces-sary or unused drug listings once a year. Use tall man lettering to make one drug name look different from another.”

EHRs present certain risks over paper records, Mr. Grissinger added. “Lead-ers may not realize the level or number of staff that it takes to keep health IT updated and improved. The risk is not

knowing what has to be done.” He added that a bigger risk was a mix of paper and electronic order entry—“a chaotic, hybrid system, where orders can be missed. I am far more concerned about that.”

Asked how their study should affect clinical practice, Ms. Sparnon said it should “raise awareness that health IT can play a role in medical error.” Mr. Marella said it should “raise the question of how to modify the system so a com-mon format for health IT is developed.”

—George Ochoa

Mr. Grissinger reported serving as a manager of medication safety analysis for the Pennsylvania Patient Safety Authority.

Mr. Marella and Ms. Sparnon reported no relevant financial conflicts of interest.

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Pharmacy Practice News • April 2013

Medication Safety

Technology 19

that vigilance by all hospital staff—those in pharmacy, nursing, security, human resources and administration—is required to address this looming problem.

Accrediting and regulating agencies have responded by requiring pharmacy departments to secure all controlled substances and identify the diversion of drugs in a timely manner. Advanced monitoring and dispensing systems, such as anesthesia dispensing carts, are helping hospitals better control their medication inventories, but diversion detection still remains a daunting task.

Pharmacy Practice News spoke with Deborah Riffel, RN, MS, a senior clini-cal sales consultant for CareFusion’s Pyxis Technologies, in Kansas City, Miss., about diversion prevention and detection in the hospital setting, the focus of the webinar sponsored by the company. Ms. Riffel recommended that hospitals take a systemized, multidi-mensional approach.

“Hospitals must have explicit poli-cies, detection methods, investigation processes and an organizational cul-ture of readiness,” she said. “Without a systemized approach, hospitals are vulnerable to major drug diversion and subsequent public and legal repercus-sions. Pharmacy, nursing and anesthe-sia are the main players, but when developing policies and procedures we also recommend including human resources, security, risk management [and] administration—all of those peo-ple potentially can be involved.”

Technology Can Be a Potent weapon …

Technology upgrades are an important weapon in the fight against drug diver-sion, Ms. Riffel noted. She cited, as an example, moving from hospital narcotic storage boxes to automated controlled substance cabinets. One study showed a 321% increase in diversion detection rates after the installation of automated cabinets in the controlled substance vault in central pharmacy (0.36 diversions detected per 100 beds per year before installation vs. 1.12 diversions detected per 100 beds per year after installation; Hosp Pharm 2005;40:977-983).

The monitoring and reporting tools built into many technology systems also can be invaluable in fighting diver-sion. Such tools “[enable] us to look at behavior patterns,” Ms. Riffel said. One productive strategy is to closely examine data on two employees who always seem to waste drugs together or employees who are canceling a lot of medication transactions, both of which can be mechanisms for drug diversion. “Having usable data is really the key to

curbing diversion and allowing hospi-tals to have better means for detection,” she said. In addition to any reports gen-erated from advanced monitoring tech-nology, there also needs to be internal reporting to provide checks and bal-ances, Ms. Riffel added.

Tricia Meyer, PharmD, an associate vice president of pharmacy at Scott & White Memorial Hospital, and an associate professor of anesthesiology in the Department of Anesthesiology at the Texas A&M University College of Medicine, in Temple, echoed Ms. Riffel’s sentiments of how timely reports generated by technological advances result in improved detection rates. However, Dr. Meyer said that she strongly believes in implementing checks and balances as well. “The information in the reports needs to be confirmed or validated by manual chart auditing, and inconsistencies or irregularities ... found in the automated reports must be checked,” she said. Additionally, she said, a representative from the department with the team member involved in the discrepancy should be involved in conducting the verifying audits along with a representative from pharmacy.

Ms. Riffel also suggested including a pharmacy presence by having pharmacy participation in the nursing orientation and being very clear about expectations for controlled substance management. “One of the first steps pharmacy can take is to look at privileges and see who has access to the controlled substance vault and the automated dispensing cabinets on each floor. Make sure employees have enough privileges to perform their job but not excess privileges to inappropri-ately access the system.”

Ms. Riffel noted that because tech-nology has moved into the operating room (OR) suite to specifically handle

anesthesia medications, this may be a big change for anesthesia providers. “Nurses may be used to having this oversight but many anesthesiologists

may not, and it is a change in their practice to get used to technology in each individual OR suite.” (For more practical strategies for reducing drug diversion, see Table 1.)

… But It’s Not a Cure-All

Even with the most advanced technol-ogy and monitoring systems in place, diverters who are familiar with a system still can find creative ways to divert med-ication. Hospitals, therefore, should seek to incorporate a human component that may be absent from monitoring tech-nology. “Nurse managers can be help-ful in diversion prevention because they perform patient interviews asking about pain control,” Ms. Riffel said. “We discov-ered a case where a patient reported only receiving one pill, but it was documented that the nurse was removing two pills from the dispensing machine.”

Observing unusual employee behav-ior is another way hospitals can be vigilant for controlled substance abuse in the health care setting. Key behav-iors to look for when trying to identify diverters include work absenteeism, excessive time spent near drug sup-ply, confusion, memory loss, deteriora-tion in personal appearance, personal-ity change, denial and trying to deflect attention. For more information, visit the Drug Enforcement Administra-tion’s Office of Diversion Control (http://www.deadiversion.usdoj.gov/pubs/brochures/drug_hc.htm).

Dr. Meyer stressed the importance of educational programming for hospital employees so that they can recognize the signs and warnings of impaired col-leagues (Table 2). “The substance abuser rarely reports his or her addiction, and coworkers are hesitant to become involved or [divulge their concerns],” she said. “Staff must be informed that the consequences of not reporting the indi-vidual in question can be significantly worse than reporting him or her. Addict-ed health care workers who are not dis-covered ... are in danger of hurting them-selves, patients, the workplace and their profession,” Dr. Meyer cautioned.

How can hospitals enforce controlled substance policies without making employees feel like they are constantly being watched by Big Brother? It can require walking a fine line. “Estab-lish a culture of diversion prevention and detection overall in the hospital and emphasize that it is every hospi-tal employee’s responsibility,” Ms. Riffel said. “If employees know that there is a zero tolerance policy for medication diversion, they will be held accountable for their actions. For new employees, hospitals might emphasize controlled substance management and detection and the possibility of drug testing.”

—Megan Block, MPH

Table 1. Practical Tips To Secure your Pharmacy Unit

Havetwoemployeestoplaceandreceiveorders.

Haverotatingpersonnelperforminventoryinthecontrolledsubstancevaultincentralpharmacy.

Keepkeystothecontrolledsubstancevaultandautomateddispensingcabinetsinasecureplace.Numberthekeysandhaveonesetlockedinthevaultandgiveanothersettothedirectorofpharmacy.

Createanautomatedorpaperaudittrailforanymovementofcontrolledsubstances.Theremustbeareconciliationsystemofwhatwaspurchasedversuswhatwasreceivedinthevault.Auditsshouldbecompletedbyapersonwhodoesnothandlecontrolledsubstances.

Allcontrolledsubstancesinautomateddispensingcabinetsonthefloorshouldbeinsingle-jarorsingle-doseaccesspockets.Keepcontrolledsubstancesinadrawerseparatefromnoncontrolledsubstances.

Requireawitnesstoreturnbins.

Source: Deborah Riffel, RN, MS

Table 2. Signs and Symptoms of Substance Abuse in the workplace

Frequentabsencesfromworkwithoutreasonableexplanations

Consistentlylatearrivals

Missedappointmentswithpatients

Inaccessibilitytopatientsandstaff

Inappropriatebehaviorwithcolleagues,staffandpatients

Conflictswithcolleagues,staffandpatients

Avoidanceofasupervisororothercolleagues

Roundingonpatientsatoddhours

Largequantitiesofdrugsordered

Inappropriateordersandforgottenverbalorders

Adisorganizedscheduleandmisseddeadlines

Heavydrinkingathospitalfunctions

Vaguelettersofreference

Multipleprescriptionsforfamilymembers

Longlunchesorunnecessarybreaks

Decreasedchartandworkperformance

Source: Crit Care Med. 2007;35:S106-S116.

CHALLENGEcontinued from page 1

‘Addictedhealthcareworkerswhoarenot

discovered...areindangerofhurtingthemselves,

patients,theworkplaceandtheirprofession.’

—Tricia Meyer, PharmD

Pharmacy Practice News • April 2013

Diversion

20 Technology

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NDC 0517 Strength Size Shelf Pack

3605-25 500 mg/5 mL (100 mg/mL) 5 mL 25

IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONSThere are no contraindications to Levetiracetam Injection for intravenous use.ere are no cocontrntrainaindicdicatiationsons to to Le Levetvetirairacetcetam am InjInjectectionio for intravWARNINGS AND PRECAUTIONSNeuropsychiatric Adverse ReactionsParttial Onset SSeizeizureuressIn some adults experiencing partial onset seizures, levetiracetam causes the occurrence of central some adults experiencing partial onset seizures, levetiracetamnervous s em adverse reactions that can be classified into the following categories: 1) somnolence vous system adverse reacctions that can n be classified into the foand fatigue, 2) coordination difficulties, and 3) behavioral abnormalities. fatigue, 2) coordination difficulties, and 3) behavioral abnormaMyooclonic SeizuresDuring clinical development, the number of patients with myoclonic seizures exposed to levetiracetam ing clinical development, the number of patients with myoclonicwas considerably smaller than the number with partial seizures. Therefore, under-reporting of certain adverse reactions was more likely to occur in the myoclonic seizure population. In some patients experiencing myoclonic seizures, levetiracetam causes somnolence and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with juvenile myoclonic epilepsy (JME).Primary Generalized Tonic-Clonic SeizuresDuring clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to levetiracetam was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with levetiracetam treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and levetiracetam treatment groups and no appreciable discontinuations.Although it may be expected that drug related events seen in partial seizure patients would be seen in primary generalized epilepsy patients (e.g., somnolence and gait disturbance), these events may not have been observed because of the smaller sample size.Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.Hematologic AbnormalitiesPartial Onset SeizuresMinor, but statistically significant, decreases compared to placebo in total mean RBC count(0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam- treated patients in controlled trials.A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant(≤2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 109/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.Juvenile Myoclonic EpilepsyAlthough there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.Hepatic AbnormalitiesThere were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.Laboratory TestsAlthough most laboratory tests are not systematically altered with levetiracetam treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.

Adverse ReactionsBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Partial Onset SeizuresIn well-controlled clinical studies using levetiracetam tablets in adults with partial onset seizures, the most frequently reported adverse reactions in patients receiving levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness.Myoclonic SeizuresIn the well-controlled clinical study using levetiracetam tablets in patients with myoclonic seizures, the most frequently reported adverse reactions in patients using levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, neck pain, and pharyngitis.Primary Generalized Tonic-Clonic SeizuresIn the well-controlled clinical study that included patients 4 years of age and older with primamary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse reaction assocsociiated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequequency yamong placebo-treated patients, was nasopharyngitis.In addition to the adverse reactions listed above, the following adverse events have been n reportedd in patients receiving marketed levetiracetam worldwide. The listing is alphabetized: ababnormall li liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopeenia (a withh bone marrow suppression identified in some of these cases), thrombocytopenia and weighghtt lossos . AAlopecia has been reported with levetiracetam use; recovery was observed in majorrityty of cac sesses where levetiracetam was discontinued. There have been reports of suicidal behavior ((inincludinging c complp eted suicide, suicide attempt and suicidal ideation) with marketed levetiracetam.SPECIFIC POPULATIONSPregnancy Category C: There are no adequate and well-controlled stududies in preegnagnant t women. In animal studies, levetiracetam produced evidence of developmental tl toxix city, inccluludingng teratogenic effects, at doses similar to or greater than human therapeutic dosseses. Levetiraacetetam shosh uld be used during pregnancy only if the potential benefit justifies the potentiaall risks to thhe fetetus.The effect of levetiracetam on labor and delivery in humans is is unknown.Levetiracetam is excreted in breast milk. Because of the e potente ial for sseerious adverse reactions in nursing infants from levetiracetam, a decision sshould d bbe made whethethher to discontinue nursing or discontinue the drug, taking into account the importanance of the drug ug to the mother.Pediatric UseSafety and effectiveness of levetiracetam injectioni inn pa patietients below the age of 16 years have not been established.Geriatric UseOf the total number of subjects in clinical studies of levettiracetam, 347 were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients.Levetit racetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal functiono , carear should be taken in dose selection, and it may be useful to monitor renal function.

MCPPN2338.indd 1 3/15/13 8:34 PM

LEVETIRACETAM INJECTION, USP Rx OnlyINDICATIONS AND USAGE - Levetiracetam injection is an antiepileptic drug indicated for adjunct therapy in adult patients (16 years and older) when oral administration is temporarily not feasible.

Partial Onset Seizures - Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy.

Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy - Levetiracetam is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy.

Primary Generalized Tonic-Clonic Seizures - Levetiracetam is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy.

CONTRAINDICATIONS - None

WARNINGS AND PRECAUTIONSNeuropsychiatric Adverse Reactions Partial Onset Seizures - In some adults experiencing partial onset seizures, levetiracetam causes the occurrence of central nervous system adverse reactions that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of levetiracetam-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of the treated patients, compared to 0% in the placebo group. About 3% of levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced. A total of 3.4% of levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued levetiracetam treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia. Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment. In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) of levetiracetam-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient. Two (0.3%) levetiracetam-treated patients were hospitalized and their treatment was discontinued. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. Two other events, reported as hallucinations, occurred after 1 to 5 months and resolved within 2 to 7 days while the patients remained on treatment. In one patient experiencing psychotic depression occurring within a month, symptoms resolved within 45 days while the patient continued treatment. A total of 13.3% of levetiracetam patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients. Approximately half of these patients reported these events within the first 4 weeks. A total of 1.7% of treated patients discontinued treatment due to these events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of treated patients and in 0.5% of placebo patients. A total of 0.8% of treated patients had a serious behavioral event (compared to 0.2% of placebo patients) and were hospitalized. In addition, 4 (0.5%) of treated patients attempted suicide compared to 0% of placebo patients. One of these patients completed suicide. In the other 3 patients, the events did not lead to discontinuation or dose reduction. The events occurred after patients had been treated for between 4 weeks and 6 months.

Myoclonic Seizures - During clinical development, the number of patients with myoclonic seizures exposed to levetiracetam was considerably smaller than the number with partial seizures. Therefore, under-reporting of certain adverse reactions was more likely to occur in the myoclonic seizure population. In some patients experiencing myoclonic seizures, levetiracetam causes somnolence and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with JME. In the double-blind, controlled trial in patients with juvenile myoclonic epilepsy experiencing myoclonic seizures, 11.7% of levetiracetam-treated patients experienced somnolence compared to 1.7% of placebo patients. No patient discontinued treatment as a result of somnolence. In 1.7% of levetiracetam-treated patients and in 0% of placebo patients the dose was reduced as a result of somnolence. Non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of the levetiracetam-treated patients compared to 0% of placebo patients. Non-psychotic mood disorders (reported as depressed mood, depression, and mood swings) occurred in 6.7% of levetiracetam-treated patients compared to 3.3% of placebo patients. A total of 5.0% of levetiracetam-treated patients had a reduction in dose or discontinued treatment due to behavioral or psychiatric events (reported as anxiety, depressed mood, depression, irritability, and nervousness), compared to 1.7% of placebo patients.

Primary Generalized Tonic-Clonic Seizures During clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to levetiracetam was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with levetiracetam treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and levetiracetam treatment groups and no appreciable discontinuations. Although it may be expected that drug related events seen in partial seizure patients would be seen in primary generalized epilepsy patients (e.g., somnolence and gait disturbance), these events may not have been observed because of the smaller sample size. In some patients experiencing primary generalized tonic-clonic seizures, levetiracetam causes behavioral abnormalities. In the double-blind, controlled trial in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures, irritability was the most frequently reported psychiatric adverse event occurring in 6.3% of levetiracetam-treated patients compared to 2.4% of placebo patients. Additionally, non-psychotic behavioral disorders (reported as abnormal behavior, aggression, conduct disorder, and irritability) occurred in 11.4% of the levetiracetam-treated patients compared to 3.6% of placebo patients. Of the levetiracetam-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression. Non-psychotic mood disorders (reported as anger, apathy, depression, mood altered, mood swings, negativism, suicidal ideation, and tearfulness) occurred in 12.7% of levetiracetam-treated patients compared to 8.3% of placebo patients. No levetiracetam-treated patients discontinued or had a dose reduction as a result of these events. One levetiracetam-treated patient experienced suicidal ideation. One patient experienced delusional behavior that required the lowering of the dose of levetiracetam. In a long-term open label study that examined patients with various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior. Behavior in one case was characterized by auditory hallucinations and suicidal thoughts and led to levetiracetam discontinuation. The other case was described as worsening of pre-existent schizophrenia and did not lead to drug discontinuation.

Withdrawal Seizures - Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.

Hematologic Abnormalities - Partial Onset Seizures -Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant ( 2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant ( 1.0 x 109/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.

Juvenile Myoclonic Epilepsy -Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.

Hepatic Abnormalities - There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.

ADVERSE REACTIONSClinical Studies Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reactions that result from levetiracetam injection use include all of those reported for levetiracetam tablets and oral solution. Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent Cmax, Cmin, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15 minute infusion. The prescriber should be aware that the adverse reaction incidence figures in the following tables, obtained when levetiracetam was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied.

Partial Onset Seizures Table 3 lists treatment-emergent adverse reactions that occurred in at least 1% of adult epilepsy patients treated with levetiracetam tablets participating in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

Table 3: Incidence (%) of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Studies in Adults Experiencing Partial Onset Seizures by Body System (Adverse Reactions Occurred in at Least 1% of Levetiracetam-Treated Patients and Occurred More Frequently than Placebo-Treated Patients)Body System/Adverse Reaction Levetiracetam Placebo (N=769)% (N=439)%Body as a Whole

Asthenia 15 9 Headache 14 13 Infection 13 8 Pain 7 6Digestive System

Anorexia 3 2 Nervous System Somnolence 15 8 Dizziness 9 4 Depression 4 2 Nervousness 4 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Hostility 2 1 Paresthesia 2 1 Emotional Lability 2 0

Respiratory System

Pharyngitis 6 4 Rhinitis 4 3 Cough Increased 2 1 Sinusitis 2 1Special Senses

Diplopia 2 1

Myoclonic Seizures Table 4 lists treatment-emergent adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam tablets and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

Table 4: Incidence (%) of Treatment-Emergent Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients with Myoclonic Seizures by Body System (Adverse Reactions Occurred in at Least 5% of Levetiracetam-Treated Patients and Occurred More Frequently than Placebo-Treated Patients)Body System/Adverse Reaction Levetiracetam Placebo (N=60)% (N=60)%Ear and labyrinth disorders

Vertigo 5 3Infections and infestations

Pharyngitis 7 0 Influenza 5 2

Musculoskeletal and connective tissue disorders

Neck pain 8 2Nervous system disorders

Somnolence 12 2Psychiatric disorders

Depression 5 2

Primary Generalized Tonic-Clonic Seizure Table 5 lists treatment-emergent adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

Table 5: Incidence (%) of Treatment-Emergent Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 4 Years of Age and Older with PGTC Seizures by MedDRA System Organ Class (Adverse Reactions Occurred in at Least 5% of Levetiracetam-Treated Patients and Occurred More Frequently than Placebo-Treated Patients)Body System/Adverse Reaction Levetiracetam Placebo (N=79)% (N=84)%Gastrointestinal disorders

Diarrhea 8 7

General disorders and administration site conditions

Fatigue 10 8Infections and infestations

Nasopharyngitis 14 5Psychiatric disorders

Irritability 6 2 Mood swings 5 1

DRUG INTERACTIONS In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely. Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses 350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m2 basis). There was no overt maternal toxicity at the doses used in this study. Treatment of pregnant rabbits during the period of organogenesis resulted in increased embryo fetal mortality and increased incidences of minor fetal skeletal abnormalities at doses 600 mg/kg/day (approximately 4 times MRHD on a mg/m2 basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m2 basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m2 basis). Maternal toxicity was also observed at 1800 mg/kg/day. When pregnant rats were treated during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study. Treatment of rats during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis).

Patients may enroll in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free).Labor and Delivery - The effect of levetiracetam on labor and delivery in humans is unknown.

Nursing Mothers - Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use - Safety and effectiveness of levetiracetam injection in patients below the age of 16 years have not been established.

Geriatric Use - Of the total number of subjects in clinical studies of levetiracetam, 347 were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients. A study in 16 elderly subjects (age 61 to 88 years) with oral administration of single dose and multiple twice-daily doses for 10 days showed no pharmacokinetic differences related to age alone. Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Use in Patients with Impaired Renal Function - Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis.

OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of oral levetiracetam received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses in postmarketing use.

Treatment or Management of Overdose - There is no specific antidote for overdose with levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam.

Hemodialysis - Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

Storage - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature).

How Supplied-Levetiracetam injection 500 mg/5 mL is a clear, colorless, sterile solution. It is supplied in single-use 5 mL vials, available in cartons of 25 vials (NDC 0517-3605-25).

AR126 Iss. Date 1/2012

MCPPN2339.indd 1 3/15/13 8:36 PM

Carousel dispensing technology (CDT) is a popular method of stor-

ing and dispensing medications in hos-pital pharmacies. The overall reliability of CDT allows for safe and efficient dispensing of medications. However, because the CDT primarily relies on motorized machinery, there always is a risk for mechanical failure. Our institu-tion, Northeast Georgia Health Center, implemented CDT in 2009 and had essentially no downtime until 2012, when a mechanical failure rendered the CDT unusable for several hours. After this event, we undertook a proj-ect to devise a comprehensive contin-gency plan for medication distribution in the event of unexpected or pro-longed downtime of the CDT.

The first step in developing a contingency plan was to assess both the appropriateness of the medications stocked in the CDT and the potential clinical effect of a downtime that prevents access to

those medications. Medications were reviewed based on clinical urgency and availability from other locations. Items were placed in 3 categories: those with high clinical urgency that should not be stocked in the CDT, such as crash-cart medications and antidotes for poisonings; those with moderate to high clinical urgency that are stocked in other locations within the facility (eg, automated dispensing cabinets [ADC], satellite pharmacy, etc.), and items with lower clinical urgency that could be safely obtained from the pharmacy wholesaler within 2 to 3 hours (Table).

The categories were used to deter-mine the most appropriate storage location for medications. We found that high clinical urgency medica-tions should not be stored in the CDT. Although the CDT offers a convenient storage method, these high-urgen-cy medications should be stored in an area with no barriers to access. Items with a moderate to high clini-cal urgency were considered for CDT storage as long as they were avail-able from an alternate storage location within the facility (eg, ADC or satellite pharmacy). Items with a lower clinical urgency continued to be good candi-dates for CDT storage.

The review of the CDT contents resulted in the permanent removal of 4 medications from the CDT because they were deemed too time-critical to risk a delay due to mechanical failure. All

crash cart medications packaged in sin-gle-use syringes were removed as well.

The pharmacy team then developed a formal contingency plan consisting of 3 key elements:1. A written downtime plan to clearly

direct pharmacy staff to alternate locations for medications stored throughout the facility.

2. Strategies for medication removal and storage if the CDT needs to be emptied until a repair occurs.

3. The ability to place a predetermined emergency wholesaler order rap-idly for immediate delivery. This order list is stored electronically on a shared drive that is accessible to key pharmacy personnel.

When developing these 3 elements, we focused on making clear, easy-to-follow guidance for managing down-

time. The downtime plan directs staff to specific alternate storage locations for necessary medications. If the CDT needs to be emptied, staff has written directions on how to unload medica-tions safely and quickly. Finally, when developing the emergency wholesaler order, we put the most commonly dis-pensed CDT medications on the order list in quantities to last approximately 24 to 48 hours, depending on esti-mated repair time. The order list will be evaluated periodically to adjust for formulary changes.

Mechanical failure is rare with CDT, but it can and does occur. Although we have not had to use our contin-gency plan recently, having one in place ensures that staff can confidently launch the contingency plan to manage CDT downtime. ■

A contingency plan for drug dispensing

when the Carousel Stops Teresa Blakely, PharmDAutomation Coordinator

Melissa C. Frank, PharmDAssistant Director of Pharmacy

Steve Carlson, BS Pharm, MHA Director of Pharmacy

Northeast Georgia Health SystemGainesville, Georgia

In the first eight weeks since its launch, the mobile app MediSafe Project

achieved a reported medication adher-ence rate of 81% among its users. That fig-ure is 31% higher than the World Health Organization’s estimated average medi-cation adherence rate of 50%, according to a press release from the company, MediSafe Project, based in Haifa, Israel. For MediSafe Project users who record-ed their use of statins, the adherence rate was 84.25%, which is 34.25% higher than the general population.

“Medication adherence is a persis-tent and elusive problem, interrupt-ing patients’ well-being, costing health providers and insurers billions annu-ally, and causing preventable deaths,” MediSafe Project CEO Omri “Bob” Shor said in a statement. “MediSafe Proj-ect’s involvement of patients’ loved ones and caretakers is proving itself a

breakthrough in reducing the harm that comes from medication nonadherence.”

Launched in November 2012 and avail-able as a free download in both Android and iOS versions, the MediSafe Project is the first cloud-synced mobile app help-ing families prevent emergencies caused by over- or under-dosing medications, according to the press release. MediSafe Project reminds users when it is time to take a medication, and, when a user misses a dose, sends alerts to selected family members, friends and caregivers. Users have visited the app a total of 95,000 times per month and recorded taking more than 100,000 medication doses as directed.

According to the MediSafe Project web-site (www.medisafeproject.com), low-tech alternatives to the app will become available to people without smartphones in 2013, via an automated phone system.

Patients will be able to use touchtone to record medication doses, and caregivers will be able to receive alerts about missed doses via automated calls.

The MediSafe Project was inspired by the accidental and potentially fatal insu-lin double-dose of the diabetic father of brothers and co-founders Omri and Rotem Shor. The co-founders, accord-ing to the press release, regard Medi Safe Project as a way to lower hospitalization and mortality rates, promote sustainable behavior changes that prolong health, and reduce long-term health care costs.

The developers added that the Medi-Safe Project also provides aggregated patient behavior data, physician trends and other market aspects to help phar-maceutical companies better understand how their medications are used.

—George Ochoa

MediSafe Project Raises Medication Adherence Rates

Table. Medication Categories For Storage Consideration

Items that should NOT be stored in the CDT

•Medicationswithhighclinicalurgencynotstockedinalternativelocations:

- Crash-cartmedications

- Zidovudineinjection(laboringHIV+patient)

- Antidotesforpoisoning(eg,acetylcysteineinjectionforacetaminophenoverdose;cyanideantidotekitforcyanidepoisoning)

•Argatrobaninjection(HITpatients)

•Methylprednisolone1ginjection(spinalcordinjury)

•MedicationspackagedinawaythatshiftingcouldcauseCDTmalfunction

Items with moderate to high clinical urgency but are stocked in other loca-tions within the facility (eg, ADCs, satellite pharmacy, etc.)

Items with lower clinical urgency that could be safely obtained from the pharmacy wholesaler within 2-3 h

ADCs, automated dispensing cabinets; CDT, carousel dispensing technology; HIT, heparin-induced thrombocytopenia

Pharmacy Practice News • April 2013

Practice Pearl

Technology 23

for medications on the higher end of the risk spectrum—a reporting gap that has undermined any assessment of the mer-its of that REMS program component.

These issues “raise concerns about the overall effectiveness of the REMS pro-gram,” the OIG concluded in its Feb. 13, 2013 report.

Under the Food and Drug Adminis-tration Amendments Act of 2007 and subsequent legislation, the FDA has been

granted legal authority to require drug and biological product manufacturers or sponsors to establish a REMS program whenever the agency determines that one is necessary to ensure that a prod-uct’s therapeutic benefits outweigh its

risks. REMS programs typically include additional medication guides, patient package inserts, communications plans for health care providers and one or more ETASUs, such as patient and pre-scriber registries, specific training for

prescribers and practitioners, or certifi-cations in health care settings.

Some REMS programs have become controversial, such as those involving erythropoietin-stimulating agents and long-lasting, extended-release opioids. The main objections to the REMS pro-grams often revolve around delays in access to medications that can result when complicated REMS requirements are implemented. Drug manufacturers, which are responsible for REMS, have noted that they can only advise but not control physician and patient behavior when it comes to prescribing practices and medication adherence.

The OIG reviewed 199 REMS approved by the FDA between March 25, 2008, when the program officially began, and Dec. 31, 2011. The OIG selected 49 spon-sor assessments and interviewed FDA officials about them. OIG found that near-ly half of the assessments (23 of 49) were missing information that the FDA had requested. For example, one drug sponsor did not report the number of pharmacies that had been “deauthorized” to dispense its drug because of noncompliance with the REMS. The same sponsor also did not report the amount of the drug shipped to health care providers compared with actual patient orders. (The company was not identified in the report.)

Failure to report requested (i.e., volun-tary) information is not the only poten-tial weak point in REMS reporting and assessment, according to the OIG report. Federally required (i.e., mandatory) time-tables for report submission, for exam-ple, were often missed. Indeed, more than 20% of the completed REMS assess-ments (10 of 49) had been submitted by sponsors after the dates specified in the timetables (three to 70 days late, with a median of 17 days).

This presents a multipronged prob-lem with regard to FDA oversight. First, when drug companies fail to provide vol-untary information, FDA lacks author-ity to take enforcement action against them. Second, even in cases where the aqency does have enforcement author-ity—for example, when drug companies fail to comply with mandatory items that carry the force of federal law—FDA is not exercising that authority, according to the OIG. And this is despite the fact that the agency has powerful enforce-ment tools at its disposal: it can, for example, apply penalties such as barring the involved drug from interstate com-merce and imposing civil fines of up to $250,000 per violation, and up to $10 million for continued violations.

The OIG recommended that FDA should seek authority from Congress to take action when even voluntary items are not being met. The FDA “did not explicitly concur,” the OIG report noted, “but agreed that it should be considered if another opportunity arises” to make

REMScontinued from page 1

‘[REMSprograms]havenoprecedent,andeven

thoughtheyseemlike“goodideas,”tomy

knowledge,theyhaveneverbeenshowntoimprove

patientsafetyorreduceharm.’

—David S. Craig, PharmD

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Pharmacy Practice News • April 2013

Medication Safety

24 Policy

legislative changes to the REMS program.Overall, according to the OIG report,

only seven of the 49 REMS evaluated had met all of their goals, whereas 21 had not. Of the remaining 21, the FDA could not determine whether 17 had met the goals, and had not assessed the other four.

Because the FDA had evaluated only one of 32 drugs having ETASUs, it “has limited data to demonstrate that the remaining REMS with ETASUs effec-tively ensure safe use of drugs or meet statutory requirements to minimize bur-dens on patients and the health care system,” noted the OIG. In its comments, the FDA replied it had spent much of the past three years developing and imple-menting the REMS program.

The OIG stated that the FDA needs to develop a plan to “identify, develop, validate, and assess the effectiveness of REMS.” The report also said that the FDA should identify REMS that are not meeting their goals and work with spon-sors to correct deficiencies; evaluate one ETASU per year as required by law; work with sponsors to obtain missing infor-mation; and complete its own reviews within 60 days. The FDA agreed with these recommendations.

The nation’s branded drug industry association did not have much to say about the OIG’s findings. “We look for-ward to reviewing the report and con-tinuing to work with FDA to help ensure that REMS effectively improve the safety of medicines while not unnecessarily burdening patients and health care pro-fessionals,” said Matthew Bennett, the senior vice president of Pharmaceutical Research and Manufacturers of America.

Silver Lining?

James M. Hoffman, PharmD, a medica-tion safety officer at St. Jude Children’s Research Hospital, in Memphis, Tenn., pointed to a dropoff in REMS programs as evidence that the initiative is working. Since its inception in 2008, 199 REMS have been created; by 2012, only 99 were still in place. That falloff “is evidence of the FDA’s work to refine the program,” Dr. Hoffman said. “Keep in mind that some REMS (those with ETASUs) are designed to enable drugs to be on the market that would otherwise be with-drawn for safety risks. Thus, REMS con-tinue to [help maintain] access to impor-tant therapies, which is a clear success.”

Others disagree. REMS programs “have no precedent, and even though they seem like ‘good ideas,’ to my knowl-edge, they have never been shown to improve patient safety or reduce harm,” said David S. Craig, PharmD, the director of the pain and palliative care residency program at the H. Lee Moffitt Cancer Center and Research Institute, in Tampa, Fla. “The FDA is doing its best with the new authority given to them, but I think they also don’t really want to monitor

and oversee both the implementation and impact all of these REMS programs. In addition, they have very [few] tools to evaluate the impact and outcome of any REMS and also likely lack the manpower

to ensure that all drug manufacturers are carcomplying with the requirements.”

Bonnie Kirschenbaum, MS, FASHP, a health care consultant based in Breck-enridge, Colo., said the concept of REMS

“has merit.” After all, “one really can’t argue [against] educating prescribers, pharmacists and patients about using a drug in the most advantageous and safest way possible.” Unfortunately, the REMS program has been weakened, she said, by ongoing controversy over how to interpret the specific components of the program and the overcomplication of its implementation. “This has significantly diminished any possible returns we might have gotten from this initiative, however well-intentioned it may be.”

—Ted Agres

‘KeepinmindthatsomeREMS(thosewithETASUs)

aredesignedtoenabledrugstobeonthemarket

thatwouldotherwisebewithdrawnforsafetyrisks.

Thus,REMScontinueto[helpmaintain]accessto

importanttherapies,whichisaclearsuccess.’

—James M. Hoffman, PharmD

Thrombate III® (antithrombin III [human])—proven effective for patients with hereditary antithrombin (AT) defi ciency during surgery, childbirth, and in the prevention and treatment of thromboembolism1

Thrombate III provides predictable amounts of AT to replace what is normally present in the body AT concentrate purifi ed from human plasma and pasteurized to inactivate viruses, with no confi rmed cases of virus transmission

In clinical studies, no cases of thrombotic complications during surgical and obstetrical procedures were reported

Important Safety InformationThrombate III® (antithrombin III [human]) is indicated for the treatment of patients with hereditary antithrombin defi ciency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism.

In clinical studies with Thrombate III, the most common side effects were dizziness, chest discomfort, nausea, and dysgeusia.

The anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT-III defi ciency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III.

Thrombate III is made from human plasma. Plasma products carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk. No cases of transmission of viral disease or CJD have ever been identifi ed for Thrombate III.

Please see brief summary of Thrombate III complete Prescribing Information on adjacent page.Reference: 1. Thrombate III® (antithrombin III [human]) [prescribing information]. Research Triangle Park, NC: Grifols Inc; 2012.

© 2013 Grifols Inc. All rights reserved. February 2013 TH05-0113

Convenient to store and reconstitute1

500 IU vials with sterile water for injection Filter and transfer needles provided Room temperature storage

Easy to administer1

One dosing formula Bolus intravenous infusion (not continuous infusion)

Pregnancy category B

To learn more, visit www.thrombate.comWhen thrombotic risk is high in

hereditary antithrombin deficiency

PROCEED SAFELY

Pharmacy Practice News • April 2013

Medication Safety

Policy 25

Congress should authorize and fund the FDA to establish a mandato-

ry, national track-and-trace system for pharmaceuticals, according to an Insti-tute of Medicine (IOM) report released Feb. 13. In the meantime, stated the report, the FDA should convene a work-ing group of stakeholders to promote voluntary track and trace.

This advice, labeled Recommendation 5-2, is part of Countering the Problem of

Falsified and Substandard Drugs (pub-lished by the National Academies Press in Washington, D.C.), written by an IOM

committee. The report concerns the global problem of illegitimate drugs, whether they are falsified or fake, carry-

ing a false representation of identity or source, or substandard, failing to meet accepted specifications. Many recom-mendations in the report are largely relevant to developing countries, but some, including the track-and-trace rec-ommendation, are of special importance to the United States.

The relevance of the track-and-trace recommendation was swiftly noted by the Pharmaceutical Distribution Secu-rity Alliance (PDSA), a coalition of phar-macies, distributors, manufacturers and others committed to strengthening the nation’s pharmaceutical distribution supply chain. “[PDSA] applauds the [IOM] for recognizing that new legisla-tion is needed to protect all Americans from the threat of counterfeit drugs,” said a statement from PDSA.

Indicators are “good” in Congress for “potential enactment into law,” Vince Ventimiglia, principal, FaegreBD Con-sulting, Washington, D.C., and an advi-sor to PDSA, wrote by email. “Key com-mittee leadership and other important members of Congress in both congres-sional bodies have stated that supply-chain traceability legislation remains a high priority for enactment into law this year; the FDA has asked for increased authority of this nature; and Congress has spent countless hours negotiating an effective policy.”

In contrast, a co-editor of the IOM report, Gillian J. Buckley, PhD, MPH, told Pharmacy Practice News, “Realisti-cally, it might take Congress a while.”

voluntary Global Effort

ReposiTrak, a joint venture of Leavitt Partners and Park City Group, is a vol-untary track-and-trace system that aims at an even larger scale than the national scope specified by the IOM recommen-dation. “ReposiTrak is a track-and-trace system with which we anticipate serving the entire global food supply system, as well as supplement nutraceuticals and pharmaceuticals,” said Randy Fields, MA, chairman, Park City Group, Salt Lake City. “It will keep track of all docu-ments related to safety and compliance, track and trace movement of ingredients and tell where inventory is now.”

“Although we’re not in a position to talk about mandatory versus voluntary systems, the market is moving toward greater use of track and trace,” said Kristina Lunner, senior advisor, Leavitt Partners, Washington, D.C.

“The world is trying to agree on stan-dards for identification. On a global scale, they want to agree on an identifier. It’s a huge obstacle and very expensive,” Mr. Fields said. “Our secret sauce is to track and trace without a common identifier. Our system is completely interoperable.”

IOM Report Recommends National Track-and-Trace System‘Theworldistryingtoagreeonstandardsfor

identification.Onaglobalscale,theywantto

agreeonanidentifier.It’sahugeobstacleandvery

expensive.’—Randy Fields, MA

THROMBATE III®Antithrombin III (Human)

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR

FULL PRESCRIBING INFORMATION

FOR INTRAVENOUS USE ONLYDESCRIPTIONAntithrombin III (Human), THROMBATE IIIw is a sterile, nonpyrogenic, stable, lyophilizedpreparation of purified human antithrombin III (ATIII).THROMBATE III is prepared from pooled units of human plasma from normal donors bymodifications and refinements of the cold ethanol method of Cohn. When reconstituted withSterile Water for Injection, USP, THROMBATE III has a pH of 6.0–7.5, a sodium content of110–210 mEq/L, a chloride content of 110–210 mEq/L, an alanine content of 0.075–0.125 M,and a heparin content of not more than 0.1 IU heparin/IU ATIII. THROMBATE III contains nopreservative and must be administered by the intravenous route. Each vial of THROMBATE III contains the labeled amount of antithrombin III in internationalunits (IU) per vial. The potency assignment has been determined with a standard calibratedagainst a World Health Organization (WHO) antithrombin III reference preparation.The capacity of the THROMBATE III manufacturing process to remove and/or inactivateenveloped and non-enveloped viruses has been validated by laboratory spiking studies on ascaled down process model using a wide range of viruses with diverse physicochemicalproperties. There are two dedicated virus inactivation/removal steps included in theTHROMBATE III manufacturing process: a heat treatment step at 60°C ± 0.5°C for not lessthan 10 hours for virus inactivation and a nanofiltration step for effective removal of viruses assmall as 18 nm.The manufacturing process was also investigated for its capacity to decrease the infectivity ofan experimental agent of transmissible spongiform encephalopathy (TSE), considered as amodel for the vCJD and CJD agents.An individual production step in the THROMBATE III manufacturing process has been shownto decrease TSE infectivity of that experimental model agent. The TSE reduction step is theEffluent I to Effluent II + III fractionation step (6.0 log10). These studies provide reasonableassurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, wouldbe removed.

CLINICAL PHARMACOLOGYAntithrombin III, an alpha2-glycoprotein of molecular weight 58,000, is normally present inhuman plasma at a concentration of approximately 12.5 mg/dL and is the major plasmainhibitor of thrombin. Inactivation of thrombin by ATIII occurs by formation of a covalent bondresulting in an inactive 1:1 stoichiometric complex between the two, involving an interactionof the active serine of thrombin and an arginine reactive site on ATIII. ATIII is also capable ofinactivating other components of the coagulation cascade including factors IXa, Xa, XIa, andXIIa, as well as plasmin.The neutralization rate of serine proteases by ATIII proceeds slowly in the absence ofheparin, but is greatly accelerated in the presence of heparin. As the therapeuticantithrombotic effect in vivo of heparin is mediated by ATIII, heparin is ineffective in theabsence or near absence of ATIII.The prevalence of the hereditary deficiency of ATIII is estimated to be one per 500 to 5000 inthe general population. The pattern of inheritance is autosomal dominant. In affectedindividuals, spontaneous episodes of thrombosis and pulmonary embolism may be associatedwith ATIII levels of 40%–60% of normal. These episodes usually appear after the age of 20,the risk increasing with age and in association with surgery, pregnancy and delivery. Thefrequency of thromboembolic events in hereditary ATIII deficiency during pregnancy has beenreported to be 70%, and several studies of the beneficial use of Antithrombin III (Human)concentrates during pregnancy in women with hereditary deficiency have been reported. Inmany cases, however, no precipitating factor can be identified for venous thrombosis orpulmonary embolism. Greater than 85% of individuals with hereditary ATIII deficiency have hadat least one thrombotic episode by the age of 50 years. In about 60% of patients thrombosis isrecurrent. Clinical signs of pulmonary embolism occur in 40% of affected individuals. In someindividuals, treatment with oral anticoagulants leads to an increase of the endogenous levelsof ATIII, and treatment with oral anticoagulants may be effective in the prevention of thrombosisin such individuals.In clinical studies of THROMBATE III conducted in 10 asymptomatic subjects with hereditarydeficiency of ATIII, the mean in vivo recovery of ATIII was 1.6% per unit per kg administeredbased on immunologic ATIII assays, and 1.4% per unit per kg administered based onfunctional ATIII assays. The mean 50% disappearance time (the time to fall to 50% of the peakplasma level following an initial administration) was approximately 22 hours and the biologichalf-life was 2.5 days based on immunologic assays and 3.8 days based on functional assaysof ATIII. These values are similar to the half-life for radiolabeled Antithrombin III (Human)reported in the literature of 2.8–4.8 days.In clinical studies of THROMBATE III, none of the 13 patients with hereditary ATIII deficiencyand histories of thromboembolism treated prophylactically on 16 separate occasions withTHROMBATE III for high thrombotic risk situations (11 surgical procedures, 5 deliveries)developed a thrombotic complication. Heparin was also administered in 3 of the 11 surgicalprocedures. Eight patients with hereditary ATIII deficiency were treated therapeutically withTHROMBATE III as well as heparin for major thrombotic or thromboembolic complications, withseven patients recovering. Treatment with THROMBATE III reversed heparin resistance in twopatients with hereditary ATIII deficiency being treated for thrombosis or thrombo embolism.During clinical investigation of THROMBATE III, none of 12 subjects monitored for a median of8 months (range 2–19 months) after receiving THROMBATE III became antibody positive tohuman immunodeficiency virus (HIV-1). None of 14 subjects monitored for � 3 monthsdemonstrated any evidence of hepatitis, either non-A, non-B hepatitis or hepatitis B.

INDICATIONS AND USAGETHROMBATE III is indicated for the treatment of patients with hereditary antithrombin IIIdeficiency in connection with surgical or obstetrical procedures or when they suffer fromthromboembolism.

Subjects with ATIII deficiency should be informed about the risk of thrombosis in connectionwith pregnancy and surgery and about the inheritance of the disease.The diagnosis of hereditary antithrombin III (ATIII) deficiency should be based on a clear familyhistory of venous thrombosis as well as decreased plasma ATIII levels, and the exclusion ofacquired deficiency.ATIII in plasma may be measured by amidolytic assays using synthetic chromogenicsubstrates, by clotting assays, or by immuno assays. The latter does not detect all hereditaryATIII deficiencies.The ATIII level in neonates of parents with hereditary ATIII deficiency should be measuredimmediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children ofwomen with hereditary antithrombin III deficiency, has been reported.)Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% innormal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIIIlevels, especially in a premature infant, therefore, do not necessarily indicate hereditarydeficiency. It is recommended that testing and treatment with THROMBATE III of neonates bediscussed with an expert on coagulation.

CONTRAINDICATIONSNone known.

WARNINGSBecause THROMBATE III is made from human plasma, it may carry a risk of transmittinginfectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD)agent. No cases of transmission of viral diseases or CJD have ever been identified forTHROMBATE III. Inform patients that THROMBATE III is made from human plasma andmay contain infectious agents that can cause disease. While the risk thatTHROMBATE III can transmit an infectious agent has been reduced by screening plasmadonors for prior exposure, testing donated plasma, and by inactivating or removingpathogens during manufacturing, patients should report any symptoms that concernthem. ALL infections thought by a physician possibly to have been transmitted by thisproduct should be reported by the physician or other healthcare provider to GrifolsTherapeutics Inc. [1-800-520-2807].The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE IIIin patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage ofheparin is recommended during treatment with THROMBATE III.

PRECAUTIONSGeneral1. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution.2. Administer only by the intravenous route.3. THROMBATE III, once reconstituted, should be given alone, without mixing with other

agents or diluting solutions.4. Product administration and handling of the needles must be done with caution.

Percutaneous puncture with a needle contaminated with blood can transmit infectious virusincluding HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs.Place needles in sharps container after single use. Discard all equipment including anyreconstituted THROMBATE III product in accordance with biohazard procedures.

The diagnosis of hereditary ATIII deficiency should be based on a clear family history of venousthrombosis as well as decreased plasma ATIII levels, and the exclusion of acquired deficiency.Laboratory TestsIt is recommended that ATIII plasma levels be monitored during the treatment period.Functional levels of ATIII in plasma may be measured by amidolytic assays using chromogenicsubstrates or by clotting assays.Drug InteractionsThe anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE IIIin patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage ofheparin is recommended during treatment with THROMBATE III.Pregnancy Category BReproduction studies have been performed in rats and rabbits at doses up to four times thehuman dose and have revealed no evidence of impaired fertility or harm to the fetus due toTHROMBATE III. It is not known whether THROMBATE III can cause fetal harm whenadministered to a pregnant woman or can affect reproduction capacity. Because animalreproduction studies are not always predictive of human response, this drug should be usedduring pregnancy only if clearly needed.Pediatric UseSafety and effectiveness in the pediatric population have not been established. The ATIII levelin neonates of parents with hereditary ATIII deficiency should be measured immediately afterbirth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women withhereditary antithrombin III deficiency, has been reported.)Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% innormal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIIIlevels, especially in a premature infant, therefore, do not necessarily indicate hereditarydeficiency. It is recommended that testing and treatment with THROMBATE III of neonates bediscussed with an expert on coagulation.

ADVERSE REACTIONSIn clinical studies involving THROMBATE III, adverse reactions were reported in associationwith 17 of the 340 infusions during the clinical studies. Included were dizziness (8), chestdiscomfort (3), nausea (3), dysgeusia (3), chills (2), pain (cramps) (2), dyspnoea (1), chest pain(1), vision blurred (1), intestinal dilatation (1), urticaria (1), pyrexia (1), and wound secretion andhematoma (1). If adverse reactions are experienced, the infusion rate should be decreased, orif indicated, the infusion should be interrupted until symptoms abate.

CAUTION& onlyU.S. federal law prohibits dispensing without prescription.

Grifols Therapeutics Inc.Research Triangle Park, NC 27709 USAU.S. License No. 1871 08941115-BS

Pharmacy Practice News • April 2013

Supply Chain

26 Policy

Another recommendation relevant to the United States is Recommenda-tion 5-1, which says, “State licensing boards should only license wholesalers and distributors that meet the Nation-al Association of Boards of Pharmacy [NABP] accreditation standards.” Dr. Buckley, who is study director, Board on Global Health, IOM, explained that NABP has high standards and a pro-cess that includes criminal background checks. “Currently, three states require wholesalers to have NABP accredita-tion: Indiana, North Dakota and Wyo-

ming,” Dr. Buckley said. “Any state having a low standard is a vulnerability for others.”

Another part of Recommendation 5-1 is the establishment of a public data-base to share information on suspend-ed and revoked wholesale licenses. Right now, according to Dr. Buckley, “if your license is revoked, you can go to another state and get a license there.”

An international code of practice on the global problem of falsified and substandard medicines, as specified by Recommendation 7-1, would poten-

tially involve the United States as well as other countries. This is the commit-tee’s “boldest recommendation, one that reaches out to the world,” co-edi-tor Lawrence O. Gostin, JD, the Linda D. and Timothy J. O’Neill Professor of Global Health Law, Georgetown Uni-versity Law Center, Washington, D.C., said at a press briefing. The recom-mendation states, “The code should include guidelines on surveillance, reg-ulation, and law enforcement, empow-ering states and the international com-munity to prevent and respond to drug

quality problems.”“Every country has a stake in being

part of that,” Dr. Buckley said. “Keeping bad medicine out of our supply is the FDA’s job.” However, “no matter how good the FDA is, in an era of global med-icines, no country can totally act alone.”

“These IOM reports are helpful,” commented Rich McKeown, JD, presi-dent and CEO, Leavitt Partners. “They provide useful data for dialogue and development of strategic direction.”

—George Ochoa

Medi-Dose®, Inc./EPS®, Inc. Partners with Emily Jerry Foundation for Pediatric Safety Initiative

Problem: Because of their small size, pediatric patients are par-

ticularly vulnerable to medication errors. An error that might have min-imal effect in an adult could be cata-strophic to a child. Solution: To help promote awareness of this issue, Medi-Dose/EPS is working with the Emily Jerry Foundation to incorpo-rate their Blue Angel warning logo into our MILT 3.0 software.

The Emily Jerry Foundation is determined to help make medi-cal facilities safer for every-one, beginning with babies and children. The

foundation focuses on increasing public awareness of key patient safety-related issues and identifying technology and best practices proven to minimize the “human error” component of medicine.

Facilities using Medi-Dose’s MILT 3.0 can now download the Emily Jerry Foundation Blue Angel warn-ing logo and add this image to their printed unit-dose labels, calling atten-tion to medication requiring special care and handling. Separate auxiliary labels with the Blue Angel also can be created. In addition to its inclusion in MILT, this important warning symbol will soon be available preprinted on any of our LiquiDose labels.

“Accurate labeling of medication has always been an issue for phar-macy and nursing,” Bob Braverman, Medi-Dose’s director of market-ing, stated in a press release. “We encourage facilities with our MILT software to start using the Emily Jerry Foundation Blue Angel logo on labels for all medication types. It’s our desire that this will increase awareness of pediatric dosing and the need for increased safety pro-cedures for the most vulnerable patients in hospitals—our children.”

For more information on the use of the Blue Angel Logo with the Medi-Dose MILT software, please call 800-523-8966 or e-mail info@medidose.com.

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Learn how Omnicell technology can lead to greater medication safety in your healthcare facility.

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Pharmacy Practice News • April 2013

Supply Chain

Policy 27

resistance, under the new guidelines, a 10-mcg/mL trough level became the minimum rather than the maximum level. The new maximum trough level was set at 20 mcg/mL, a level low enough to reduce the risk for vancomy-cin-induced nephropathy.

In late 2009, after NGMC made the changes, Melissa C. Frank, Phar-mD, a clinical coordinator at NGMC, said the center’s Medication Safety Committee noticed a trend in medica-tion errors—specifically, nurses were administering vancomycin to patients whose trough levels were already greater than 20 mcg/mL.

A multidisciplinary team worked to make several initial changes to patient care. The lab initially adjusted the crit-ical lab alert level, the point at which the lab would be required to directly notify the patient’s nurse or physician, from 40 to 30 mcg/mL.

NGMC also educated nurses about the risks associated with pushing trough levels higher than 20 mcg/mL and educated all pharmacists on the new guidelines, encouraging them to be “extra vigilant.”

But as the hospital moved into 2010, they noticed another four-month trend of the exact same type of errors. To address the problems, they built a “dummy drug” tool in their medication management software that allowed them to enter a vancomycin trough level together with the time it was due for nursing to see and chart against in the electronic medication admin-istration record.

“So the time due is the actual time that the trough level will be drawn by the lab or by nursing in the critical care units,” Dr. Frank said. “The nurse is required to manually document the dose level as it is given. If their document for a van-

comycin trough level is greater than 20 [mcg/mL], an alert fires in the system.”

The first alert is a soft stop that tells the nurse a trough level is higher than the upper limit. If the nurse tries to override, a second alert fires, which again reminds him or her of the risk level. The nurse also sees a note telling him or her to withhold the dose if the level is at or above 20 mcg/mL.

Following the implementation of the dummy drug tool and the training, Dr. Frank said, there have been “no cases in which patients with trough levels above 20 mcg/mL were administered a dose of vancomycin.”

vA Tackles Electronic Prescriptions for Controlled Substances

In a presentation on creating elec-tronic prescriptions for controlled sub-stances, Robert Silverman, PharmD, the program manager of pharmacy ben-efits management for the Department of Veterans Affairs (VA), outlined steps

that hospitals can take to facilitate implementation of ePrescrib-

ing for controlled substances (EPCS) via their computerized

prescriber order entry (CPOE) systems.

Through its CPOE system, the VA has been electronically

prescribing lower-level schedules of controlled substances for more than 15 years. Electronic prescriptions of controlled substances for physicians require a two-factor authentication “that you can’t get around,” Dr. Silver-man explained. “You need any two of these: something you have (e.g., a smart card used as a personal iden-tification verification card), something you know (a password) or something you are (a bio-metric ID of a fingerprint or an eye).” The com-puterized system that an EPCS prescriber uses must present them with an “attesta-tion statement,” stating that what they are about to

do is the equivalent of their legal signa-ture. Additionally, the prescriber appli-cation for EPCS needs to be able to cap-ture the ePrescriber’s explicit “intent to sign” for each individual prescription, and both ePrescribing and pharmacy applications need a third-party audit to verify that they are fully compliant with Drug Enforcement Administration (DEA) rules.

At press time, the VA was still finaliz-ing the interview and reporting process for security and was anticipating that its CPOE EPCS system would be DEA-certified in the first quarter of this year.

Dr. Silverman said that hospitals pursuing certification for controlled substance ePrescribing should “check out the EPCS certification status of your vendors via the DEA’s approved website [http://www.deadiversion.usdoj.gov/ecomm/e_rx/thirdparty.htm#approved]; evaluate the certifica-tion practices as shown there; evaluate practices for receiving fax or paper copies after electronic prescribing; and, most importantly, make sure your CPOE EPCS providers have their two-factor authentication systems in place.”

Software Snafu Points To Need for Pharmacist Input in IT Systems

In November 2011, Lifespan, a Provi-dence, R.I.-based health system that includes Rhode Island Hospital, dis-covered that some 2,000 patients may have received prescriptions or con-tinuity-of-care documents with the wrong form of medications because “of a software issue that affected patient discharges,” said Donald McKaig, RPh, CDOE, a clinical pharmacist specialist in medication safety at the private, not-for-profit 719-bed hospital. The changes occurred after final electronic approval of the order by the physician when the order was in post-process-ing, Mr. McKaig noted. He explained that when the hospital’s CPOE master drug database’s software reached out to a national drug database to per-form clinical checking, information from that database’s fields for a dif-ferent form of the prescribed drug was pulled into Lifespan’s CPOE data-base, “overriding some of the data in our systems, leading to changes in the drug sentence,” Mr. McKaig said. The replaced fields included drug descrip-tions, dose forms and strengths that were originally present in the inpa-tient medication orders. For example, an inpatient order for “morphine SR 30 mg 2XD” was changed to morphine 30 mg 2XD.”

A pharmacy-led review of the CPOE master drug database’s 13,500 drug entries and 357,000 data fields con-taining drug descriptions, dose forms and dosing strengths from Lifespan’s

four hospitals was undertaken and the data were compared with output from the national drug database. The review detected 3,132 potentially problematic drug entries. Lifespan also discovered “errors during manual entry of data into our CPOE database that led to incor-rect, invalid descriptions of medication dosages and dose forms in our system,” Mr. McKaig said. They also discovered that in some cases, unlicensed person-nel were performing data entry pro-cesses manually.

Now with a new process in place, Lifespan is performing enhanced test-ing and verification of all data fields in its CPOE master drug database, and is verifying all data fields populated during data entry as well as outputs for reporting purposes. They also are developing automated scripting tools to eliminate manual entries of data.

The lesson learned from the software problem, according to Mr. McKaig, is that “pharmacists need to be involved in the testing, implementation, design and ongoing monitoring of [medica-tion] management technology. We need to be out there with our IT teams knowing exactly what the source of truth is for all the documentations used in our electronic systems. Stan-dardized tools must be developed to ensure accuracy of data entry process-es. Manual data entry by unlicensed personnel must not be allowed.”

—Liz Parks

Follow PPN on

@PharmPracNews

IT STRATEGIEScontinued from page 17

Pharmacy Practice News • April 2013

Informatics Pearls

28 Technology

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was following the ASHP 1999 stress ulcer prophylaxis guidelines,” said Paige Cuellar, PharmD, a critical care special-ist with the five-hospital Baptist Health System, in San Antonio.

Because those patients often are not good candidates for SUP, Dr. Cuel-lar decided to shift use of SUP where it is needed most—in the ICU, where patients often are ventilated for more than 48 hours and thus face a height-ened risk for gastrointestinal (GI) bleed-ing (poster 5-050). “Our goal was to reduce PPI overuse among patients who no longer needed mechanical ventila-tion and who had no other primary risk factors for GI bleeding,” she said.

The ICU proved an ideal venue for tracking and changing PPI prescribing habits, because all 134 of the system’s adult ICU beds are monitored around the clock by a tele-ICU, which augments observation and care by the on-site staff. Critical care physicians and nurses at a remotely located tele-health facility continuously track real-time patient information, including lab values, med-ications and vital signs. The system, called the eICU LifeGuard initiative, is supported by Philips Healthcare’s Intel-liSpace eCareManager platform.

The remote staff, for example, alerts floor nurses to check daily if SUP is appropriate. “Without that electronic

reminder, floor nurses could of course assess patients at the bedside every day,” Dr. Cuellar explained. “But with the tele-ICU assisting, our on-site nurses have become much more aware and involved with this aspect of care. They began approaching pharmacists and telling us when they thought SUP was no longer appropriate.”

Every evening during a two-month verification phase, tele-ICU nurses assessed the risk for GI bleeding for each patient in the 38-bed ICU at one of the system’s hospitals. The three-week intervention phase that followed

involved all adult ICU beds. On-site nurses and pharmacists recommended 102 conversions from IV to oral PPIs; 86 (84.3%) were accepted. Discontinu-ation of SUP was recommended 173 times; prescribers accepted 91 (52.6%) of the recommendations. The cost of SUP treatment decreased from $1.06 per adjusted patient-day to 77 cents and the projected annual cost savings from decreased SUP amounted to $78,052.

“We were able to get nurses well educated about the appropriateness of SUP,” Dr. Cuellar said. “It was very important to start weaning patients from PPIs when they were sent to the floors, because after that there aren’t enough clinical pharmacists to cover all patients and check for appropriate PPI use.” Monitoring PPI use in the ICU is now standard practice.

“This study offers excellent findings and underscores the need to educate clinicians and patients that PPIs may be harmless in the short term, but that overuse can lead to unexpected prob-

lems,” said Chandra Sekar, RPh, PhD, an associate professor of pharmaceuti-cal science at the University of Findlay School of Pharmacy, in Findlay, Ohio. “Physicians and other providers need to follow current guidelines for stress ulcer prophylaxis in hospitalized patients and use PPIs only for patients who really need them—which is less than 10% of the population—and not to prevent a bleed that’s never going to occur.”

when Is Use in Noncritical Patients OK?

At Northeastern University, Bouvé School of Health Sciences in Boston, researchers analyzed the econom-ic effects of misusing PPIs for SUP in the general patient population (poster 3-097). “Our institution might save more than $1 million annually if PPIs—specifi-cally, pantoprazole—were [prescribed] more appropriately and if institution-al guidelines regulated their use,” said lead author Chau Chu, a PharmD can-didate. An examination of the literature revealed that inappropriate PPI use for SUP occurred in 58% to 92% of cases. By extrapolating those best- and worst-case scenarios to a local 191-bed teaching hos-pital, Ms. Chu and her colleagues pro-jected savings that ranged from $338,397 to $2,844,477 annually. Their calcula-tions accounted not just for drug costs, but also for treating patients with C. diffi-cile and community-acquired pneumonia that may have resulted from PPI use. The researchers determined the inci-dence of PPI-induced illness from previ-ous research and concluded that strict enforcement of ASHP guidelines for SUP simultaneously promotes optimal patient care and reduces costs.

In a third investigation, researchers found that 163 of 744 patients (21.9%) were taking PPIs when they were admit-ted to Swedish Covenant Hospital, a 313-bed teaching facility in Chicago (poster 3-101). Of those 163 patients, 37 (22.7%) were admitted with pneumonia, and five (3.1%) were admitted with a fracture—rates comparable to those noted in other investigations of PPI risk, according to

Zoon Park, PharmD, BCPS, an assistant director of pharmacy services. Docu-

mentation of any indication for PPI use was lacking in nearly half of the 163 patients using PPIs.

“PPI use prior to admission definitely increased the risk of community-acquired pneumo-

nia,” Dr. Park said. “Overall, the high rate of PPI use is concerning

and may place patients at risk for complications.”These studies confirm previous find-

ings about the overuse and risks associ-ated with imprudent PPI use, said Dr. Sekar. “Reducing inappropriate prescrib-ing for inpatients must be done one hos-pital at a time, and clinical pharmacists can play a big part in making that happen by encouraging new behaviors,” he said. “The beauty here is that all hospitals want to save money, and this is a very simple way to improve the bottom line while at the same time getting better patient outcomes.”

—Steve Frandzel

Drs. Sekar, Cuellar and Park, and Ms. Chu reported no relevant financial conflicts of interest.

The Case Against PPI Overuse

Inappropriate—and potentially harmful—use of proton pump inhibitors (PPIs) for stress ulcer prophylaxis (SUP) is well documented in the scientific literature. Which is not to say the drugs can’t be effective: PPIs clearly can reduce the incidence of gastric stress

ulcers and resultant GI bleeding (Interact Cardiovasc Thorac Surg 2013;16:356-360). But as early as the mid-1990s, some researchers raised alarms that these drugs were prescribed too liberally for critically ill patients, few of whom develop clinically important GI bleeds (N Engl J Med 1994;330:377-381). More recently, concerns about PPI overuse have expanded to include indiscriminate prescribing among general hospital populations and outpatients. Many patients on general medicine floors, for example, receive PPIs whether or not they need them (Am J Health Syst Pharm 2007;64:1396-1400). One study that well represents the problem found that an intravenous PPI was prescribed for nearly 70% of inpatients who had no indications for the drug (J Clin Med Res 2010;2:215-219).

Moreover, many patients often are told to continue taking the medications when they return home from the hospital, despite no sound reasons for doing so. In one hospital, the cost of inappropriate SUP post-discharge was nearly $70,000 annually (Am J Gastroenterol 2006;101:2200-2205).

Beyond the financial burden, what worries a growing number of clinicians is the link between prolonged PPI use and potentially serious adverse events, such as rebound acid secretion, community-acquired pneumonia, bone fractures, hypergastrinemia, nutritional deficiencies and C. difficile infection (Proc Bayl Univ Med Cent 2009;22:373-376; Drugs 2012;72:437-445; Am J Gastroenterol 2012;107:1001-1010). In 2012, an FDA drug safety communication warned that PPIs “may be associated with an increased risk of [C. difficile]–associated diarrhea.”

Although the absolute risk for complications attributed to PPIs may be low, they’re real enough to prompt clinicians to step back and take a fresh look at PPI prescribing practices and ensure proper use. According to the ASHP’s Therapeutic Guidelines on Stress Ulcer Prophylaxis, “Prophylaxis is recommended in patients with coagulopathy or patients requiring mechanical ventilation for more than 48 hours. Prophylaxis is also recommended in patients with a history of GI ulceration or bleeding within one year before admission and in patients with at least two of the following risk factors: sepsis, ICU stay of more than one week, occult bleeding lasting six days or more, and use of high-dose corticosteroids” (Am J Health Syst Pharm 2007;64:1396).

“These are very effective drugs, but we use them too often, and extended use can lead to unexpected consequences,” said Chandra Sekar, RPh, PhD, an associate professor of pharmaceutical science at the University of Findlay School of Pharmacy, in Findlay, Ohio. “Many clinicians are still unaware of the risk.”

—S.F.

STRESS ULCERScontinued from page 1

‘Withthetele-ICUassisting,ouron-sitenurses

havebecomemuchmoreawareandinvolvedwith

[stressulcerprophylaxis].Theybeganapproaching

pharmacistsandtellinguswhentheythoughtSUP

wasnolongerappropriate.”—Paige Cuellar, PharmD

Pharmacy Practice News • April 2013

Critical Care

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KEY TO TABLES

1Computerized prescriber order entry (CPOE)—A fully integrated CPOE system includes the capability to build medication safety alerts

(eg, look-alike names) and clinical decision rules. Additionally, the CPOE system should directly interface with the laboratory system and pharmacy, list drug–drug and drug–disease interactions, and offer clinical order-screening capability.

2Bar code–enabled point-of-care (BPOC) systems—These systems are designed to prevent medication errors at the point of medication

administration. BPOC systems verify and record all medications administered to the patient through the use of a bar-code scanner that matches the medication to the patient by scanning a bar code on the medication and a bar code on the patient’s wristband.

3“Smart” infusion pumps—These infusion systems allow users to enter various drug infusion protocols into a drug library with predefined

dose limits. If a dose is programmed outside of established limits or clinical parameters, the pump halts or sounds an alarm, informing the clinician that the dose is outside the recommended range. Some pumps can integrate patient monitoring and other patient parameters, such as age or clinical condition.

4Automated dispensing cabinets (ADCs)—These are robust, point-of-use dispensing systems. ADCs should be integrated with the health

ca re facility’s information system and directly interface with the pharmacy system. Additionally, ADCs must be able to use bar-coding technology for the restocking process to prevent medication errors.

5“Robust” pharmacy order entry system—This order entry system is fully interfaced with a CPOE system. The pharmacy system must be

able to produce medication safety alerts as well as directly interface with a health care facility’s information systems, such as the laboratory system. Additionally, this system must be used to generate a computerized medication administration record (MAR) to be used by the nursing staff while administering medications.

Medication Errors:A Year in Review—Part 1 of a 2-Part Series

The prevention of

medication errors

is an essential

component of pharmaceutical care

and must be a core mission of every

pharmacy. For medication error

prevention efforts to be effective,

they must become a priority.

The first step in setting up an error-reduction program is to establish a multidisciplinary team to improve medication use. The team must be given reasonable time and resources to assess medication safety and implement system-wide changes that make it difficult or impossible for practitioners to make mis-takes that reach the patient. This multidisciplinary team should accept ownership of the medication-use process and enthusiastically embrace the opportunity to improve medication safety.

The goals of the team should include the following:• Promote a culture of safety to lower medication errors;• Increase detection and reporting of medication

errors and potential hazardous drug-use situations;• Explore and understand the root causes of medica-

tion errors;• Educate practitioners about the system-based

causes of errors and their prevention;• Recommend methods to facilitate the implementation

of organization-wide, system-based changes to pre-vent medication errors;

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Table 1. Safety Issues Associated With Order Communication

Title Problem/Discussion Point Recommendation Technology

ARIXTRA (fondaparinux sodium, GlaxoSmithKline) and ARISTA AH (Medafor) mix-ups

• A pharmacy received a request for “Aristra” from the OR.

• The pharmacy dispensed Arixtra, a factor Xa inhibitor, but the surgeon wanted Arista AH, a synthetic, absorbable hemostatic agent.

• Although Arixtra might be used postoperatively to prevent VTE in adults undergoing certain types of surgery, it isn’t started until 6 hours after the procedure, so OR requests for Arixtra should raise suspicion and require verification.

Chemotherapy mix-up between eribulin mesylate (HALAVEN, Eisai) and epirubicin

• An order for “eribulin” was misinterpreted by a pharmacist and entered into the computer as epirubicin.

• Both drugs are associated with breast cancer treatment, but typical dosing is very different, and this should have prompted a call to the prescriber for verification.

• Add the salt “mesylate” to the eribulin listing in computer systems, and apply tall man lettering (eriBULin mesylate, EPIrubicin) to prevent name mix-ups.

• A pharmacist should verify and independently recalculate the dose of any antineoplastic agent before dispensing it.

• Any questions should result in a direct query to the prescriber.

1, 5

Insulin concentration rarely needed on orders

• On a medication reconciliation form, the U-100 strength for LANTUS (insulin glargine, Sanofi-Aventis) was listed instead of the dose under the “dosage” section.

• This could be mistaken as an insulin dose of 100 units.

• Do not include the U-100 concentration with typical insulin orders.

• The strength should only be listed parenthetically with doses of U-500 insulin.

• Educate staff to be suspicious of an insulin dose that is exactly 100 units and to verify its accuracy.

1

Mismatched prescribing and pharmacy templates for PN lead to data entry errors

• A physician prescribed PN for a 16-year-old boy (72 kg) using a standard pediatric template that prompted orders for most nutrients in per kg units (eg, mEq/kg), but the pharmacy template for patients more than 40 kg required entry of nutrients in per day units (eg, mEq/day).

• The pharmacist failed to change the prescribed per kg doses to per day doses and the patient received an exceedingly hypotonic solution (138 mOsm/L) because 2,600 mL of sterile water for injection was used erroneously.

• Be sure the templates for prescribing PN and entering orders into the automated compounding device software (or pharmacy computer) match, both in chronological order and measurement units.

• Use a total daily dose when prescribing nutrients for adults and daily weight-based doses (mg/kg per day) when prescribing nutrients for pediatric patients.

• Build and heed automated warnings regarding excessive nutrient doses.

1, 5

Mix-ups between RAPAFLO (silodosin, Watson) and RAPAMUNE (sirolimus, Pfizer)

• An order for Rapaflo 8 mg daily was transcribed incorrectly as Rapamune.

• Due to a bug in a software upgrade (since corrected), some of the medications in the database would not appear on the screen if the full drug name was entered.

• This reinforced an at-risk behavior of only typing in the first few characters of a drug name, which in this case (R-A-P) called up the wrong drug.

• Hospitals should add this drug name pair to their list of look-alike drug names.

• Prescribers can help prevent mix-ups by including the drug’s purpose when ordering medications and regularly reviewing the patient’s medication list.

• The full drug name should be used whenever feasible instead of the first few characters when entering orders into the pharmacy computer.

1, 5

Mix-ups between various formulations of amphotericin B

• Mix-ups have occurred between liposomal and conventional formulations of IV amphotericin B.

• Harm, even death, may result if a mix-up between the 2 products occurs.

• Communicate orders using both the proprietary and complete generic name (eg, AMBISOME [amphotericin B liposomal]), and include the reason for use, the patient’s weight in kg, the mg/kg dose, and the final dosage calculation.

• Restrict the preparation and dispensing of amphotericin B to the pharmacy.

• Dose checking alerts should be used in computer systems for both liposomal and conventional formulations.

• Consider adding warnings to “question all doses over 50 mg” in areas where conventional form is stored.

1, 5

PRADAXA (dabigatran etexilate, Boehringer Ingelheim) and PLAVIX (clopidogrel, Bristol-Myers Squibb) mix-up

• Plavix was mistakenly dispensed in response to an order for Pradaxa.

• Plavix is available in 75-mg and 300-mg tablets (usual dose is 75 mg/day), and Pradaxa is available in the US in 75-mg and 150-mg capsules.

• Use signs or reminders on shelves in storage areas to warn staff of this look-alike drug name risk to help prevent mix-ups.

2

INDEPENDENT LY DEVELOP ED BY M C M AH ON P UBL ISHIN G2

Table 1. Safety Issues Associated With Order Communication

Title Problem/Discussion Point Recommendation Technology

Searching by drug name gives information on wrong drug

• Tranexamic acid 500 mg, a drug for certain bleeding disorders was found on the discharge medication profile of a patient who takes RANEXA (ranolazine, Gilead) 500 mg for angina.

• The hospital’s computer system, PowerChart by Cerner, listed tranexamic acid when searching for “Ranexa.”

• Both options were listed when Ranexa was typed, and the wrong name was chosen for the list of discharge medications.

• The name Ranexa is completely and correctly spelled within the word tranexamic acid.

• Hospitals should check their drug information and internal computer system to determine how it performs searches, which depends on the specific search functionality set up by the computer system vendor or the hospital.

• There may be ways to modify how searches are performed; however, if you are using external databases, you may not have this option.

1, 5

Unnecessary drug release time (72 h) within fentaNYL order misunderstood as dose

• An order for “fentaNYL transdermal 72 h apply 1 patch 12 mcg/hour externally q3d” was misunderstood as 75 mcg/h because the number 72 was read as 75 and mistaken as the mcg/h dose.

• Advise prescribers to avoid listing the patch release rate (72 h) when ordering fentaNYL patches.

• Ensure that patients who receive fentaNYL patches are opioid tolerant, not opioid naive.

1, 5

OR, operating room; PN, parenteral nutrition; VTE, venous thromboembolism

• Respond to potentially hazardous situations before errors occur; and

• Learn from errors occurring in other organizations through the ISMP Medication Safety Alert! and other published accounts of medication errors, and proac-tively take measures to prevent similar errors.Effective results depend on understanding the

entire medication-use process through varied per-spectives and disciplines.

ISMP is a nonprofit organization that works closely with health care practitioners and institutions, regula-tory agencies, professional organizations, and the pharmaceutical industry to provide education about medication errors and their prevention. ISMP indepen-dently reviews medication errors that practitioners and patients have voluntarily submitted to the ISMP Medication Error Reporting Program. ISMP is an acces-sible resource for any pharmacist or organization inter-ested in implementing the actions recommended herein. Among the many products and services that ISMP offers is the ISMP Medication Safety Alert! Acute Care Edition, a biweekly newsletter that provides timely information related to error prevention. It iden-tifies errors that have been reported by other organi-zations and offers recommendations to prevent those errors from occurring in the pharmacy.

The information in the tables of this review summa-rizes many of the significant error-prevention strate-gies that were recommended in the ISMP Medication Safety Alert! Acute Care Edition during 2012. The errors presented in the tables are actual or potential errors reported to ISMP. Each table consists of 4 columns. The first column lists the medications, devices, or other prob-lematic issues involved. The second column describes the specific error or problem involved. The third col-umn contains ISMP’s recommendations to proactively address and prevent errors from occurring. The fourth column lists technology that may help prevent these errors. Technology can be a powerful tool in the fight against medication errors but only when it is used appro-priately within a well-designed medication-use system.

The key summarizes the technology addressed in the tables, along with specific criteria that ISMP feels should be included.

Suggested ReadingCohen MR, ed. Medication Errors. 2nd ed. Washington, DC: American Pharmacists Association; 2007.

Institute for Safe Medication Practices. ISMP Medication Safety Alert! Acute Care Edition newsletters 2012. www.ismp.org/newsletters/default.asp. Accessed March 19, 2013.

Institute for Safe Medication Practices website: www.ismp.org.

IN D E PE N D E N TLY D E VE LOPE D BY MCMA HON PUBL ISHING 3

Table 2. Problems Involving Drug Information, Patient Information and Staff Education

Title Problem/Discussion Point Recommendation Technology

ADEs with dabigatran (PRADAXA, Boehringer Ingelheim) during quarter 1 of 2011

• QuarterWatch™ analysis of ADEs reported to FDA showed a large number (505) of hemorrhagic events with dabigatran, more than with any other drug including warfarin (176).

• These events involved mostly elderly patients.

• Alert prescribers to reports of hemorrhagic events and dosing issues associated with elderly patients with renal impairment.

• The drug’s manufacturer reported that it is working with the FDA to provide better guidance to physicians on treating elderly patients, especially those with either transiently impaired (eg, contrast media–related) or chronically impaired renal function.

Avoiding inadvertent IV injection of oral liquids

• Not all nurses know that oral syringes are available, their purpose, or how to use them.

• One nurse expelled an oral syringe of LORazepam into a parenteral syringe and administered it IV after voicing frustration that the pharmacy-dispensed syringe could not be connected to the IV port.

• Another nurse expelled oral morphine solution into a dosing cup, diluted it, drew it into a parenteral syringe, and injected it IV.

• Include education about accidental injection of oral liquids and the purpose for using oral syringes during nursing orientation and new graduate mentorship.

• Ensure that oral syringes are available in all patient care units, and affix auxiliary labels that state “ORAL” to all medications dispensed in oral syringes.

Bortezomib (VELCADE, Millennium) deaths due to intrathecal misadministration

• At least 3 fatalities have been reported in Europe due to inadvertent administration of IV bortezomib into the intrathecal space.

• These events involved intrathecal chemotherapy scheduled on the same day/time as IV bortezomib.

• Intrathecal chemotherapy and IV bortezomib are both administered in small volumes via syringes, increasing the likelihood of a mix-up.

• Administer intrathecal chemotherapy at a different time than IV chemotherapy.

• Verify that intrathecal medication has been administered before dispensing IV bortezomib (or vice versa) for patients receiving medications via both routes.

• Label bortezomib syringes with warnings about IV use only.

• Require a time-out procedure and an independent check before administering intrathecal medication or chemotherapy.

Do not infuse DACTINomycin in sterile water

• Studies show that DACTINomycin diluted at concentrations of 10 mcg/mL or higher in sterile water, normal saline, and 5% dextrose are stable for 10 hours (room temperature).

• But dilution with sterile water could result in a hypotonic solution that would cause hemolysis if administered IV.

• Dilute DACTINomycin only in 5% dextrose or normal saline during preparation for IV administration.

ISMP survey reveals user issues with Carpuject™ prefilled syringes

• An ISMP survey of 540 nurses using Carpuject prefilled syringes found that 68% were unaware of significant cartridge overfill that could lead to overdoses.

• Nurses also reported using the prefilled cartridges as multiple-dose vials, risking contamination and unlabeled syringe contents.

• Factors that encourage this practice include unavailability of Carpuject syringe holders, the need to dilute the product, and preventing drug waste.

• Do not use the Carpuject cartridges as multiple-dose vials.

• Drugs that require further dilution should be prepared by the pharmacy when possible.

• If dilution is required on the unit and a 1:1 ratio is acceptable, drawing a small volume of a diluent from a single-dose vial directly into a cartridge (1 mL fill or less) may be considered.

• Provide an adequate supply of Carpuject syringe holders.

Medications associated with ADEs that led to hospitalization

• According to a recent study (www.nejm.org/doi/full/10.1056/NEJMsa1103053?query=featured_home), warfarin, insulin, oral antiplatelet agents, and oral hypoglycemics accounted for more than two-thirds of the drugs tied to hospitalization for ADEs in older adults.

• Most ADEs were associated with unintentional overdoses.

• Provide specific medication error–prevention education to hospitalized patients who are discharged on warfarin, insulin, oral antiplatelet agents, and oral hypoglycemic agents.

• Pay particular attention to the prevention of dosing errors.

1, 5

INDEPENDENT LY DEVELOP ED BY M C M AH ON P UBL ISHIN G4

Table 2. Problems Involving Drug Information, Patient Information and Staff Education

Title Problem/Discussion Point Recommendation Technology

Medication within IV tubing may be overlooked

• A nurse flushed a post-op patient’s IV line previously used by anesthesia.

• The patient became unresponsive because several mg of rocuronium present in the tubing was inadvertently flushed into the patient.

• Depending on the drug concentration, IV set volume, and point of injection, unintended doses of drugs are possible when lines are flushed or IV medications are administered.

• Flush IV lines as proximal to the patient access site as possible after clamping the line immediately above the point of injection.

• For IV piggybacks, the insertion point should be at a Y-site closest to the patient’s access site.

• Post-procedure, anesthesia should flush lines or change the tubing, and remove any source medication, before extubation.

NOVOLOG FLEXPEN (insulin aspart) dose misread by patient

• A patient administered 46 units instead of 6 units of insulin when she misread the dose she had dialed using a NovoLOG FlexPen by reading the numbers to the right of the dosing window, not within the dosing window.

• Other pen issues experienced by patients include inserting the needle but not pressing the button to release the dose or turning the dial to release the dose.

• Patients who are prescribed an insulin pen should meet with a certified diabetes educa-tor, pharmacist, or nurse to demonstrate proper dose selection and use.

Phosphate enemas may pose problems for renal patients

• A patient admitted with acute renal failure also had constipation and received 2 Fleet enemas, each containing 7 g of dibasic sodium phosphate and 19 g of monobasic sodium phosphate, or more than 160 mmol of phosphate.

• The patient developed secondary hypocalcemia due to diminished phosphate clearance resulting from her renal failure. She required emergency hemodialysis, then daily hemodialysis followed by IV calcium.

• During order entry, computer systems should warn practitioners when these agents are about to be prescribed for patients with decreased renal function.

• Fleet enemas should not be stored in patient care areas unless they are secured in an ADC with restricted access to limit removal before a pharmacist’s clinical review of the order.

1, 5

Prescription drug time guarantees and their effects on patient safety in community pharmacies

• ISMP and APhA cooperatively conducted a survey between June 9 and July 7, 2012, that demonstrated how policies and procedures related to pharmacy guarantees to fill prescriptions within a specified time are implemented and how pharmacists link these pharmacy time guarantees to medication errors.

• Helping patients recognize what the pharmacist does behind the scenes and to accept, even demand, patient counseling is crucial to our collective efforts to improve patient safety.

• We need to improve patients’ perceptions of the value of community pharmacies and to achieve this, every health care provider needs to be part of the effort to address the adverse effects of time guarantees on safety.

• The adverse effects of time guarantees in community pharmacy practice spill over into the inpatient pharmacy practice.

• It is crucial for hospital pharmacists, nurses, and physicians to promote the important role of both hospital and community pharmacists when teaching hospitalized patients about their medications.

Prevent counterfeit drugs from reaching patients

• The FDA discovered an unlicensed supplier selling fake bevacizumab injectables (using Genentech’s brand name AVASTIN) to oncology practices.

• The fake product contained no active ingredient.

• All health care professionals, not just pharma-cists, need to be aware of proper procedures for safely procuring medications for patients.

• The Partnership for Safe Medicines provides the resources for pharmacists, nurses, and physicians to help prevent counterfeit medicines from reaching patients: http://safedr.ug/for_pharmacists, http://safedr.ug/for_nurses, http://safedr.ug/for_physicians.

Protocol needed for drug concentration change

• A DOCEtaxel order was entered into the pharmacy computer system.

• The pharmacy technician preparing the product saw that the DOCEtaxel concentration in stock had changed, but the computer system did not have the new concentration listed in its inventory, so the drug amount on the label in mL was incorrect.

• When purchasing alternative products or strengths that are different from those normally stocked, a verification process is needed to ensure that changes are made in computer systems, including IV compounders and robots, ADCs, computer order entry systems, smart pumps, and other affected technology.

5

Table continues on next page

IN D E PE N D E N TLY D E VE LOPE D BY MCMA HON PUBL ISHING 5

Table 2. Problems Involving Drug Information, Patient Information and Staff Education

Title Problem/Discussion Point Recommendation Technology

Reduce readmissions with pharmacy community liaison program and patient education

• Medicare is reducing payments to hospitals with high readmission rates for 3 conditions—heart failure, myocardial infarction, and pneumonia.

• Studies have identified that ADEs are at the very core of readmissions.

• External programs offered by community pharmacies and hospital-run community liaison programs can help hospitals reach readmission goals and decrease preventable ADEs.

• These programs provide in-home or telephone support of pharmaceutical care for recently discharged patients.

• Before and after discharge, education should focus on patients prescribed high-alert medications, especially warfarin, insulin, antiplatelet agents, and hypoglycemic agents.

• ISMP offers free patient handouts for several of these high-alert medications to help prevent errors and other ADEs with these drugs (www.ismp.org).

Remove glacial acetic acid from pharmacies

• Several patients sustained severe skin or mucosal burns after undiluted glacial acetic acid (99.5%) was dispensed and applied instead of a 5% acetic acid solution.

• The strength of the solution was not readily visible on the bottle label, and the pharmacist believed glacial acetic acid was a 5% solution prediluted by the manufacturer.

• Remove glacial acetic acid from the pharmacy and replace it with vinegar (5% solution) or commercially available diluted acetic acid.

• Educate staff about the differences between glacial acetic acid and lesser concentrations.

• Take precautions if pharmacy dilution of acetic acid must occur, including development of a standard mixing procedure and double-checks.

Safe fentaNYL patch disposal

• A 2-year-old boy accidentally gained access to a used fentaNYL patch while visiting his great-grandmother in a nursing home.

• The boy died and the medical examiner found a fentaNYL patch in the boy’s throat.

• Investigators later found improperly discarded used patches at the nursing home.

• The National Alert Network (NAN) issued a warn-ing about proper disposal of fentaNYL patches (www.ismp.org/NAN/files/NAN-20120425.pdf).

• Product labeling states used patches should be flushed down the toilet.

• Follow-up with the FDA revealed that flushing is the recommended disposal method for used patches in the home; in health care organiza-tions, patches should be disposed of in a secure sharps container, witnessed and documented according to policy.

Sterile compounding safety guidelines

• ISMP has finalized the Proceedings from the ISMP Sterile Preparation Compounding Safety Summit: Guidelines for SAFE Preparation of Sterile Compounds.

• The proceedings and guidelines stem from the October 2011 National Sterile Preparation Compounding Safety Summit held by ISMP in response to frequent sterile compounding ADEs reported to the ISMP National Medication Errors Reporting Program and other reporting programs, and published in the scientific literature and lay press.

• The guideline can be found at www.ismp.org/Tools/guidelines/IVSummit/IVCGuidelines.pdf.

Teach patients to remove older transdermal fentaNYL patches

• An unresponsive patient was brought to the hospital with multiple fentaNYL patches on his body.

• The patient followed the directions to “apply one patch every 72 hours” but was not told to remove the older patch prior to applying a new patch.

• Ensure that patients who are prescribed transdermal patches understand proper use and disposal of patches.

• ISMP has developed a safety checklist that can be used by those providing education and given to the patient afterward for reference (www.ismp.org/sc?id=90).

Topical analgesics and burns

• Certain OTC topical products used for muscle and joint pain have caused rare cases of first- to third-degree chemical burns.

• These OTC products, including Icy Hot (Sanofi), Bengay (Johnson & Johnson), Capzasin (Sanofi), and Flexall (Sanofi), generally contain menthol, methyl salicylate, or capsaicin.

• Alert patients to the risk, and advise them to use these products exactly as stated on the label and to discontinue use if they feel actual pain (rather than a warming sensation) after applying them.

• Additional strategies can be found at www.ismp.org/sc?id=103.

ADC, automated dispensing cabinet; ADE, adverse drug event; APhA, American Pharmacists Association; OTC, over-the-counter

(continued)

INDEPENDENT LY DEVELOP ED BY M C M AH ON P UBL ISHIN G6

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INDICATION• TEFLARO (ceftaroline fosamil) is indicated for the

treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive and Gram-negative micro-organisms: Staphylococcus aureus (including methicil-lin-suscepti ble and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca.

IMPORTANT SAFETY INFORMATION

Contraindications• TEFLARO is contraindicated in patients with known

serious hypersensitivity to ceftaroline or other mem-bers of the cephalosporin class. Anaphylaxis and anaphylactoid reactions have been reported with ceftaroline.

Sponsored by

Brought to You by APRIL 2013

REPORTTefl aro® (ceftaroline fosamil) for

the Treatment of Acute Bacterial Skin and Skin Structure Infections Caused by Designated Susceptible Bacteria

The incidence of Gram-positive skin and skin structure infections (SSSI) requiring hospitalization has increased significantly over the past several decades as a result of changes in virulence pro-files and antibiotic resistance of common causative organisms.1,2

Staphylococcus aureus is a lead-ing cause of these SSSI.2,3 Meth-icillin-resistant S. aureus (MRSA) has been a common infection in the hospital setting for decades, and currently represents approximately 33% to 55% of all hospital strains and 60% of all isolates iden-tified in critical care units.4-6 Since the late 1990s, new strains of MRSA have emerged in the community among patients who lacked traditional MRSA risk factors such as

hospital exposure.7 These strains of community-associated MRSA (CA-MRSA) are now the most common cause of SSSI in the U.S., accounting for 59% of these infections presenting to emer-gency departments.1,2 CA-MRSA strains have not simply replaced the strains of S. aureus that were previously most common in skin infections; rather, it appears that

they have resulted in an overall increase in the num-ber of skin infections in the U.S., many of which result in hospitalization.2,8

Because CA-MRSA is recognized as a common etiology of SSSI, it is recommended that empiric therapy for hos-pitalized patients include activity against this pathogen.9

Faculty

Greg Moran, MD, FACEP, FIDSADepartment of Emergency Medicine and

Division of Infectious DiseasesOlive View–UCLA Medical Center

Sylmar, California

Please see additional Important Safety Information throughout and brief summary of Prescribing Information on page 7.

2

REPORT

Understanding the TerminologyIn addition to changes in the epidemiology of SSSI, there

have been changes in the terminology used in studies of these infections. In 1998, the FDA issued draft guidance using the term complicated skin and skin structure infections (cSSSI)10,11 to refer to infections that characteristically involve deeper skin structures, polymicrobial infections, or coexistence of comor-bidities or immune suppression—all of which are more likely to require surgical intervention.10

In 2010, the FDA proposed the new classification of acute bacterial skin and skin structure infections (ABSSSI) in an effort to standardize definitions within clinical trials and establish objectives in assessing the clinical response to treatment.11 The main clinical criterion of ABSSSI that distin-guishes them from cSSSI is the minimum surface area of ery-thema, edema, and/or induration of 75 cm2, which defines the extent of disease in order to document the infection clearly and objectively, and assess any improvement or deteriora-tion.11 ABSSSI consist of 4 categories of infections—exten-sive cellulitis/erysipelas, wound infections, major cutaneous abscesses, and infected burns—all accompanied by lymph node enlargement or systemic symptoms such as a fever of at least 38 degrees Celsius.11

Current Management of Skin InfectionsThe causative pathogen is typically identified by growth in

culture (not possible within the first 24 to 48 hours—or even at all in the context of cellulitis without pus), so patients with cSSSI are typically initiated on empiric antibiotic therapy before the pathogen is known.12,13 The increasing prevalence of MRSA isolates has shifted treatment toward the empiric use of agents active against MRSA.14

In the past, vancomycin was used most often in this setting, although sometimes other agents such as daptomycin or line-zolid were used.11 Another recent study demonstrated that the majority of empiric regimens used in many U.S. emergency departments now include activity against CA-MRSA.15

Although many agents such as vancomycin, linezolid, and daptomycin have good activity against Gram-positive cocci, cli-nicians should consider several factors, including susceptibility of

resistant strains and adverse events when determining the course of treatment for their patients.16,17 Medical societies have empha-sized the importance of optimal vancomycin dosing in serious infections.16,18 The increasing potential for the development of resistance to agents such as vancomycin suggests a need for alternative agents that are effective and safe in treating SSSI.9

TEFLARO (ceftaroline fosamil): A Treatment Option for ABSSSI Caused by Designated Susceptible Bacteria

TEFLARO (ceftaroline fosamil), a prodrug form of ceftaro-line, is a broad-spectrum parenteral cephalosporin indicated for the treatment of ABSSSI due to designated susceptible bacteria with bactericidal activity against the following Gram-positive and Gram-negative pathogens: S. aureus (ie, meth-icillin-resistant [MRSA] and -susceptible [MSSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, Esche-richia coli, Klebsiella pneumoniae, and Klebsiella oxytoca.19

The affinity of TEFLARO for S. aureus penicillin-binding pro-teins (PBPs), specifically PBP2a, accounts for its activity against MRSA.19

The efficacy of TEFLARO for ABSSSI was investigated in the CANVAS (Ceftaroline vs Vancomycin in Skin and Skin Struc-ture Infections) Phase 3 program.20,21 This program consisted of 2 identical, randomized, multicenter, multinational, dou-ble-blind, noninferiority studies (CANVAS 1 and CANVAS 2), in which 1,396 patients with cSSSI requiring hospitalization and IV therapy were randomized to receive either 600 mg of TEFLARO every 12 hours for 5 to 14 days or 1 g of vancomycin plus 1 g of aztreonam (for coverage of potential Gram-nega-tive pathogens) every 12 hours for 5 to 14 days.20-22 A test-of-cure (TOC) visit was scheduled 8 to 15 days following the last dose of treatment to compare the 2 regimens in the mod-ified intent-to-treat (MITT, those who received any amount of study drug as part of the randomization) population and the clinically evaluable (CE, those MITT patients who met clinical disease criteria for cSSSI, received a prespecified amount of study drug, and for whom outcome information was available) population.19-21

Warnings and PrecautionsHypersensitivity Reactions• Serious and occasionally fatal hypersensitivity (anaphylac-

tic) reactions and serious skin reactions have been report-ed with beta-lactam antibacterials. Before therapy with TEFLARO is instituted, careful inquiry about previous hyper-sensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. If this product is to be given to a penicillin- or other beta-lactam-allergic patient, caution should be exercised because cross sensitivity among beta-lactam antibacterial agents has been clearly established.

• If an allergic reaction to TEFLARO occurs, the drug should be discontinued. Serious acute hypersensitivity (anaphylac-tic) reactions require emergency treatment with epinephrine and other emergency measures that may include airway management, oxygen, intravenous fluids, antihistamines, corticosteroids, and vasopressors as clinically indicated.

IMPORTANT SAFETY INFORMATION (continued)

Please see additional Important Safety Information throughout and brief summary of Prescribing Information on page 7.

USAGE• To reduce the development of drug-resistant bacteria

and maintain the effectiveness of TEFLARO® and other antibacterial drugs, TEFLARO should be used to treat only ABSSSI that is proven or strongly suspected to be caused by susceptible bacteria.

• When culture and susceptibility information are avail-able, they should be considered in selecting or modify-ing antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

REPORT

3

In CANVAS 1, clinical cure rates at TOC in the CE pop-ulation were similar for TEFLARO (ceftaroline fosamil) and vancomycin plus aztreonam: 91.1% vs 93.3%, respectively.19

In CANVAS 2, clinical cure rates at TOC for TEFLARO and vancomycin plus aztreonam in the CE population were 92.2% and 92.1%, respectively (Figure 1).19 Neither trial established that TEFLARO was statistically superior to

vancomycin plus aztreonam in terms of clinical response rates. There are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at a TOC time point. Therefore, comparisons of TEFLARO to vancomycin plus aztreonam based on clin-ical response rates at TOC cannot be utilized to establish noninferiority.

Clostridium difficile-associated Diarrhea• Clostridium difficile-associated diarrhea (CDAD) has been

reported for nearly all systemic antibacterial agents, includ-ing TEFLARO, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is sus-pected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible.

Direct Coombs’ Test Seroconversion• Seroconversion from a negative to a positive direct Coombs’

test result occurred in 120/1114 (10.8%) of patients receiv-ing TEFLARO and 49/1116 (4.4%) of patients receiving com-parator drugs in the four pooled Phase 3 trials. No adverse reactions representing hemolytic anemia were reported in any treatment group. If anemia develops during or after

treatment with TEFLARO, drug-induced hemolytic anemia should be considered. If drug-induced hemolytic anemia is suspected, discontinuation of TEFLARO should be con-sidered and supportive care should be administered to the patient if clinically indicated.

Development of Drug-Resistant Bacteria• Prescribing TEFLARO in the absence of a proven or strongly

suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Drug Interactions• No clinical drug-drug interaction studies have been conduct-

ed with TEFLARO. There is minimal potential for drug-drug interactions between TEFLARO and CYP450 substrates, inhibitors, or inducers; drugs known to undergo active renal secretion; and drugs that may alter renal blood flow.

IMPORTANT SAFETY INFORMATION (continued)

Please see additional Important Safety Information throughout and brief summary of Prescribing Information on page 7.

Figure 1. Clinical cure rates at TOC by pathogen from 2 integrated Phase 3 trials.* There are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at a TOC time point. Therefore, comparisons of TEFLARO to vancomycin plus aztreonam based on clinical response rates at TOC cannot be utilized to establish noninferiority.ABSSSI, acute bacterial skin and skin structure infections; CANVAS, Ceftaroline vs Vancomycin in Skin and Skin Structure Infections; CE, clinically evaluable; CI, confidence interval; TOC, test of cure

Based on reference 19.

ABSSSI TEFLARO (ceftaroline fosamil) Demonstrated Efficacy at TOC* (CE) in Acute Bacterial Skin and Skin Structure Infections

Treatment Difference –2.2 (95% CI: –6.6, 2.1)

Treatment Difference 0.1 (95% CI: –4.4, 4.5)

0 20 40 60 80 100

CAN

VAS

1

TEFLARO monotherapy91.1%

(288/316)

Vancomycin + aztreonam93.3%

(280/300)

CAN

VAS

2

TEFLARO monotherapy92.2%

(271/294)

Vancomycin + aztreonam92.1%

(269/292)

Clinical cure rates, % (n/N)

Neither trial established that TEFLARO was statistically superior to vancomycin plus aztreonam in terms of clinical response rates.

4

REPORT

The per-pathogen clinical cure rates in the TOC microbio-logically evaluable (ME) population (ie, consisting of a subset of subjects from the CE population who had at least 1 bacte-rial pathogen identified and who had susceptibility testing on at least 1 of the isolated baseline pathogens) for MRSA was 93.4% for TEFLARO (ceftaroline fosamil) monotherapy and 94.3% for vancomycin plus aztreonam; for MSSA, the clini-cal cure rates were 93.0% and 94.5%, respectively.19,21 Nei-ther trial established that TEFLARO was statistically superior to vancomycin plus aztreonam in terms of clinical response rates.

In adherence with the FDA recommendations on clinical end points, a clinical response at Day 3 was also assessed in

Phase 3 trials (n=797).11,19 In the 2 Phase 3 trials, a response was defined as the cessation of lesion spread and absence of fever by Day 3.11,19 The Day 3 analysis evaluated patients with lesions 75 cm2 or greater and having one of the following infection types: major abscess with surrounding erythema of 5 cm or greater; wound infection; or deep/extensive cellulitis. In the first trial, TEFLARO-treated patients had a response rate of 74.0% and vancomycin plus aztreonam–treated patients had a response rate of 64.6% on Day 3.19 In the second trial, TEFLARO-treated patients had a response rate of 74.0% and vancomycin plus aztreonam–treated patients had a response rate of 68.1% on Day 3 (Figure 2).21 Neither trial established

Adverse Reactions• In the four pooled Phase 3 clinical trials, serious adverse

events occurred in 98/1300 (7.5%) of patients receiving TEFLARO and 100/1297 (7.7%) of patients receiving com-parator drugs. Treatment discontinuation due to adverse events occurred in 35/1300 (2.7%) of patients receiving TEFLARO and 48/1297 (3.7%) of patients receiving com-parator drugs with the most common adverse events leading to discontinuation being hypersensitivity for both treatment groups at a rate of 0.3% in the TEFLARO group and 0.5% in the comparator group.

• No adverse reactions occurred in greater than 5% of patients receiving TEFLARO. The most common adverse reactions occurring in >2% of patients receiving TEFLARO in the pooled Phase 3 clinical trials were diarrhea, nausea, and rash.

Use in Specific Populations• TEFLARO has not been studied in pregnant women. There-

fore, TEFLARO should only be used during pregnancy if the

potential benefit justifies the potential risk to the fetus.• It is not known whether ceftaroline is excreted in human

milk. Because many drugs are excreted in human milk, caution should be exercised when TEFLARO is adminis-tered to a nursing woman.

• Safety and effectiveness in pediatric patients have not been established.

• Because elderly patients, those ≥65 years of age, are more likely to have decreased renal function and ceftaroline is excreted primarily by the kidney, care should be taken in dose selection in this age group and it may be use-ful to monitor renal function. Dosage adjustment for elderly patients should therefore be based on renal function.

• Dosage adjustment is required in patients with moderate (CrCl >30 to ≤50 mL/min) or severe (CrCl ≥15 to ≤30 mL/min) renal impairment and in patients with end-stage renal disease (CrCl <15 mL/min).

• The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established.

IMPORTANT SAFETY INFORMATION (continued)

Figure 2. TEFLARO demonstrated clinical response at Day 3 in ABSSSI.

ABSSSI, acute bacterial skin and skin structure infections; CANVAS, Ceftaroline vs Vancomycin in Skin and Skin Structure Infections; CI, confidence interval

Based on reference 21.

ABSSSI TEFLARO (ceftaroline fosamil) Demonstrated Clinical Response at Day 3 in Acute Bacterial Skin and Skin Structure Infections

Treatment Difference 9.4 (95% CI: 0.4, 18.2)

Treatment Difference 5.9 (95% CI: –3.1, 14.9)

0 20 40 60 80 100

CAN

VAS

1

TEFLARO monotherapy74.0%

(148/200)

Vancomycin + aztreonam64.6%

(135/209)

CAN

VAS

2

TEFLARO monotherapy74.0%

(148/200)

Vancomycin + aztreonam68.1%

(128/188)

Clinical responders, % (n/N)

Neither trial established that TEFLARO was statistically superior to vancomycin plus aztreonam in terms of clinical response rates.

Please see additional Important Safety Information throughout and brief summary of Prescribing Information on page 7.

REPORT

5

that TEFLARO (ceftaroline fosamil) was statistically superior to vancomycin plus aztreonam in terms of clinical response rates.

The FDA approved the use of TEFLARO for the treatment of ABSSSI, including cases caused by S. aureus (including MRSA), S. pyogenes, S. agalactiae, E. coli, K. pneumoniae, and K. oxytoca.19 The recommended dose for ABSSSI is 600 mg every 12 hours by IV infusion administered over 1 hour in adults at least 18 years of age, with adjustments for renal impairment.19

Please see Important Safety Information for TEFLARO below and on previous pages. Please also see accompany-ing brief summary of the Prescribing Information on page 7.

ConclusionThe prevalence of MRSA-related SSSI has increased dra-

matically over the past 2 decades. TEFLARO has been proven effective for the treatment of ABSSSI due to designated sus-ceptible bacteria, including MRSA.

IMPORTANT SAFETY INFORMATION

Contraindications

• TEFLARO is contraindicated in patients with known seri-ous hypersensitivity to ceftaroline or other members of the cephalosporin class. Anaphylaxis and anaphylactoid reac-tions have been reported with ceftaroline.

Warnings and PrecautionsHypersensitivity Reactions• Serious and occasionally fatal hypersensitivity (anaphy-

lactic) reactions and serious skin reactions have been reported with beta-lactam antibacterials. Before therapy with TEFLARO is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, pen-icillins, or carbapenems should be made. If this product is to be given to a penicillin- or other beta-lactam-allergic patient, caution should be exercised because cross sen-sitivity among beta-lactam antibacterial agents has been clearly established.

• If an allergic reaction to TEFLARO occurs, the drug should be discontinued. Serious acute hypersensitivity (anaphylac-tic) reactions require emergency treatment with epinephrine and other emergency measures that may include airway management, oxygen, intravenous fluids, antihistamines, corticosteroids, and vasopressors as clinically indicated.

Clostridium difficile-associated Diarrhea• Clostridium difficile-associated diarrhea (CDAD) has been

reported for nearly all systemic antibacterial agents, includ-ing TEFLARO, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible.

Direct Coombs’ Test Seroconversion• Seroconversion from a negative to a positive direct Coombs’

test result occurred in 120/1114 (10.8%) of patients receiv-ing TEFLARO and 49/1116 (4.4%) of patients receiving com-parator drugs in the four pooled Phase 3 trials. No adverse

reactions representing hemolytic anemia were reported in any treatment group. If anemia develops during or after treatment with TEFLARO, drug-induced hemolytic anemia should be considered. If drug-induced hemolytic anemia is suspected, discontinuation of TEFLARO should be con-sidered and supportive care should be administered to the patient if clinically indicated.

Development of Drug-Resistant Bacteria• Prescribing TEFLARO in the absence of a proven or

strongly suspected bacterial infection is unlikely to pro-vide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Adverse Reactions• In the four pooled Phase 3 clinical trials, serious adverse

events occurred in 98/1300 (7.5%) of patients receiving TEFLARO and 100/1297 (7.7%) of patients receiving com-parator drugs. Treatment discontinuation due to adverse events occurred in 35/1300 (2.7%) of patients receiving TEFLARO and 48/1297 (3.7%) of patients receiving com-parator drugs with the most common adverse events leading to discontinuation being hypersensitivity for both treatment groups at a rate of 0.3% in the TEFLARO group and 0.5% in the comparator group.

• No adverse reactions occurred in greater than 5% of patients receiving TEFLARO. The most common adverse reactions occurring in >2% of patients receiving TEFLA-RO in the pooled Phase 3 clinical trials were diarrhea, nau-sea, and rash.

Drug Interactions• No clinical drug-drug interaction studies have been con-

ducted with TEFLARO. There is minimal potential for drug-drug interactions between TEFLARO and CYP450 substrates, inhibitors, or inducers; drugs known to under-go active renal secretion; and drugs that may alter renal blood flow.

Use in Specific Populations• TEFLARO has not been studied in pregnant women. There-

fore, TEFLARO should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

• It is not known whether ceftaroline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TEFLARO is adminis-tered to a nursing woman.

• Safety and effectiveness in pediatric patients have not been established.

• Because elderly patients, those ≥65 years of age, are more likely to have decreased renal function and ceftaroline is excreted primarily by the kidney, care should be taken in dose selection in this age group and it may be useful to monitor renal function. Dosage adjustment for elderly patients should therefore be based on renal function.

• Dosage adjustment is required in patients with moderate (CrCl >30 to ≤50 mL/min) or severe (CrCl ≥15 to ≤30 mL/min) renal impairment and in patients with end-stage renal disease (CrCl <15 mL/min).

• The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established.

Please see additional Important Safety Information throughout and brief summary of Prescribing Information on page 7.

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References

1. Edelsberg J. Trends in US hospital admissions for skin and soft tissue infections. Emerg Infect Dis. 2009;15(9):1516-1518.

2. Moran GJ. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med. 2006;355(7):666-674.

3. King MD. Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue infections. Ann Intern Med. 2006;144(5): 309-317.

4. Appelbaum PC. MRSA—the tip of the iceberg. Clin Microbiol Infect. 2006;12(suppl 2):3-10.

5. National Nosocomial Infections Surveillance (NNIS) System Report. Data summary from January 1992 through June 2004 issued October 2004. Am J Infect Control. 2004;32(8):470-485.

6. Klein E. Hospitalizations and deaths caused by methicillin-resis-tant Staphylococcus aureus, United States, 1999-2005. Emerg Infect Dis. 2007;13(12):1840-1846.

7. Davis SL. Epidemiology and outcomes of community-associated methicillin-resistant Staphylococcus aureus infection. J Clin Microbiol. 2007;45(6):1705-1711.

8. Pallin D. Increased U.S. emergency department visits for skin infections and changes in antibiotic choices during the commu-nity-associated MRSA epidemic. Ann Emerg Med. 2008;51(3): 291-298.

9. Liu C. Clinical practice guidelines by the Infectious Diseases Society of America (IDSA) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in adults and children. Clin Infect Dis. 2011;52(3):285-292.

10. U.S. Food and Drug Administration 1998. Guidance for industry uncomplicated and complicated skin and skin structure infec-tion—developing antimicrobial drugs for treatment. http://www.fda.gov/ohrms/dockets/98fr/2566dft.pdf. Accessed October 12, 2012.

11. U.S. Food and Drug Administration 2010. Guidance for industry acute bacterial skin and skin structure infections: developing drugs for treatment. http://www.fda.gov/downloads/Drugs/Guid-anceComplianceRegulatoryInformation/Guidances/ucm071185.pdf. Accessed October 12, 2012.

12. Breen JO. Skin and soft tissue infections in immunocompetent patients. Am Fam Physician. 2010;81(7):893-899.

13. Wound and skin infections. American Association of Clinical Chemistry, 2011. http://labtestsonline.org/understanding/condi-tions/wound-infections?start=3. Accessed October 12, 2012.

14. Oster G. Use of vancomycin in initial antibiotic therapy for complicated skin and skin structure infections (cSSSI) in US hospitals, 2000-2009. Presented at: 48th Annual Meeting of the Infectious Diseases Society of America; Vancouver, British Columbia, Canada; October 21-24, 2010. Abstract 282.

15. Talan DA. Comparisons of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008. Clin Infect Dis. 2011;53(2):144-149.

16. Rybak M. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1):82-98.

17. Vancomycin prescribing information. New York, NY: Pfizer, Inc.; 2011.

18. American Thoracic Society and Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilatory-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416.

19. TEFLARO (ceftaroline fosamil) [prescribing information]. St Louis, MO: Forest Laboratories, Inc.; 2012.

20. Corey GR. CANVAS 1: the first Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother. 2010;65(suppl 4):iv41-iv51.

21. Corey GR. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreo-nam in complicated skin and skin-structure infection. Clin Infect Dis. 2010;51(6):641-650.

22. Corrado ML. Integrated safety summary of CANVAS 1 and 2 trials: Phase III, randomized, double-blind studies evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother. 2010;65(suppl 4):iv67-iv71.

AcknowledgmentsFinancial Support: The article was sponsored by Forest Laboratories, Inc (“Forest”). Dr. Moran is a paid consultant for Forest and received funding for his participation.

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Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Forest Laboratories, Inc., and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

Please see additional Important Safety Information throughout and brief summary of Prescribing Information on page 7.

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TEFLARO® (ceftaroline fosamil) injection for intravenous (IV) use Rx OnlyBrief Summary of full Prescribing InformationInitial U.S. Approval: 2010INDICATIONS AND USAGE: Teflaro® (ceftaroline fosamil) is indicated for the treatment of patients with the following infections caused by susceptible isolates of the designated microorganisms. Acute Bacterial Skin and Skin Structure Infections - Teflaro is indicated forthe treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Strepto coc-cus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca. Community-Acquired Bacterial Pneumonia - Teflaro is indicated for thetreatment of community-acquired bacterial pneumonia (CABP) caused by susceptible isolatesof the following Gram-positive and Gram-negative microorganisms: Streptococcus pneumoniae(including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptibleisolates only), Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli. Usage - To reduce the development of drug-resistant bacteria and maintain theeffectiveness of Teflaro and other antibacterial drugs, Teflaro should be used to treat only ABSSSI or CABP that are proven or strongly suspected to be caused by susceptible bacteria.Appropriate specimens for microbiological examination should be obtained in order to isolateand identify the causative pathogens and to determine their susceptibility to ceftaroline. Whenculture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.CONTRAINDICATIONS: Teflaro is contraindicated in patients with known serious hyper -sen siti vity to ceftaroline or other members of the cephalosporin class. Anaphylaxis and anaphylactoid reactions have been reported with ceftaroline.WARNINGS AND PRECAUTIONS: Hypersensitivity Reactions - Serious and occasionally fatalhypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterials. Before therapy with Teflaro is instituted, carefulinquiry about previous hypersensitivity reactions to other cephalosporins, penicillins,or carbapenems should be made. If this product is to be given to a penicillin- or other beta-lactam- allergic patient, caution should be exercised because cross sensitivity among beta-lactam antibacterial agents has been clearly established. If an allergic reaction to Teflaro occurs,the drug should be discontinued. Serious acute hypersensitivity (anaphylactic) reactions require emergency treatment with epinephrine and other emergency measures, that may include airway management, oxygen, intravenous fluids, antihistamines, corticosteroids, and vasopressors as clinically indicated. Clostridium difficile-associated Diarrhea - Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterialagents, including Teflaro, and may range in severity from mild diarrhea to fatal colitis. Treatmentwith antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD.Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must beconsidered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after theadministration of antibacterial agents. If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible. Appropriate fluid and electrolytemanagement, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated [see Adverse Reactions]. Direct Coombs’Test Seroconversion - Seroconversion from a negative to a positive direct Coombs’ test resultoccurred in 120/1114 (10.8%) of patients receiving Teflaro and 49/1116 (4.4%) of patients receiving comparator drugs in the four pooled Phase 3 trials. In the pooled Phase 3 CABP trials, 51/520 (9.8%) of Teflaro-treated patients compared to 24/534 (4.5%) of ceftriaxone-treated patients seroconverted from a negative to a positive direct Coombs’ test result. No adverse reactions representing hemolytic anemia were reported in any treatment group. If anemia develops during or after treatment with Teflaro, drug-induced hemolytic anemia shouldbe considered. Diagnostic studies including a direct Coombs’ test, should be performed. If drug-induced hemolytic anemia is suspected, discontinuation of Teflaro should be considered andsupportive care should be administered to the patient (i.e. transfusion) if clinically indicated.Development of Drug-Resistant Bacteria - Prescribing Teflaro in the absence of a proven orstrongly suspected bacterial infection is unlikely to provide benefit to the patient and increasesthe risk of the development of drug-resistant bacteria.ADVERSE REACTIONS: The following serious events are described in greater detail in the Warnings and Precautions section: Hypersensitivity reactions; Clostridium difficile-associateddiarrhea; Direct Coombs’ test seroconversion. Adverse Reactions from Clinical Trials - Because clinical trials are conducted under widely varying conditions, adverse reaction ratesobserved in clinical trials of a drug cannot be compared directly to rates from clinical trials ofanother drug and may not reflect rates observed in practice. Teflaro was evaluated in four controlled comparative Phase 3 clinical trials (two in ABSSSI and two in CABP) which included1300 adult patients treated with Teflaro (600 mg administered by IV over 1 hour every 12h) and 1297 patients treated with comparator (vancomycin plus aztreonam or ceftriaxone) for atreatment period up to 21 days. The median age of patients treated with Teflaro was 54 years,ranging between 18 and 99 years old. Patients treated with Teflaro were predominantly male (63%) and Caucasian (82%). Serious Adverse Events and Adverse Events Leading to Discontinuation - In the four pooled Phase 3 clinical trials, serious adverse events occurred in98/1300 (7.5%) of patients receiving Teflaro and 100/1297 (7.7%) of patients receiving com-parator drugs. The most common SAEs in both the Teflaro and comparator treatment groupswere in the respiratory and infection system organ classes (SOC). Treatment discontinuation due to adverse events occurred in 35/1300 (2.7%) of patients receiving Teflaro and 48/1297 (3.7%)of patients receiving comparator drugs with the most common adverse events leading to discontinuation being hyper sensitivity for both treatment groups at a rate of 0.3% in the Teflarogroup and 0.5% in comparator group. Most Common Adverse Reactions - No adverse reactions occurred in greater than 5% of patients receiving Teflaro. The most common adverse reactions occurring in > 2% of patients receiving Teflaro in the pooled phase 3 clinical

trials were diarrhea, nausea, and rash. Table 4 in the full prescribing information lists adverse reactions occurring in ≥ 2% of patients receiving Teflaro in the pooled Phase 3 clinical trials (two in ABSSSI and two in CABP). The first value displays the percentage of patients inthe pooled Teflaro trials (N=1300) and the second shows the percentage in the Pooled Comparatorsa trials (N=1297). Gastro intestinal disorders: Diarrhea (5%, 3%), Nausea (4%,4%), Constipation (2%, 2%), Vomiting (2%, 2%); Investigations: Increased transaminases(2%, 3%); Metabolism and nutrition disorders: Hypokalemia (2%, 3%); Skin and sub -cutaneous tissue disorders: Rash (3%, 2%); Vascular disorders: Phlebitis (2%, 1%) a

Comparators included vancomycin 1 gram IV every 12h plus aztreonam 1 gram IV every 12hin the Phase 3 ABSSSI trials, and ceftriaxone 1 gram IV every 24h in the Phase 3 CABP trials.Other Adverse Reactions Observed During Clinical Trials of Teflaro - Following is a list of additional adverse reactions reported by the 1740 patients who received Teflaro in any clinicaltrial with incidences less than 2%. Events are categorized by System Organ Class. Blood andlymphatic system disorders - Anemia, Eosinophilia, Neutropenia, Thrombocytopenia; Cardiacdisorders - Bradycardia, Palpitations; Gastrointestinal disorders - Abdominal pain; General disorders and administration site conditions - Pyrexia; Hepatobiliary disorders - Hepatitis; Immune system disorders - Hypersensitivity, Anaphylaxis; Infections and infestations -Clostridium difficile colitis; Metabolism and nutrition disorders - Hyperglycemia, Hyperkalemia;Nervous system disorders - Dizziness, Convulsion; Renal and urinary disorders - Renalfailure; Skin and subcutaneous tissue disorders - Urticaria.DRUG INTERACTIONS: No clinical drug-drug interaction studies have been conducted withTeflaro. There is minimal potential for drug-drug interactions between Teflaro and CYP450 substrates, inhibitors, or inducers; drugs known to undergo active renal secretion; and drugsthat may alter renal blood flow [see Clinical Pharmacology in the full prescribing information].USE IN SPECIFIC POPULATIONS: Pregnancy Category B. - Developmental toxicity studies performed with ceftaroline fosamil in rats at IV doses up to 300 mg/kg demonstrated no maternal toxicity and no effects on the fetus. A separate toxicokinetic study showed that ceftaroline exposure in rats (based on AUC) at this dose level was approximately 8 times the exposure in humans given 600 mg every 12 hours. There were no drug-induced malformationsin the offspring of rabbits given IV doses of 25, 50, and 100 mg/kg, despite maternal toxicity.Signs of maternal toxicity appeared secondary to the sensitivity of the rabbit gastrointestinal system to broad-spectrum antibacterials and included changes in fecal output in all groups anddose- related reductions in body weight gain and food consumption at ≥ 50 mg/kg; these were associated with an increase in spontaneous abortion at 50 and 100 mg/kg. The highest dose wasalso associated with maternal moribundity and mortality. An increased incidence of a commonrabbit skeletal variation, angulated hyoid alae, was also observed at the maternally toxic dosesof 50 and 100 mg/kg. A separate toxicokinetic study showed that ceftaroline exposure in rabbits (based on AUC) was approximately 0.8 times the exposure in humans given 600 mgevery 12 hours at 25 mg/kg and 1.5 times the human exposure at 50 mg/kg. Ceftaroline fosamil did not affect the postnatal development or reproductive performance of the offspringof rats given IV doses up to 450 mg/kg/day. Results from a toxicokinetic study conducted inpregnant rats with doses up to 300 mg/kg suggest that exposure was ≥ 8 times the exposurein humans given 600 mg every 12 hours. There are no adequate and well-controlled trials inpregnant women. Teflaro should be used during pregnancy only if the potential benefit justifiesthe potential risk to the fetus. Nursing Mothers - It is not known whether ceftaroline is excretedin human milk. Because many drugs are excreted in human milk, caution should be exercisedwhen Teflaro is administered to a nursing woman. Pediatric Use - Safety and effectiveness inpediatric patients have not been established. Geriatric Use - Of the 1300 patients treated withTeflaro in the Phase 3 ABSSSI and CABP trials, 397 (30.5%) were ≥ 65 years of age. The clini-cal cure rates in the Teflaro group (Clinically Evaluable [CE] Population) were similar in patients≥ 65 years of age compared with patients < 65 years of age in both the ABSSSI and CABP trials. The adverse event profiles in patients ≥ 65 years of age and in patients < 65 years of agewere similar. The percentage of patients in the Teflaro group who had at least one adverse eventwas 52.4% in patients ≥ 65 years of age and 42.8% in patients < 65 years of age for the two indications combined. Ceftaroline is excreted primarily by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients aremore likely to have decreased renal function, care should be taken in dose selection in this agegroup and it may be useful to monitor renal function. Elderly subjects had greater ceftaroline exposure relative to non-elderly subjects when administered the same single dose of Teflaro.However, higher exposure in elderly subjects was mainly attributed to age-related changes in renal function. Dosage adjustment for elderly patients should be based on renal function [seeDosage and Administration and Clinical Pharmacology in the full prescribing information].Patients with Renal Impairment - Dosage adjustment is required in patients with moderate(CrCl > 30 to ≤ 50 mL/min) or severe (CrCl ≥ 15 to ≤ 30 mL/min) renal impairment and in patients with end-stage renal disease (ESRD – defined as CrCl < 15 mL/min), including patients on hemodialysis (HD) [see Dosage and Administration and Clinical Pharmacology inthe full prescribing information].OVERDOSAGE: In the event of overdose, Teflaro should be discontinued and general sup portivetreatment given. Ceftaroline can be removed by hemodialysis. In subjects with ESRD adminis-tered 400 mg of Teflaro, the mean total recovery of ceftaroline in the dialysate following a 4-hourhemodialysis session started 4 hours after dosing was 76.5 mg (21.6% of the dose). However,no information is available on the use of hemodialysis to treat overdosage [see Clinical Pharmacology in the full prescribing information].

Distributed by:Forest Pharmaceuticals, Inc.Subsidiary of Forest Laboratories, Inc.St. Louis, MO 63045, USATeflaro® is a registered trademark of Forest Laboratories, Inc.IF95USCFR06Revised: October 2012© 2010-2012 Forest Laboratories, Inc. All rights reserved. 069-13000079-BS-A-OCT12

Please also see full Prescribing Information at www.teflaro.com.

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