June 2013

The Pharmacist’s News Source

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Volume 40 • Number 6 • June 2013

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in this issue UP FRONT

3

Opioid–antidepressant combo plays major role in U.S. drug deaths.

CLINICAL

4 13 26

In cancer, new oral anticoagulants can be tricky.

Tips for managing medications in dementia.

Pharmacist-driven discharge process boosts drug compliance.

OPERATIONS & MGMT

28

Parkview Health slashes 30-day readmissions.

POLICY

33

FDA reverses itself on abuse deterrence requirement for generic opioids.

38

Are GPOs to blame for drug shortages?

EDUCATIONAL REVIEW

Medication Errors: A Year In Review, Part 2 See insert after page 12.

Closed System Transfer Devices See insert after page 20.

Does HELP Bill Go Far Enough?

Canadian Chemo Dilutions Hint at U.S. Vulnerabilities

A

M

Compounding legislation:

s the Senate Health, Education, Labor, and Pensions (HELP) Committee put the final touches on legislation that would give the FDA new powers to regulate pharmacy compounding, stakeholders issued mixed reviews on whether the bill does enough to ensure patient safety.

One major feature of the bill is to exempt hospital pharmacies from regulations that prohibit compounding batches of drugs without patient-specific prescriptions. Although the exemption was applauded by the American Society of Health-System Pharmacists (ASHP), others were not as sanguine.

The exemption is “a terrifying part of the legislation,” said Eric Kastango, RPh, MBA, the president and chief executive of Clinical IQ. The bill “will drive more compounding into facilities that don’t have the expertise to ... comply with USP Chapter <797>.

It’s only a matter of time before we have a catastrophic event in a hospital because of poor oversight.”

•

ore than 1,200 oncology patien nts in five Canadian hospital s received diluted doses of gemcitabinee and cyclophosphamide for a year orr longer because labels on bags of pre-mixed IV drug solutions prepared byy an outsource compounding pharmacyy did not make clear that the bags weree intended for single individuals only.

In its May newsletter, the London Health Sciences Centre, where 651 adults and 40 children were said to have received insufficient doses, explained how the mistake went undetected for a year. “It was not known to us that these bags from thee supplier were improperly labeled. It has since been learned that these bags were o overfilled, containing small amounts of extra saline liquid.

This meant that the medication con ncentration was lower than [what was] indicated o on the label.

The small amount of extra liquid was vvery difficult to see with the naked eye and, becausee several people would withdraw small amounts fro om the bags to prepare individual doses for patients, th his overfill [and dosage dilution] went undetected.”

•

see HELP BILL, page 32

In Carboplatin Dosing, Lack of Guidelines Cited Renal function testing a major source of confusion Los Angeles—Many pharmacists are unclear about how they should be dosing carboplatin and would like an organization to come forward and provide standards, according to a panel discussion during the recent annual meeting of the Hematology/Oncology Pharmacy

•

see DOSING, page 6

see CAN NADA ERRORS, page 10

Accreditation for Community Pharmacies Get Mixed Reactions

C

ommunity pharmacies will soon face the decision of whether to become accredited by the Center for Pharmacy Practice Accreditation (CPPA), URAC or to forego accreditation—at least for now. Supporters of the push for accreditation claim it will raise the overall quality of the profession, whereas opponents argue it is duplicative of existing state and federal laws, and overly burdensome in terms of cost, time and effort.

Last summer, both URAC (formerly known as the Utilization Review Accreditation Commission) and CPPA, the most recent entrant

into the accreditation arena, held public comment periods on proposals to establish accreditation programs for community pharmacies— from independents, chains, and mail-order pharmacies, to outpatient pharmacies associated with health systems and hospitals. More recently, CPPA released consensus-based standards in an attempt to identify pharmacies that are focused on advancing patient care, safety and quality. The nonprofit organization is a partnership between the American Pharmacists Association (APhA), the

FDA Watch

The Book Page

•

see ACCREDITATION, page 31

FDA approves Invokana tablets for adults with type 2 diabetes.

Mosby’s Drug Reference for Health Professions

See page 35.

See page 37.

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111886 03/13

Up Front 3

Pharmacy Practice News • June 2013

Capsules

surf

Opioid-Antidepressant Combinations Prominent in Drug Overdose Deaths

JUNE 2013

watch

O

The five most-viewed articles last month on pharmacypracticenews.com: 1. A Dangerous Interplay: Rx Shortages and Med Errors 2. Clot-Busting in Pulmonary Embolism: Worth the Risk?

3. FDA Inspections Taking a Toll on Compounders 4. Making the Case for Hiring an Oncology Pharmacist 5. Anticoagulation Experts Argue a Bloody Debate Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here

‘We are operating in

an evidence vacuum when it comes to

first

management of bleeding in patients receiving novel oral anticoagulants.’

See article, page 26

—Nathan Clark, PharmD

f the 22,134 drug overdose deaths involving pharmaceuticals in the United States in 2010, three-fourths involved opioid analgesics, according to an analysis by officials from the Centers for Disease Control and Prevention (CDC).

In a research letter published in the Journal of the American Medical Association (2013;309:657-659), Christopher M. Jones, PharmD, a health scientist with the CDC’s Injury Center, in Atlanta, and two o his colleagues, parsed data from the National Vital Statistics System multiple cause-of-death file.

The file contains information gleaned from death certificates submitted to the CDC by medical examiners or coroners.

They determined that 57.7% (22,134) of the 38,329 drug overdose deaths in the United States in 2010 involved prescription pharmaceuticals. The top drugs that were involved in those overdose deaths included opioid analgesics (75.2%); benzodiazepines (29.4%), antidepressants (17.6%); antiepileptic and antiparkinson drugs (7.8%); systemic and hematologic drugs (7.2%), and undetermined (8.4%). Nearly three-fourths (74.3%) of the medication-related deaths were deemed unintentional and 17.1% were suicides.

Among the overdose deaths that involved opioids, the most common medications taken concomitantly were benzodiazepines (30.1%), antidepressants (13.4%) and antiepileptic and antiparkinson agents (6.8%).

The team also looked at what fraction of overdose deaths involving other medications also involved opioids. They found opioids were implicated in 77.2% of overdose deaths that involved benzodiazepines; 65.5% of deaths in which antiepileptic and antiparkinson drugs also were implicated; 58% of deaths involving antipsychotics and neuroepileptics; and 50% of barbiturate-related deaths.

Among central nervous system and psychotherapeutic drugs, opioid analgesics were the drug class with the highest percentage of deaths in which no other drug class was involved: Nearly 30% of opioid analgesic–related deaths involved no other drugs. Benzodiazepines were involved in the smallest proportion of single-drug class deaths, with only 2.7% of benzodiazepine-related deaths involving no other drugs.

“The main take-away message from our work is that beyond the opioid analgesics, mental health medications are commonly involved in overdose deaths,” Dr. Jones told Pharmacy Practice News. “That really highlights the importance of screening for mental health or substance abuse disorders when a patient [is seen by a clinician].”

He noted that other studies have shown that patients with mental health disorders are at increased risk for an overdose death (J Clin Psychiatry 2010;71:491-496). They also are more likely to be prescribed higher doses of opioids, and also may be more likely to self-escalate the dose, said Dr. Jones. His team now intends to study the medication combinations that have been involved in drug overdose deaths over time.

—Rosemary Frei, MSc

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Volume 40 • Number 6 • June 2013 • pharmacypracticenews.com

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NUCLEAR PHARMACY

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ONCOLOGY

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CNS/PSYCHIATRY

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4

Hem/Onc Pharmacy

Pharmacy Practice News • June 2013

In Focus

New Oral Anticoagulants Pose Challenges in Cancer Los Angeles—In recent years, three new oral anticoagulants have entered the market. In a standing-room-only session at the annual meeting of the Hematology/Oncology Pharmacy Association, pharmacists were given an overview of the agents and cued into some of the challenges they may face in using them for managing venous thromboembolism (VTE) in cancer patients.

“Cancer patients can benefit from these agents because they have ease of administration, less drug interactions compared with warfarin and monitoring is not required,” said Surabhi Palkimas, PharmD, who presented the data.

Hypercoagulability state and bleeding, however, are risks, said Dr. Palkimas, a benign hematology pharmacy coordinator at University of Virginia Health System, Charlottesville..

The Path to Approval In 2010, the FDA approved dabigatran (Pradaxa, Boehringer Ingelheim) for atrial fibrillation (AF). In 2011, the agency approved rivaroxaban (Xarelto, Bayer) for both prevention of VTE in patients undergoing knee or hip replacement surgery and for AF; in 2012, rivaroxaban received additional indications for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). The newest addition to the anticoagulant arsenal is apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), approved for AF in 2013.

Rivaroxaban, given once daily, and apixaban, given twice daily, are direct factor Xa inhibitors that are absorbed rapidly and have a bioavailability of approximately 50%. Dabigatran, which is a prodrug, is given twice daily, is a direct factor IIa inhibitor, requires an acidic environment for absorption and has a bioavailability of 6%.

These drugs have quick onset and offset of action, but differ with regard to metabolism, dosing frequency and a variety of other factors (Table 1).

“They are all reversible agents, but something we don’t have with all three drugs is an antidote,” Dr. Palkimas said.

“With warfarin, if someone comes in with a bleed, we have vitamin K. With [the other agents], we don’t have that. But these agents have a short half-life and quick time to peak compared with warfarin, so do we really need an antidote?” She pointed out that the procoagulant reversal agents noted in the package inserts for these drugs, including prothrombin complex concentrate (PCC or aPCC) and recombinant factor VIIa (rFVIIa), are not supported by evidence-based medicine.

Pharmacists, she said, need to be really smart when thinking about drug–drug interactions. Dabigatran’s FDA label

Table 1. Pharmacokinetic and Pharmacodynamic Properties Dabigatran

Rivaroxaban

Apixaban

Time to peak, h

1.25-3

2-4

3-4

Half-life, h

12-17

5-9

8-15

Dosing frequency

bid

qd

bid

Metabolism

Conjugation

CYP3A4 (primary) CYP232, oxidation

CYP3A4

Elimination

Renal (80%) Biliary (20%)

Renal (66%) Biliary/Fecal (25%)

Renal (~27%) Fecal (25%)

Plasma protein binding, %

35

>90

Binding to catalytic site

Reversible

Reversible

~87 Reversible

bid, twice daily; CYP, cytochrome P4 P450; 450; qd, once daily

‘None of these drugs have been studied in depth in cancer patients. There could be potential interactions with chemotherapeutic drugs.’

—Agnes Lee, MD warns that it interacts with ketoconazole, droneclarone (Multaq, Sanofi), amiodarone (Nexterone, Baxter), quinidine, verapamil, rifampicin and St. John’s wort.

Rivaroxaban and apixaban interact with ketoconazole, clarithromycin, ritonavir (Norvir, Abbott) and St. John’s wort.

Looking Beyond the Label For a True Picture of Risk The labels, however, don’t tell the whole story. The lists of drug interactions are much longer on the Canadian and European labels of the three drugs, according to Dr. Palkimas. “As pharmacists, we need to be diligent and look at the metabolism of concomitant drugs to assess potential drug–drug interactions,” she said. For example, because dabigatran is a substrate of P-glycoprotein, pharmacists need to think about all the drugs that affect its metabolism— there are approximately 21 of them.

With rivaroxaban and apixaban, pharmacists need to take precautions when patients are on drugs that inhibit P-glycoprotein and cytochrome P450 3A4.

Pharmacists also need to be aware that these oral drugs require different dosing for different creatinine clearance rates.

Dr. Palkimas pointed out that the MAGELLAN and ADOPT VTE prevention trials include few cancer patients.

In these trials, rivaroxaban and apixaban were evaluated for VTE prophylaxis in medically ill patients and shown to be noninferior to enoxaparin (Lovenox, Sanofi) but resulted in higher rates of major bleeding events. In the MAGELLAN trial that evaluated rivaroxa-

ban, 7% of patients had cancer. In the ADOPT trial, 3.5% of patients receiving apixaban had active cancer and 6.1% had remote cancer. Dabigatran has not been evaluated for VTE prevention in medically ill patients.

VTE treatment trials also include few cancer patients (Table 2). The EINSTEIN and RECOVER trials pitted the new oral agents against the standard treatment of starting patients on enoxaparin for five days and then switching them over to warfarin. In EINSTEIN, rivaroxaban was shown to be noninferior to standard therapy. Although the incidence of major and non-major bleeding was similar in both treatment groups, rivaroxaban was associated with a significantly lower risk for major bleeding compared with stan-

Table 2. Cancer Patients in VTE Treatment Trials Trial/Arm

Patients Receiving New Oral Agent, %

EINSTEIN-DVT, 6.3 rivaroxaban EINSTEIN-PE, rivaroxaban

4.7

AMPLIFY-EXT, apixaban

Not included

RECOVER, dabigatran

5

V , ve VTE, venous ous tthromboembolism o boe e bo s

‘These [new] agents have a short half-life and quick time to peak compared with warfarin, so do we really need an antidote?’

—Surabhi Palkimas, PharmD dard therapy. In RECOVER, dabigatran was noninferior to warfarin and had similar bleeding risks. In the AMPLIFY-EXT trial, apixaban was superior to placebo.

“At our institution, we started using rivaroxaban for VTE treatment [in some cancer patients] since its approval for that indication,” Dr. Palkimas said. She added that pharmacists should consider offering the new oral anticoagulants to cancer patients with VTE who have difficulty getting their international normalized ratio (INR) test or difficulty staying in their INR therapeutic range, who also have normal renal function and are not taking medications that interact with the new oral anticoagulants.

Cost could be a stumbling block for some patients, Dr. Palkimas noted, pointing out that a month’s supply of dabigatran and rivaroxaban is approximately $290 and $320, respectively.

A Note of Caution Asked to comment on the three new oral anticoagulants, Agnes Lee, MD, the director of the thrombosis program at Vancouver General Hospital and an associate professor of medicine at the University of British Columbia, in Vancouver, said she would be hesitant to use the drugs in oncology patients because so few cancer patients were included in the trials. “None of these drugs have been studied in depth in cancer patients,” Dr. Lee said. “There could be potential interactions with chemotherapeutic drugs.”

Patients on chemotherapy, she said, tend to have gastrointestinal problems that lead to unpredictable absorption, and these drugs could increase the risk for gastrointestinal bleeding. “I would really like to see these drugs tested in a clinical trial of cancer patients,” she said.

“It is desperately needed.”

—Kate O’Rourke Dr. Palkimas had no relevant disclosures.

Dr. Lee reported honoraria and advisory board involvement with BMS, and honoraria from Bayer and Boehringer Ingelheim.

More oral anticoagulant therapy tips See page 26

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6

Hem/Onc Pharmacy

Pharmacy Practice News • June 2013

In Focus

DOSING continued from page 1

Association (HOPA).

“Currently, there is no uniform standard, so unfortunately if you come to Yale in New Haven, Temple in Texas or MD Anderson, your carboplatin dose will be different,” said Scott Soefje, PharmD, MBA, BCOP, the associate director of oncology pharmacy services and the PGY2 oncology residency director at the Smilow Cancer Hospital at Yale-New Haven, in Connecticut.

Carboplatin dosing is calculated using estimates of a patient’s renal function.

A variety of formulas have been used, but none are perfect, according to the panel (Table).

For example, the Egorin formula is troublesome because clinicians do not agree on the proper platelet nadir. “You can ask 10 people and get 10 different answers,” said Jon Herrington, PharmD, BCPS, BCOP, the PGY1 residency assistant program director at the Scott & White Memorial Hospital and Vasicek Cancer Center, in Temple, Texas.

The Calvert formula, which was designed to simplify the measurement of carboplatin dosing, relies on glomerular filtration rate (GFR) measured using the radioisotope Cr-ethylenediaminetetraacetic acid (Cr-EDTA). However, according to Dr. Herrington, Cr-EDTA is expensive and not readily available at all clinical practice sites or hospitals.

Substitution of an estimate of creatinine clearance (CrCl) calculated using formulas such as Cockcroft-Gault in place of the GFR in this formula is routine in clinical practice. Although CrCl is always slightly higher than GFR, the two estimates of renal function are used interchangeably in the Calvert formula, said Dr. Herrington, but he noted that determining an accurate CrCl for the Calvert formula is challenging.

Another method, the Chatelut equation, provides an assessment that doesn’t use radioisotopes and doesn’t require a calculation of CrCl, but is complicated, according to Dr. Herrington. “It has a lot of different numbers.” He also noted that the research that supported its use in the first place (J ( Natl Cancer Inst 1995;87:573-580) has not been corroborated in further studies. The Chatelut equation also provides a wide variance compared with the Calvert method.

A Look at the Literature Dr. Herrington highlighted results from a study in the British Journal of Cancer that assessed the accuracy of three equations to estimate GFR (eGFR) for use in the Calvert equation (2012;107:1310-1316).

In the study, the investigators selected 288 patients referred for a radionuclide GFR during a three-year period; eGFR was calculated using the Modification of

Table. Carboplatin Dosing Formulas Name of Formula

Computation

Egorin

For chemotherapy-naive patients: Carboplatin dose mg/m2 = (0.091 × [CrCl/BSA]) × ([pretreatment platelet count-platelet nadir desired/ / pretreatment platelet count] × 100) + 86

Calvert formula

For heavily pretreated patients: Total carboplatin dose (mg) = (target AUC) × (GFR + 25)

Chatelut formula

Carboplatin clearance = (0.134 × kg) + ([1 if male, 0.686 if female]) × 218 × kg) × (1 - [0.00457 × age])/ serum creatinine (mg/dL) × 88.4 Dose = CrCl × AUC

AUC, area under the curve; BSA, body surface area; CrCl, creatinine clearance; GFR, glomerular filtration rate

‘If you come to Yale in New Haven, Temple in Texas or MD Anderson, your carboplatin dose will be different.’

—Scott Soefje, PharmD

Figure. Cockcroft-Gault equation to determine CrCl. CrCl, creatinine clearance

Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault equations. Compared with the reference standard (rGFR), MDRD, CKD-EPI and Cockcroft-Gault equations overestimated carboplatin dose by 12%, 14% and 8%, respectively. The researchers recommended that the Cockcroft-Gault should be used if rGFR is unavailable (Figure).

This recommendation supports a National Cancer Institute (NCI) recommendation made five years ago in favor of the Cockcroft-Gault equation for CrCl estimations in adults, but questions remain about this approach, according to Judith Smith, PharmD, BCOP, an associate professor of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, in Houston. There is uncertainty regarding which weight should be used for calculating CrCl and how the equation should be adjusted for obesity, Dr. Smith said. According to the literature, she noted, actual body weight should be used in most nonobese patients—the Cockcroft-Gault formula was designed and validated using actual body weight.

Adjusted body weight, however, is appropriate for patients with a body mass index greater than 30 kg/m.

Also, it is not clear whether it is appropriate to round serum creatinine levels to prespecified values in elderly or cachectic patients. “Serum creatinine levels can run quite low in patients

with low muscle mass or the elderly,” said Dr. Smith. “We see a lot of variation … in practice in recommendations of what you should round off to in that scenario. Rounding off to 1 will generally underestimate creatinine clearance.”

Clinicians often round off to 0.7 or 0.8, she said, but “there is no magic answer.

Until we have a standard, use the lower limit of serum creatinine assay parameters at your institution.”

She also pointed out that wide interlaboratory variation exists in reported serum creatinine. This led the National Kidney Disease Education Program to published recommendations in 2006 to recalibrate serum creatinine assays to an isotope dilution mass spectrometry (IDMS) traceable reference method. All laboratories were expected to comply

by Dec. 31, 2010, but this never happened, said Dr. Smith. In some patients with normal renal function, the new standardized IDMS method produced creatinine values that were, on average, 10% to 20% lower than older, non-IDMS values. In patients with low serum creatinine, the IDMS method generated abnormally low values, leading to an overestimation of CrCl and higher calculated carboplatin doses.

HOPA Survey Shows Lack of Consensus A multidisciplinary HOPA survey conducted in 2010 sheds light on the widely varying practice patterns. Of the 525 respondents, 80.5% of whom were

pharmacists, h i 96.5% said id they h used d the h Calvert equation and 94.1% said they use estimated CrCl when calculating this equation. When asked which methods they used to make this estimation, many used Cockcroft-Gault (90%); some used Jelliffe (37.9%); and a few individuals employed MDRD (2.5%) or another method (3.5%). When asked which body weight they used to determine calculations for obese patients, responses fluctuated widely. Survey participants were asked, ‘do you use an adjusted/assigned value for serum creatinine when below (less than) your laboratory normal limit?’

Fifty-six percent answered affirmatively.

When asked whether or not they had a cap for CrCl when dosing carboplatin, 48% responded “yes.”

The NCI recommends capping GFR used in the Calvert formula at 125 mL/min for the majority of patients, and the survey showed that many clinicians are complying with this. Although capping at 125 mL/min may be suitable for many patients, it might not be the most appropriate method for everyone, said Dr. Soefje. This being the case, Dr. Smith recommended that clinicians consider goals of therapy and use their clinical judgment.

“What we have concluded from this whole [survey] process is there is no standard,” said Dr. Soefje, adding, “We believe there should be a standard method.” Such a standard, he said, would state that Cockcroft-Gault is the preferred equation to calculate CrCl in the Calvert equation, that adjusted body weight is recommended for estimating renal function in obese patients, and that clinicians should round up low CrCl values to their institutional lower limit of normal. Additionally, he said, capping CrCl at 125 mL/min is appropriate for the majority of patients.

Dr. Soefie is not alone in seeking a standard approach to carboplatin dosing. At the end of the session, Robert Ignoffo, PharmD, a professor of pharmacy at Touro University California and a clinical professor emeritus at the University of California, San Francisco, also recommended that dosing standards be developed, and a large majority of audience members agreed.

—Kate O’Rourke Dr. Soefje reported being on the speaker’s bureau for Amgen, Eisai and Millennium.

Drs. Herrington, Smith and Ignoffo reported no relevant financial conflicts of interest.

What if those costs could be reduced?

Adverse drug events created by mistakes in a hospital pharmacy are expensive and can be fatal – especially when they involve IV medications.

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8

Hem/Onc Pharmacy

Pharmacy Practice News • June 2013

In Focus

Taming Infusion-Site Reactions With IV Fosaprepitant Los Angeles—Peripheral IV administration of fosaprepitant (Emend, Merck) at 150 mL over 20 minutes results in an almost 15% rate of infusion-site reactions in selected patients, according to a poster study from the Ohio State University (OSU), in Columbus. This rate is much higher than the 3% rate reported in the literature and has spurred the investigators to make changes at their facilities.

“Because of the [results], we’ve already [revised] the dilution and rate of our default [infusion] in the computer system,” said Jordan Lundberg, PharmD, a postgraduate year 1 pharmacy resident at the OSU Wexner Medical Center. “We’re now using a 250-mL base solution given over 30 minutes,” based on manufacturer-provided external stability data, added Dr. Lundberg, who presented the poster study at the annual meeting of the Hematology/Oncology Pharmacy Association.

‘If [further data show that] less infusion-related reactions occur with this method, then we would likely recommend it for those few patients who may receive fosaprepitant.’

—Lisa Holle, PharmD, BCOP Preliminary evaluation of the 192 doses revealed 28 infusion-site reactions for an incidence of 14.6%, with most reactions being grade 1 or 2. “What we

[saw was] some pretty high rates of infusion-site reactions compared to what is reported in the literature. Almost 15% of patients had infusion-site reactions,”

said Dr. Lundberg. “I didn’t expect it would be that high.”

Based on the data, the hospital’s pharmacy and therapeutics committee recommended changing the dilution and rate of fosaprepitant to the aforementioned 250mL base solution given over 30 minutes.

Lisa Holle, PharmD, BCOP, an oncology pharmacist at the University of Connecticut Health Center’s (UCHC) Carole and Ray Neag Comprehensive Cancer

The Fosaprepitant Rationale Last September, OSU’s Arthur G. James Cancer Hospital first added the 150-mL fosaprepitant regimen to its formulary.

The addition was made, Dr. Lundberg noted, because the IV drug offered a more convenient alternative to the standard three-day course of oral aprepitant (Emend, Merck). The decision was bolstered by a Phase III trial showing that single-dose IV fosaprepitant is noninferior to the multiday oral aprepitant therapy ((J Clin Oncoll 2011;29:1495-1501).

After the cancer hospital started to use the IV regimen (based on the package insert [PI] recommendation, started approximately 30 minutes before chemotherapy)—clinicians noticed the higher-than-expected spike in infusion-site reactions.

To document the true rates of infusion reactions, Dr. Lundberg and his colleagues retrospectively reviewed the records of all patients who received fosaprepitant through a peripheral line preceding chemotherapy between Sept. 1, 2012 and Dec. 31, 2012. In the study, 100 patients received 192 doses of the fosaprepitant PI regimen through a peripheral line that was placed in the hand, forearm or antecubital fossa.

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INDICATION: Venofer ® (iron sucrose injection, USP) is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD).

IMPORTANT SAFETY INFORMATION: • Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been lifethreatening and fatal, have been reported in patients receiving Venofer ® (iron sucrose injection, USP).

Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse.

If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer ® immediately.

Monitor patients for signs and symptoms of hypersensitivity during and after Venofer ® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions.

• Venofer ® may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer ®. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered.

davidb@mcmahonmed.com.

Leading anemia management.™

Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2011 American Regent, Inc. VEN040 • Rev. 12/2011 • venofer.com

Hem/Onc Pharmacy 9

Pharmacy Practice News • June 2013

In Focus Center, in Farmington, said she found the study results “surprising,” given that its documented rate of infusion-site reactions is more than 10% higher than what has previously been reported. “We use oral aprepitant almost exclusively at UCHC’s Neag Cancer Center because we prefer the all-oral antiemetic regimens,” she said. “I look forward to the full results of this research (i.e., the results following use of a more dilute solution over a prolonged period). If less infusionrelated reactions occur with this method, then we would likely recommend such a

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• Venofer ® is contraindicated in patients with known hypersensitivity to Venofer ®. Do not administer to patients with evidence of iron overload.

• In efficacy studies in non-dialysis dependent-CKD patients (N=139), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were nausea (8.6%), taste disturbance (7.9%), peripheral edema (7.2%), diarrhea (7.2%), dizziness (6.5%), hypertension (6.5%), infusion site pain or burning (5.8%), dyspnea (5.8%), and vomiting (5.0%).

• In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the most frequent adverse events (>5%) whether or not related to Venofer® administration, were hypotension (39.4%), muscle cramps (29.4%), nausea (14.7%), headache (12.6%), graft complications (9.5%), vomiting (9.1%), dizziness (6.5%), hypertension (6.5%), chest pain (6.1%), and diarrhea (5.2%). In the study of peritoneal dialysis-CKD patients (N=75), the most frequent adverse events, whether or not related to Venofer ®, reported by 5% of these patients were infections and infestations (nasopharyngitis, sinusitis, upper respiratory tract, pharyngitis) (16.0%), diarrhea (8.0%), vomiting (8.0%), hypertension (8.0%), peripheral edema (5.3%), and nausea (5.3%). *100 mg vials and ampules worldwide from 1992 to February 2011.

Reference: 1. Data on file. American Regent, Inc. Shirley, NY.

Please see brief Prescribing Information on adjacent page.

change in our institution for those few patients who may receive fosaprepitant.”

Both antiemetics are included as options in treatment guidelines from the National Comprehensive Cancer Network and the American Society of Clinical Oncology: The groups recommend a three-drug cocktail of oral aprepitant or IV fosaprepitant, a 5HT-3 receptor antagonist and dexamethasone.

—Kate O’Rourke Drs. Lundberg and Holle have no relevant financial conflicts of interest.

10

Hem/Onc Pharmacy

Pharmacy Practice News • June 2013

In Focus

CANADA ERRORS continued from page 1

Although the clinical effect on patients who received the lower doses of chemotherapy remained unclear, the disclosures triggered a storm of controversy and a spate of investigations into the safety of the Canadian medication supply system as well as the lack of federal or provincial oversight of compounding manufacturers that prepare drugs for institutional use.

In May, the province of Ontario, where the compounding company and four of

the five hospitals are located, issued new rules intended to close the regulatory gap. The Ontario College of Pharmacists, which governs pharmacy practice registration and regulation in the province, was given clear authority to inspect all drug preparation facilities where pharmacists and technicians work, including those of compounding manufacturers.

Implications for U.S. Practice The diluted chemo drug issue, while limited to Canada, has wider implications for pharmacists in other countries,

Adverse Reactions (Preferred Term)

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Venofer safely and effectively. See full prescribing information for Venofer.

Initial U.S. Approval: 2000 RECENT MAJOR CHANGES Warnings and Precautions 6/2011 INDICATIONS AND USAGE Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD).

DOSAGE AND ADMINISTRATION Administer Venofer intravenously either by slow injection or by infusion.

CKD patients on hemodialysis: 100 mg undiluted slow intravenous injection over 2 to 5 minutes or as an infusion of 100 mg, diluted in a maximum of 100 mL of 0.9% NaCl, over a period of at least 15 minutes.

CKD patients not on dialysis: 200 mg undiluted slow IV injection over 2 to 5 minutes.

• CKD patients receiving peritoneal dialysis: infuse 300 mg over 1.5 hours given on two occasions 14 days apart followed by a single infusion 14 days later of 400 mg given over 2.5 hours. Dilute each Venofer dose in a maximum volume of 250 mL of 0.9% NaCl. DOSAGE FORMS AND STRENGTHS • 10 mL single use vial / 200 mg elemental iron (20 mg/mL) • 5 mL single use vial / 100 mg elemental iron (20 mg/mL) • 2.5 mL single use vial / 50 mg elemental iron (20 mg/mL) CONTRAINDICATIONS • Known hypersensitivity to Venofer WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions.

• Hypotension:Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Venofer.

• Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer to patients with iron overload.

ADVERSE REACTIONS • The most common adverse reactions (≥ 2%) following the administration of Venofer are diarrhea, nausea, vomiting, headache, dizziness,hypotension,pruritus,pain in extremity,arthralgia,back pain,muscle cramp,injection site reactions,chest pain,and peripheral edema.

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION 2 DOSAGE AND ADMINISTRATION Venofer must only be administered intravenously either by slow injection or by infusion. The dosage of Venofer is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron. The usual total treatment course of Venofer is 1000 mg. Venofer treatment may be repeated if iron deficiency reoccurs.

2.1 Adult Patients with CKD on dialysis Administer Venofer 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session.Venofer should be administered early during the dialysis session.

2.2 Adult Patients CKD not on dialysis Administer Venofer 200 mg undiluted as a slow IV injection undiluted over 2 to 5 minutes on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on day 1 and day 14.

2.3 Adult Patients with CKD receiving peritoneal dialysis Administer Venofer in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg overr 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Venofer in a maximum of 250 mL of 0.9% NaCl. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion.

5.2 Hypotension Venofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer. Hypotension following administration of Venofer may be related to the rate of administration and/or total dose administered.

5.3 Iron Overload Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Patients receiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation).

Do not administer Venofer to patients with evidence of iron overload. Transferrin saturation values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing.

6 ADVERSE REACTIONS Venofer injection may cause serious hypersensitivity reactions and hypotension. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

6.1 Adverse Reactions in Clinical Studies The frequency of adverse reactions associated with the use of Venofer has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse events reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Venofer exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

Table 1. Treatment-Emergent Adverse Reactions Reported in ≥ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate for Comparator

Subjects with any adverse reaction Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain Diarrhea Dysgeusia Nausea Vomiting

HDD-CKD Venofer (N=231) %

NDD-CKD Venofer Oral Iron (N=139) (N=139) % %

Venofer (N=75) %

PDD-CKD EPO* Only (N=46) %

78.8

76.3

73.4

72.0

65.2

0

2.2

0.7

0

0

0.4

0

0

2.7

0

2.9 10.1 0 12.2 8.6

4.0 8.0 0 5.3 8.0

6.5 4.3 0 4.3 2.2

3.5 5.2 0.9 14.7 9.1

1.4 7.2 7.9 8.6 5.0

—Ryan Zimmerly, PharmD including the United States, which is in the midst of its own broad effort to strengthen regulation of compounding pharmacies following last year’s deadly fungal meningitis outbreak originating in Massachusetts.

(Table 1. Continued)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Adverse Reactions (Preferred Term)

‘As a patient, knowing that you didn’t get a full [chemotherapy] dose, there would always be the question in your mind: Did that have an effect?’

General Disorders and Administration Site Conditions Asthenia Chest pain Feeling abnormal Infusion site painor burning Injection site extravasation Peripheral edema Pyrexia Infections and Infestations Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis Injury, Poisoning and Procedural Complications Graft complication Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia Hypoglycemia Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Nasal congestion Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension Hypotension

HDD-CKD Venofer (N=231) %

NDD-CKD Venofer Oral Iron (N=139) (N=139) % %

Venofer (N=75) %

PDD-CKD EPO* Only (N=46) %

2.2 6.1 3.0 0 0 2.6 3.0

0.7 1.4 0 5.8 2.2 7.2 0.7

2.2 0 0 0 0 5.0 0.7

2.7 2.7 0 0 0 5.3 1.3

0 0 0 0 0 10.9 0

2.6

2.2

4.3

16.0

4.3

9.5

1.4

0

0

0

3.0 0 0 0.4

1.4 2.9 2.9 0.7

0.7 1.4 0 0.7

1.3 0 0 4.0

0 0 2.2 0

3.5 2.2 29.4 0 5.6

1.4 2.2 0.7 3.6 4.3

2.2 3.6 0.7 0 0

4.0 1.3 2.7 1.3 2.7

4.3 4.3 0 0 6.5

6.5 12.6

6.5 2.9

1.4 0.7

1.3 4.0

4.3 0

3.0 3.5 0

2.2 5.8 1.4

0.7 1.4 2.2

1.3 1.3 1.3

0 2.2 0

3.9

2.2

4.3

2.7

0

6.5 39.4

6.5 2.2

4.3 0.7

8.0 2.7

6.5 2.2

*EPO=ERYTHROPOIETIN 6.2 Adverse Reactions from Post-Marketing Spontaneous Reports In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following additional adverse reactions have been identified with the use of Venofer from postmarketing spontaneous reports: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Symptoms associated with Venofer total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Symptoms may respond to IV fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

7 DRUG INTERACTIONS Drug interactions involving Venofer have not been studied. However, Venofer may reduce the absorption of concomitantly administered oral iron preparations.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Venofer should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers It is not known whether iron sucrose is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Venofer is administered to a nursing woman.

8.4 Pediatric Use Safety and effectiveness of Venofer in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of Venofer did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE No data are available regarding overdosage of Venofer in humans. excessive dosages of Venofer may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. do not administer Venofer to patients with iron overload.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How supplied Venofer is supplied sterile in 10 mL, 5 mL, and 2.5 mL single use vials. Each 10 mL vial contains 200 mg elemental iron, each 5 mL vial contains 100 mg elemental iron, and each 2.5 mL vial contains 50 mg elemental iron (20 mg/mL).

16.2 Stability and storage Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Do not freeze. Do not dilute to concentrations below 1 mg/mL. Do not mix Venofer with other medications or add to parenteral nutrition solutions for intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION Prior to Venofer administration: • Question patients regarding any prior history of reactions to parenteral iron products.

• Advise patients of the risks associated with Venofer • Advise patients to report any symptoms of hypersensitivity that may develop during and following Venofer administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems.

AMERICAN REGENT, INC. SHIRLEY, NY 11967 Venofer is manufactured under license from Vifor (International) Inc., Switzerland.

IN2340BS, Rev. 6/2011

Michael R. Cohen, RPh, MS, ScD, the president of the Institute for Safe Medication Practices (ISMP), said the Canadian underdosing issue highlighted the need for more rigorous universal standards for preparing, labeling and administering chemotherapy and other highalert drugs. He noted that even in U.S. hospitals, there is “an inconsistency in the way we make things in IV admixture areas” that “can lead to serious errors.”

He explained that some pharmacists just add drug to the IV bag, intending that the bag’s entire contents be administered. Others draw fluid out of the bag so that “exactly the right amount is given.

But unfortunately, some of it gets hung up in the IV tubing,” and a patient might not receive the full dose. Still other pharmacists, he said, start with an empty bag and put in the exact amount, and “again [a patient] may not get the whole dose because there could be 20 mL left in the IV tubing at the end of the infusion.”

Clearly, such problems are common on both sides of the border. In April, ISMP Canada called for a national standard for labeling chemotherapy solutions with overfill volumes, in direct response to the Ontario underdosing errors.

Dr. Cohen noted that his organization had worked with its Canadian counterpart on an earlier initiative to help hospitals and ambulatory care centers worldwide evaluate the safety of their oncology drug programs. The result of the collaboration was the 2012 ISMP International Medication Safety Self Assessment (IMSSA) for Oncology. y Dr. Cohen said only 50% of those who responded to the selfassessment survey reported that there was a standard way by which their hospitals prepared and labeled oncology drugs for administration.

No Patient Harm? Still Unknown Could the chemotherapy underdosing in Canada have led to patient harm? “Not in terms of toxicities,” said Ryan Zimmerly, PharmD, an oncology pharmacist at St. Luke’s Mountain States Tumor Institute, in Fruitland, Idaho, “but potentially in terms of responses. That is something we will never know. There is some leeway as to the strength of the product you’re compounding, but in no way would 20% ever be within that window. And as a patient, knowing that you didn’t get a full dose, there would always be the question in your mind: Did that have an effect?”

Dr. Zimmerly noted that the Canadian compounding facility prepared the chemotherapy bags “in the same way you

Hem/Onc Pharmacy 11

Pharmacy Practice News • June 2013

In Focus would typically see done for an individual patient.” But he added, “Never do you give standardized doses of chemotherapy. It would be rare that everybody got 2,000 mg of gemcitabine or 1,500 mg of cyclophosphamide. All of those doses are tailored based on patients’ height and weight and on organ function, whether hepatic or renal. It would be hard for me to believe that they didn’t think that those medications were being used on multiple patients, but they claim they didn’t.”

Dr. Zimmerly pointed out that “if you use a premixed bag and dilute your chemotherapy to reconstitute it and infuse it back into that bag, it’s standard that there is overfill in the bag. That’s not a concern if it’s used for a single patient, because the whole volume gets infused.

But if you try to come up with an exact concentration for the bag, there is no way to do that without drawing everything out and measuring the exact volume. So if you’re going to manufacture something that’s not patient-specific, you would probably want to do that as an exact volume. You would use an empty bag and put in the exact amount of fluid that you want to have in there.”

‘If you’re not preparing the [chemotherapy] drug in your setting, then it is important to understand the integrity of the facility where the drug is prepared and what the safety guidelines are for that facility.’

—Lisa Holle, PharmD, BCOP in your setting, then it is important to understand the integrity of the facility where the drug is prepared and what the guidelines are for that facility.”

Dr. Holle recommended using known

vendors with a reputation for quality and safety—ones that adhere to United States Pharmacopeia Chapter <797> standards and employ pharmacists trained in oncology practice. “An oncol-

YOUR SMART PUMP

Echoes of NECC? Although the Canadian situation has certain similarities to the U.S. meningitis outbreak, which was tied to tainted medications manufactured by the New England Compounding Center (NECC), Dr. Cohen said there was at least one key difference. “I don’t think there are too many U.S. hospitals that would order chemotherapy bags from an outsourcer— whether multiple-dose containers or single-dose—although there may be some oncology clinics that do. It probably takes place now and then—maybe syringes, for example. But chemotherapy drugs are hard to transport. You’re always worried about leakage and breakage.”

But for hospitals that do order oncology drugs from outsourcers, there are steps that pharmacists can take to minimize the risk for errors, said Lisa Holle, PharmD, BCOP, immediate past president of the Hematology/Oncology Pharmacy Association and an assistant clinical professor at the University of Connecticut School of Pharmacy and Neag Cancer Center, in Storrs. “The best thing that a pharmacist can do is to be as responsible as possible to ensure the integrity of the supply chain,” Dr. Holle said. “So if you’re not preparing the drug

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ogy pharmacist can be crucial to ensuring that all of the rules and regulations associated with safe manufacturing practices are followed,” she said, adding that such pharmacists should have full access to information for every patient, including diagnosis and lab values, in order to assure that doses are appropriate and compatible with other drugs the patients may be taking.

“Ideally, it would be helpful for oncology pharmacists to be involved in the whole spectrum of care.”

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12 Clinical

Pharmacy Practice News • June 2013

Endocrinology

Pharmacists Help Improve Diabetes Control P

atients with type 2 diabetes who receive more pharmacist care are more likely to experience better disease control, according to studies conducted by pharmacists who specialize in managing the chronic disease.

The studies, which documented significant decreases in glycosylated hemoglobin (HbA1c) levels when pharmacists became more involved in the management of patients with diabetes, are the latest in a growing body of evidence supporting a rethinking of the role that pharmacists can play in diabetes care.

“We are getting more and more reports of pharmacist-managed interventions with diabetes patients that result in significant and important improvements in outcomes,” commented R. Keith Campbell, PharmD, CDE, a distinguished professor in diabetes care and pharmacotherapy at Washington State University College of Pharmacy, in Pullman, who was not involved in the studies.

Collaborative Care Pays Off In Tennessee, for example, a prospective analysis of 206 type 2 diabetes patients who received one year of collaborative physician–pharmacist care at one of seven primary care centers affiliated with the University of Tennessee showed reductions in HbA1c levels under this model. Lead researcher Michelle Farland, PharmD, BCPS, CDE, an associate professor at the University of Tennessee Health Science Center’s College of Pharmacy in Knoxville, said that pharmacists working within this treatment paradigm adjust Intervention group Control group

Hemoglobin A 1c (%)

10

9.1

9.1 8.7

9 8.0

8 7 6 5 4 3 2 1 0

Baseline

Two Years

Figure. Effect of collaborative physician–pharmacist care on hemoglobin A1c level.

m e d i c a t i o n d o s e s, order vaccines, provide patient education, conduct health maintenance tests like sensory foot examinations, and also refer patients for eye examinations if needed. The study participants had been receiving the usual primary care prior to entering the program, Dr. Farland said.

According to the researcher, HbA1c levels under the collaborative care model dropped from a mean of 8.90% ( 1.97%) at baseline to a mean of 7.74% (± ( 1.69%) after one year ((P<0.0001). That (± 1.2% difference may not seem like much, but at least one study has shown that every 1% reduction in HbA1c is associated with an approximately 40% decrease in the incidence of microvascular complications ((Diabetes 1995;44:968-983).

The proportion of patients with HbA1c less than 7% also increased from 12.75% to 36.76% ((P=0.0002), while the number of those with HbA1c more than 9% decreased from 34.15% to 16.5% ( <0.0001). Dr. Farland noted that there (P was no change in the frequency of hypoglycemic events with lower HbA1c levels.

“The highest-impact components of the program were medication dose titrations and providing diabetes selfmanagement education,” Dr. Farland told Pharmacy Practice News.

Monthly Visits Part of Plan A more aggressive pharmacist-initiated dose titration schedule accounted for the improvements in HbA1c levels that Taniyah Dawson, PharmD, a pharmacy resident at Scott & White Health Plan in Temple, Texas, and her team have documented. Dr. Dawson and several colleagues enrolled 69 patients with type 2 diabetes in a two-year intervention that consisted of monthly visits with a clinical pharmacist in addition to their usual medical care. At each visit, the patient’s medications, recent lab values and selfmonitoring blood glucose log book were reviewed. Patients had their copayment for diabetic medications and supplies waived for the duration of the program.

For the comparison group, the researchers matched each participant with a patient who had been treated at the Scott & White Health Plan and followed for two years. The controls were similar to the participants in age, baseline HbA1c levels, gender and Charlson comorbidity index scores, but had not taken part in the program.

According to Dr. Dawson, average HbA1c levels in both groups were 9.1% at baseline. By the end of the two-year program, patients in the intervention group

‘The highest-impact components of the program were medication dose titrations and providing diabetes self-management education.’

—Michelle Farland, PharmD, BCPS, CDE saw their average HbA1c levels drop to 8%—significantly lower than the level of 8.7% in the control group ((P<0.01; Figure).

The researcher said that there were more dose titrations (86 vs. 57) and more new oral hypoglycemic medications (41 vs. 30) initiated in the intervention group than in the controls. However, the number of new medications was offset by a similar number of drug discontinuations, keeping the average total amount of oral medications in the intervention and control groups relatively the same over the study period.

Dr. Dawson told Pharmacy Practice News that the level of medication adherence in the intervention group rose as the program progressed. She believed that this was an important factor in driving down HbA1c levels. “The relationship that developed between the patient and the pharmacist, along with the educational information taught during each visit, was critical in improving adherence,” Dr. Dawson said. “Patients like to be held accountable and participate in their own care. They are excited to bring in their blood glucose books with comments next to abnormal values and discuss these.”

Remote Yet Effective The absence of an in-person relationship did not hamper the efficacy of a telehealth pharmacist–based diabetes care program that was rolled out in January 2010, at Edward Hines, Jr. Veterans Affairs Hospital, in Hines, Ill. Lead researcher Danielle Alsip, PharmD, a clinical pharmacy specialist at the hospital, and her colleagues retrospectively examined medical records of 60 patients with type 2 diabetes who met

in person with a clinical pharmacist at one of four community outpatient clinics affiliated with the hospital, and compared their outcomes with those of 58 patients from one of two hospital-affiliated clinics that do not have a clinical pharmacist on staff but offer pharmacist care through a telehealth system.

Dr. Alsip and her team found no significant differences between the in-person and telehealth care patient groups: HbA1c levels fell from an average of 9.8% to 8.7% after six months of in-clinic treatment, which was statistically similar to the drop from 9.2% to approximately 8.3% among telehealth patients ( =0.46). Other measures, including (P weight, number of diabetes medications, medication-related adverse events and missed appointments, also did not differ significantly between the two groups.

“Everything is conducted the same way via telehealth as when the patient is sitting in front of you,” Dr. Alsip said.

She noted, however, that poor lighting or poor sound can be challenging for elderly patients.

Dr. Alsip said that she does not think “there is a significant difference in the quality of the relationship we build in person or through telehealth.” In contrast, she said, “there is a significant difference between phone follow-ups and seeing someone, whether in person or through a telehealth platform. It’s important to be able to put a face to a name.”

—David Wild The studies were presented at the 2012 annual meeting of the American College of Clinical Pharmacists. Drs. Campbell, Farland, Dawson and Alsip reported no relevant financial conflicts of interest.

Clinical 13

Pharmacy Practice News • June 2013

Psychopharmacology

A Measured Approach To Managing Dementia P

harmacists, working as part of a multidisciplinary health care team, should be conservative when treating behavioral and psychological symptoms associated with dementia, according to Christopher Thomas, PharmD, a clinical pharmacy specialist in psychiatry at the Chillicothe VA Medical Center, in Chillicothe, Ohio.

When patients present to the emergency department (ED) or are admitted to a hospital floor or long-term care facility with signs of delirium, dementia or mental status changes, clinicians should initiate a stepwise process for patient evaluation and management, said Dr. Thomas, who is also an assistant professor of pharmacology at the Ohio University College of Osteopathic Medicine, in Athens.

The American College of Neuropsychopharmacology white paper on the use of antipsychotic drugs in elderly individuals with dementia recommends a comprehensive step-by-step intervention plan to guide clinicians through the process (Table 1). The first step, noted Dr. Thomas, is to determine whether life changes, underlying conditions or medications may have triggered a patient’s symptoms. Once these factors have been assessed, the next step is to initiate nonpharmacologic therapies, such as music therapy or behavioral management techniques. Only after these steps have been taken should they initiate a targeted pharmacologic therapy regimen, he said. Once such therapy is started, he added, patients should be monitored to assess the regimen’s effectiveness and safety, and there should be regular, documented efforts to reduce doses of antipsychotics.

“It’s really important whenever patients come in that you don’t go in with guns blazing with medications,” Dr. Thomas said. “You have to really look to see what’s going on with the etiology, then start nonpharmacologic therapy, and then introduce medicines.”

Table 1. Stepwise Interventions for Antipsychotic Use in Elderly Patients 1. Determine etiology of symptoms.

2. Initiate general therapeutic interventions (nonpharmacologic therapies).

3. Include patient and family for guidance on how to proceed.

4. Identify target symptoms.

5. Choose specific pharmacology.

6. Dose agent at lowest effective dose.

7. Monitor effectiveness.

8. Monitor safety.

9. Continue to educate patient and caregivers.

10. Consider discontinuing or switching pharmacotherapy based on response.

11. Coordinate care among other health care providers (this occurs at each step).

Source: Jeste D et al. Neuropsychopharmacology y 2008;33:957-970. http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC2553721/.

‘It’s really important whenever patients [with dementia] come in that you don’t go in with guns blazing with medications.’

—Christopher Thomas, PharmD

Common Source of Confusion It’s easy for geriatric patients to become significantly more confused if they’re admitted to a hospital from their regular living environment, according to Lawrence J. Cohen, PharmD, BCPP, the associate dean for clinical programs at the University of North Texas System College of Pharmacy, in Fort Worth. This could lead to exacerbated symptoms and may be interpreted as resistance, noncompliance, hostility or argumentativeness on the part of the patient. Even within longterm care facilities, relatively minor changes, such as moving a patient’s bed, can cause confusion, disorientation or agitation, he added.

In the ED or an ICU, it may be nec-

Table 2. Strategies To Avoid Adverse Events Associated With Dementia Therapies Parkinsonism

Use quetiapine; avoid risperidone.

Akathisia

Avoid aripiprazole and risperidone.

Sedation

Use risperidone or aripiprazole; avoid quetiapine and olanzapine.

Metabolic disturbances

Use aripiprazole; avoid olanzapine.

essary to put a patient with delirium on antipsychotics initially and then back off after a week or two, Dr. Cohen told Pharmacy Practice News. If drug therapy is initiated, informed consent must be obtained from the patient, or the patient’s designated family member or caregiver.

Medications frequently used for dementia include aripiprazole (Abilify, Bristol-Myers Squibb), olanzapine, quetiapine and risperidone, which are associated with a variety of adverse effects (AEs), including parkinsonism, akathisia, sedation and metabolic disturbances.

AEs often can be managed by switching medications, Dr. Thomas said (Table 2).

This treatment area has a controversial history, according to Dr. Thomas. In April 2005 and June 2007, the FDA required manufacturers of first- and secondgeneration antipsychotics to add boxed warnings regarding increasing mortality. In 2011, after investigating antipsychotic use in nursing homes, the Office of Inspector General found that 88% of antipsychotics were used for off-label purposes in treating dementia symptoms and 22% were not in accordance with Centers for Medicare & Medicaid Services (CMS) rules regarding unnecessary drug use. CMS hinted that pharmacists were recommending antipsychotics to boost profitability at long-term care pharmacies. The agency has since backed off those allegations but sought to reduce antipsychotic use in nursing homes, with a goal of a 15% reduction by the end of 2012, and possible further reductions in future years. To that end, CMS dictates that gradual dose reductions in medications have to be attempted at least twice a year, in two separate quarters, Dr. Thomas said. If a patient leaves a longterm facility to go to the hospital and is later readmitted, the process should start over again as if it were a new admission.

Dr. Cohen said that he uses his “ABCs of Behavioral Disturbances” to evaluate problematic patients’ behaviors. Find out the antecedent (A) that led to the behavior, the changes in behavior (B) and the consequences (C) of the behavior changes before changing any medications. He noted that it is also imperative to get an accurate, comprehensive medication history to be certain the behavior is not associated with a recent medication change.

Pharmacists’ roles in working with this population are twofold, he said. Document routine attempts to lower antipsychotic medication doses, and advocate for patients. Some antipsychotic medicines may need to be continued for a long time, he said, but the rationale for that must be clearly documented.

—Karen Blum

14 Clinical

Pharmacy Practice News • June 2013

In Brief

Prescription Drug Council Calls for Standards-Based Approach To Preventing Rx Abuse

Poor Results in UC Achieved With Fecal Transplantation

T

O

he National Council for Prescription Drug Programs (NCPDP) announced the availability of the white paper, “NCPDP Recommendations for Improving Prescription Drug Monitoring Programs.” The document details an action plan to help standardize prescription drug monitoring programs (PDMPs) to better track and deter abuse of prescriptions for controlled substances.

Abuse of prescription drugs is the nation’s fastest growing drug problem, according to the Office of National Drug Control Policy.

“Addressing patient safety issues has always been a top priority for NCPDP,” said the group’s president, Lee Ann Stember, in an NCPDP press release. “This white paper offers state governments and other industry stakeholders a road map for how to resolve the challenges of PDMP and realize its potential by using existing industry standards and processes.”

As of February 2013, 49 states— similar legislation is pending in Missouri—have enacted laws to establish a PDMP, an electronic database that collects data on controlled substances dispensed or prescribed within their jurisdiction. However, the absence of business rules governing or allowing sharing of information from state to state and across pharmacies, lack of interoperability among the operational PDMPs, and variation in the timeliness of data reporting make it difficult for states and law enforcement to prevent misuse, abuse and fraud.

According to the NCPDP, the prescription monitoring process is not

integrated into pharmacist and prescriber workflow, and does not support proactive intervention because it does not provide information in a timely manner, making it difficult for pharmacy and medical professionals to identify potential drug abuse and diversion, evaluate patient safety risk and make appropriate clinical decisions before a prescription is written or dispensed.

Providing timely clinical data will also ensure access for patients with a valid medical need for controlled substances to treat their medical conditions, according to the group.

To download the white paper, go to: http://ncpdp.org/ind_WP.aspx —Staff

Some Diabetes Drugs Tied to Pancreatitis, Precancerous Findings

T

he FDA is evaluating new findings that suggest there is an increased risk for pancreatitis and pancreatic duct metaplasia in patients with type 2 diabetes being treated with incretin mimetics.

Drugs that fall under this category include exenatide, liraglutide (Victoza, Novo Nordisk), sitagliptin, saxagliptin, alogliptin and linagliptin. These drugs work by mimicking the naturally occurring incretin hormone that stimulates the release of insulin in response to a meal. They are used along with diet and exercise to lower blood sugar levels in adults with type 2 diabetes, according to an FDA press release.

With regard to incretin mimetics, the warnings and precautions section of drug labels and patient medication guidelines contain warnings about the risk for acute pancreatitis, but the FDA has not communicated previously about the potential risk for precancerous findings.

The current investigation is being undertaken in response to the unpublished findings of a group of academic researchers who examined a small number of pancreatic tissue specimens taken from patients after they had died from

unspecified causes. The FDA has asked the researchers to provide the methodology they used to collect and study these specimens and also to provide the tissue samples so the agency can further investigate the potential toxicity associated with incretin mimetics.

At press time, the FDA had not reached any new conclusions about the safety risks associated with incretin mimetics.

The agency plans to participate in the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute’s Pancreatitis Diabetes Pancreatic Cancer Workshop in June to gather and share additional information (www2.niddk.nih.gov/News/Calendar/PDPC2013.htm). The FDA plans to communicate its final conclusions and recommendations when its review is complete, or when it has additional information to report.

The FDA stated that “patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels.”

—Staff

FDA Approves Test To Evaluate Response to Hepatitis C Therapy

T

he FDA has approved a next-generation viral-load test from Roche to be used in the management of patients with chronic hepatitis C virus (HCV) infection. The COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test (version 2.0) uses a dual-probe approach and is designed to accurately quantitate HCV RNA levels to assess a patient’s response to antiviral therapy.

“The rapidly changing hepatitis C treatment landscape requires tests with an additional layer of protection in detecting and accurately quantifying hepatitis C RNA across genotypes,” said Roland Diggelmann, chief operating officer of Roche’s Diagnostic Division, in a company press release. “This test can play a valuable role in response-guided therapy, helping physicians and patients to better manage the disease and optimize treatment choices and duration.”

The COBAS AmpliPrep/COBAS TaqMan HCV Test is intended for use in the management of patients with chronic HCV infection, in conjunction with clinical and laboratory markers of infection. It is an in vitro nucleic acid amplification test for the quantitation of HCV RNA genotypes 1 to 6 in human plasma or serum. The test can be used to predict the probability of sustained virologic response (SVR) early during a course of antiviral therapy, and to assess response to antiviral treatment, as measured by changes in HCV RNA level.

This real-time PCR-based HCV test is designed for use with Roche’s fully automated COBAS AmpliPrep/COBAS TaqMan system, an established platform for viral-load monitoring of multiple infectious diseases that improves workflow in testing laboratories. The system can be combined with the COBAS P630 instrument that provides an integrated, preanalytical primary tube-handling solution.

—Staff

nly 20% of patients with moderate to severe ulcerative colitis (UC) who were treated with fecal transplantation (FT) experienced clinical and endoscopic improvements following the procedure, according to a small European pean study. y Lead investigator Walter Reinisch, MD, an associate professor in the Division of Gastroenterolo o ogy and Hepatology at the Me e edical University of Vienna, A Austria, conducted the proced d dure in two women and three men m with moderate to severe UC who were resistant to previous other treatments. All participants were undergoing immunosuppressant therapy before re FT and discontinued treatment before transplantation. All patients received antibiotics and probiotics for five to 10 days before the procedure and underwent a single bowel lavage immediately before transplantation. Healthy adult fecal donors were screened for enteric pathogens and viral diseases.

Dr. Reinisch noted that the investigators simultaneously administered a saline-diluted fecal solution via a nasojejunal tube (median 23.8 g) and an enema (median 20 g). All of the patients experienced fever, increased C-reactive protein (CRP) levels and exacerbated UC symptoms during the first procedure, and one recipient also experienced emesis.

The procedure was repeated over three consecutive days in all but one patient, whose fever and increases in CRP levels were more severe and required discontinuation of treatment until five weeks after initial administration.

During the follow-up period, adverse events included upper respiratory tract viral infection, pruritus, erythema, paresthesia of the hip, fainting and tongue blistering. There was no evidence of bacterial pathogens in blood cultures, Dr. Reinisch reported at the United European Gastroenterology Week (abstract P374). Hydrogen-glucose breath tests showed that none of the patients had small bowel bacterial overgrowth.

Twelve weeks after FT, clinical disease activity had worsened in two patients. The Mayo Scoring System for Assessment of UC Activity showed a decrease in median scores from 11 at baseline to 9 among the three patients who did not experience clinical disease flares and who completed the protocol. One patient experienced a Mayo endoscopic subscore change from 3 to 2.

“Although plenty of donor-derived bacteria were established in all of the patients, successful colonization by beneficial bacteria, such as Faecalibacterium prausnitzii, was achieved only in the one patient who had a good clinical response,” Dr. Reinisch noted. His group is investigating whether patients with milder UC experience a more favorable response to FT, citing positive findings from a case series that included six patients with a less aggressive form of UC (J Clin Gastroenteroll 2003;37:42-47).

—David Wild

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16 Clinical

Pharmacy Practice News • June 2013

Critical Care

A Vitamin for the Lungs Thiamine may improve ventilation in the critically ill patient

T

hiamine, a vitamin important to aerobic metabolism, may improve oxygen extraction in critically ill patients, according to the results of a study (abstract 915) presented at the 2013 annual meeting of the Society of Critical Care Medicine.

The pilot study found that administering thiamine intravenously to critically ill patients led to a significant increase in oxygen consumption (VO2). The overall increase remained statistically significant after researchers adjusted for the patients’ Cardiac Index (CI) scores.

“Although we cannot draw any conclusions about clinical significance based on this very small pilot study, our findings suggest that we may be able to improve oxygen extraction in the critically ill,” said investigator Katherine Berg, MD, a pulmonary disease and critical care specialist at Beth Israel Deaconess Medical Center, and instructor of medicine at Harvard Medical School, both in Boston. “Pathologically low oxygen extraction is known to be associated with worse outcome in critical illness, so an intervention that improves oxygen extraction could potentially improve outcomes.”

Researchers previously thought that increasing oxygen delivery (DO2) in order to raise VO2 would benefit patients, but further studies found the opposite to be true for those patients whose VO2 did not rise with DO2, suggesting that oxygen extraction plays an important role in helping these patients.

Dr. Berg and her team studied 16 patients admitted to the medical and surgical ICUs of Beth Israel who were connected to mechanical ventilators.

Researchers used the Cheetah noninvasive cardiac output monitoring system and the GE Compact Anesthesia monitor to establish baseline CI and VO2 data, then administered a single 200-mg dose of thiamine intravenously and monitored CI and VO2 levels for several hours afterward.

On average, oxygen consumption increased by 16 mL/min. In patients with a CI higher than the mean for the group, the increase was even more dramatic, averaging 71 mL/min. However, in patients with low CIs, thiamine had no effect. The patients’ initial thiamine level was not related to the results.

The findings are potentially promising for the treatment of critically ill

patients, said Gerald Maccioli, MD, a physician at Duke Raleigh Hospital and the chair of the committee on quality assurance and performance measures at American Anesthesiology of North Carolina.

“It’s very interesting from both a clinical and a cost-benefit perspective,” Dr. Maccioli said. “Thiamine is drop-dead cheap, so if this intervention could reduce ICU length of stay, the costbenefit ratio would be fantastic.”

However, Dr. Maccioli also said he would like to see the study repeated with more precise tools for monitoring CI and VO2. “If you want a quick snapshot, [the researchers’ methods were] fine; but if you really want to measure VO2, a metabolic cart is a far more precise and accurate instrument,” Dr. Maccioli said. “And if one of the end points of the study is oxygen consumption, I

think it is imperative that you use the measurement tool that is most precise for that end point.”

Results Deemed Preliminary Dr. Berg emphasized the preliminary nature of the results. She said her team did its best to exclude patients with conditions that could have changed the results but was not able to adjust for all potential confounding variables because of the small size of the study.

“The findings certainly should not alter practice at this point, but future studies are planned to see if we can validate our findings,” Dr. Berg said.

“We plan to proceed to a randomized, placebo-controlled trial looking at the effect of thiamine versus placebo on VO2 in a similar patient population.”

—Ajai Raj

Consider Continuing Low-Dose Aspirin Closer to CABG Miami Beach, Fla.—Perioperative aspirin can confer a protective effect following bypass surgery, but little is known about the optimal timing and dosage.

“In the context of cardiac surgery, patients who are taking aspirin therapy preoperatively fare better in terms of decreased morbidity and mortality than patients who don’t,” said Paul Pisklak, MD, a cardiac anesthesia fellow at the Texas Heart Institute, in Houston. “Given that we know that much, the optimal dosage timing of the last dose of aspirin before surgery has not been clearly delineated.”

All 2,634 participants in the study underwent isolated coronary artery bypass graft (CABG) surgery at Texas Heart Institute between July 2005 and May 2011. Those who took their last aspirin dose within 24 hours before surgery reduced their risk for 30-day all-cause postoperative mortality by 57% compared with patients who did not take aspirin so close to surgery or did not take it at all (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.210.90; P=0.02). The retrospective cohort study was presented at the 2013 annual

meeting of the Society of Cardiovascular Anesthesiologists (abstract 6).

“When you look at patients who take aspirin within 24 hours compared with those who don’t take it within 24 hours, the 30-day mortality is roughly half,” Dr. Pisklak said. All-cause mortality following on-pump CABG was 1.5% among the 1,093 patients who took aspirin so close to surgery versus 2.9% among the 1,541 who did not ((P=0.02).

Dr. Pisklak said. “It looks like the benefits outweigh the risks, specifically with the 81 mg dosage.”

In other words, he said, clinicians should not simply tighten the timing, but also should consider dosage.

Interestingly, in a multivariate analysis, only 81 mg per day of aspirin conferred a significant decrease in mortality compared with no aspirin therapy (OR, 0.37; 95% CI, 0.17-0.78; P<0.01).

‘Patients who are taking aspirin therapy preoperatively fare better in terms of decreased morbidity and mortality than patients who don’t.’

—Paul Pisklak, MD “We looked at 48 hours and 72 hours the same way,” Dr. Pisklak said. “The significant results were only within a 24-hour window.”

Although Dr. Pisklak acknowledged that the findings were “not in any way definitive,” he noted that the conventional approach is to hold aspirin for seven days before CABG surgery.

“We might want to reconsider that,”

In contrast, patients on 325 mg of aspirin received no mortality benefit (OR, 0.89; 95% CI, 0.45-1.73; P=0.7) compared with the no-aspirin group. The rate of all-cause 30-day mortality was 1.6% in the 81-mg group, 2.7% in the 325-mg group and 3.5% in those not taking preoperative aspirin.

“It might be a little counterintuitive, but our best guess is any benefit with

325 mg aspirin might be outweighed by possible risk for increased bleeding, but we didn’t specifically look at that,” Dr. Pisklak said.

The researchers were unable to perform a direct comparison of mortality between the 81-mg and 325-mg groups, Dr. Pisklak said.

James H. Abernathy III, MD, MPH, an associate professor of anesthesia and perioperative medicine at the Medical University of South Carolina, in Charleston, who moderated the session, said, “It would be really interesting to see less than 24 hours [administration] of 81 mg versus 325 mg.”

Dr. Pisklak agreed: “It would have been a nice way to tie this all together, but unfortunately, the numbers were not there.”

—Damian McNamara

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18 Clinical

Pharmacy Practice News • June 2013

Geriatrics

Beers Criteria Not a Cure for Polypharmacy Toronto—Using screening tools to capture inappropriate prescribing in the elderly population is not necessarily sufficient when dealing with patients who present with multiple conditions.

One common screen, the American Geriatrics Society (AGS) 2012 updated Beers Criteria for potentially inappropriate medication (PIM) use in older adults, does not capture all possible adverse drug events and interactions, accord-

‘Can we find a better, more personalized way to meet the targets set out by the clinical practice guidelines, given each patient’s unique set of health priorities?’

—Cara Tannenbaum, MD, MSc ing to Barbara Farrell, PharmD, FCSHP, the clinical and research coordinatorpharmacy at Bruyere Continuing Care,

in Ottawa, Ontario, Canada. Dr. Farrell highlighted several downsides to using such screening tools, including a paucity

of information on herbal preparations, during a session on polypharmacy and elder care at the annual meeting of the Canadian Geriatrics Society.

“You need to take a good medication history and capture all OTCs [overthe-counter medications] and [herbal medicines],” Dr. Farrell said. “We need to gather information from the patient about what is working and what is not.”

Dr. Farrell also stressed that the history-taking and evaluation process should involve multiple care providers and be collaborative. Furthermore, she urged clinicians not to assume that patients will not be open to change.

“We think there will be resistance from patients around [the issue of ] stopping medications,” she said. Yet in a majority of cases, “patients ask why they are taking so many [prescriptions]. We need to look at the effect of each medication and if that patient really needs to continue” the entire regimen.

Polypharmacy in elderly patients is largely a function of chronic disease, Dr. Farrell noted. She cited one study that found that 48% of Medicare beneficiaries aged 65 or older had at least three chronic medical conditions and 21% had five or more (Anderson G, Horvath J. Chronic Conditions: Making the Case for Ongoing Care. Princeton, NJ: Robert Wood Johnson Foundation’s Partnership for Solutions; 2002).

Unfortunately, the AGS Beers Criteria for withholding PIMs contains only an incomplete list of medications to avoid and represents the “tip of the iceberg” in terms of inappropriate prescribing, according to Paula Rochon, MD, MPH, the vice president of research at Women’s College Hospital, and a professor in the Department of Medicine at the University of Toronto, in Ontario.

Therefore, it is important to use clinical judgment along with any screening tool and re-evaluate the ongoing need for a drug therapy. “We now know that, in some cases, remaining too long on a therapy may have little ongoing benefit and may even cause harm,” Dr. Rochon said. Where possible, she added, clinicians should consider nonpharmacologic interventions, such as exercise and muscle strengthening for arthritis, before initiating drug therapy.

Dr. Farrell said one strategy is to taper medication doses and involve patients in paying attention to the result of the taper rather than halting a therapy abruptly.

“I have found it’s easier to stop medication if you slowly lower the dose and engage [patients] in monitoring the impact. They feel involved. If the dose can be reduced from 40 to 20 mg, and the patient remains on that dose, at least it has been decreased by half.”

Clinical 19

Pharmacy Practice News • June 2013

Geriatrics The Prescribing Cascade Polypharmacy—or the “prescribing cascade,” as the problem is sometimes called— is fairly common in elderly patients who have several chronic diseases, according to Thomas R. Clark, RPh, MHS, CGP, the executive director of the Commission for Certification in Geriatric Pharmacy (CCGP), in Alexandria, Va. “One of the challenges is that prescribers frequently fail to recognize new symptoms in older adults as side effects of medicines,” Dr. Clark said. As a result, “sometimes older adults may wind up on multiple drugs that are just there to treat side effects of other drugs they are taking.”

Moreover, the presence of several diseases may mean that older adults are being treated by multiple physicians, noted Dr. Clark, who worked previously as a consultant pharmacist in a nursing home. “No one may know what everybody else is prescribing, and older adults frequently wind up on duplicate medicines or drugs that interact with other drugs because no one is looking at the whole picture,” he explained.

‘Sometimes, older adults may wind up on multiple drugs that are just there to treat side effects of other drugs they are taking.’

she said. “Not only are we trying to avoid adverse drug events and drug interactions, but can we find a better, more personalized way to meet the targets set out by the clinical practice guidelines, given each patient’s unique set of health priorities?”

—Louise Gagnon

have many comorbidities. “The question is if it’s the best profile of medica-

tions for this person, given the multiple, coexisting medical conditions,”

ERROR PREVENTION

Next year’s meeting of the Canadian Geriatrics Society takes place in Edmonton, Alberta, Canada, April 9-13.

Visit www.canadiangeriatrics.ca periodically for updates on the meeting.

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—Thomas R. Clark, RPh Automation of health records is not the panacea for that lack of care coordination, because electronic records often are fragmented and there is no single pharmacist or pharmacy that has a complete, comprehensive record for that patient, Dr. Clark added. There is, however, a growing appreciation of the need to streamline drug therapy in elderly patients, particularly if they have comorbid diseases. “We need to get individuals off duplicate drugs or drugs that may not be appropriate,” he said. “It’s an opportunity for us [CCGP] and certified geriatric pharmacists to have more of a role both in hospital and in other settings.”

Cara Tannenbaum, MD, MSc, the research chair at the Institut Universitaire de Gériatrie de Montréal and an associate professor of medicine and pharmacy at the University of Montreal, noted that clinicians have to be vigilant for drug–disease interactions, drug–food interactions and drug–drug interactions.

In addition, Dr. Tannenbaum said, clinical practice guidelines address a condition in isolation and do not account for patients having several conditions, so following guidelines is a particular challenge when patients

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22 Clinical

Pharmacy Practice News • June 2013

Gastroenterology

IBD Combo Therapy May Boost Skin Cancer Risk Hollywood, Fla.—Patients with inflammatory bowel disease (IBD) who are receiving combination therapy with immunomodulators and adalimumab (Humira, AbbVie) are five times more likely than those in the general population to develop nonmelanoma skin cancer (NMSC), a pooled analysis has found.

Results also showed that adalimumab alone did not heighten the risk for malignancies in patients with IBD compared with the general population.

Drawing on data from almost 1,600 patients, the findings fall in line with previous research. “This work shows that the risks with combination therapy are likely driven by thiopurines,” said Millie Long, MD, MPH, an assistant professor of medicine, Division of Gastroenterology and Hepatology at the University of North Carolina School of Medicine in Chapel Hill, who was not involved in the current study but has conducted studies in this area.

The analysis was conducted by a team of investigators led by James Lewis, MD, MSCE, a professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia.

Dr. Lewis and his colleagues analyzed data from several completed or ongoing studies of adalimumab for IBD treatment, including subpopulations that received adalimumab with azathioprine, mercaptopurine or methotrexate.

Cancer rates among 1,594 study participants with IBD, representing 3,050 patient-years, were compared with cancer rates in the general population as

‘‘These These rresults esults p point oint ttoward oward tthe he impact impact of of thiopurines thiopurines explain tto oe xplain the the iincreased ncreased iincidence ncidence off c cancer with o ancer w ith combination combination therapy.’ therapy.’

—James — —J —Ja Ja am me ess L Lewis, ewis ew s, MD MD

estimated in the Surveillance, Epidemiology, and End Results registry. Dr. Lewis’ team controlled for the possible effects of corticosteroid use, smoking status, baseline Crohn’s Disease Activity Index scores, age, race, gender, weight, disease duration and previous anti-tumor necrosis factor use. Their final analysis was presented at the 2012 Advances in Inflammatory Bowel Diseases Crohn’s & Colitis Foundation’s Clinical & Research Conference.

The investigators found that 14 of the 694 participants in the analysis who received adalimumab and an immuno-

suppressant developed a malignancy other than NMSC. Based on those findings, Dr. Lewis’ team determined that for every 100 years of treatment with this combination therapy, there would be an average of 1.1 cases of cancers other than NMSC, which is three times higher than in the general population (standardized incidence ratio, 3.04; 95% confidence interval [CI], 1.66-5.10).

Among those receiving adalimumab with a thiopurine specifically, there was one malignancy other than NMSC per 100 patient-years, translating to a 2.78fold increase compared with the general

population (95% CI, 1.33-5.11).

In separate analyses that looked specifically at the rates of NMSCs, Dr. Lewis and his colleagues found 1.2 cases per 100 patient-years in those receiving adalimumab with any immunosuppressant, which is 4.59 times higher than what is seen in the general population (95% CI, 2.51-7.70). In the subgroup receiving adalimumab with a thiopurine specifically, they found 1.3 cases of NMSCs per 100 patientyears, translating to a 5.05-fold increase compared with the general population (95% CI, 2.61-8.82).

Notably, Dr. Lewis said that when they compared patients who received adalimumab alone with the general population, there were no differences in the rates of any malignancy.

“Because we did not see any signal that adalimumab monotherapy increased the incidence of NMSC or any other cancers, these results point toward the impact of thiopurines to explain the increased incidence of cancer with combination therapy,” he said.

Dr. Long commented that “the sample size was somewhat limited and the risks associated with rarer cancers may not have been detected. Therefore, further data and monitoring are needed as greater numbers of patients are treated with these therapies.”

—David Wild Dr. Lewis has served as a consultant for Abbott. Dr. Long reported no conflicts of interest.

Experts Downplay Link Between Thiopurines and Cancer Las Vegas—Continuous use of thiopurines in patients with ulcerative colitis (UC) increases the risk for non-Hodgkin lymphoma almost threefold, according to a retrospective cohort study of a large nationwide database. But the results may not be strong enough to warrant discontinuing the medications, experts warn.

“The absolute risk for lymphoma [documented in the study] remains very low,” commented Athos Bousvaros, MD, MPH, the associate director of the IBD Center at Boston Children’s Hospital, who was not involved in the study. “Patients with UC who are deriving significant benefit from their thiopurines should probably continue these medications, given how few effective IBD medications we have.”

The study, one of the largest in this field to date, included data from 36,826 patients with UC who were treated in the Southeast Louisiana Veterans Health Care System, in New Orleans, over a 10-year period. Researchers divided

patients into three groups: continuous users of thiopurines, discontinuous users of thiopurines and nonusers. The vast majority (87%) were nonusers. Of the 13% who had used thiopurines, only 15%—or 2% of the total study population—were continuous users.

Over a median follow-up of six years, the incidence rate of lymphoma was 2.8 per 1,000 patient-years in those using thiopurines continuously, compared with 0.7 and 0.8 per 1,000 patient-years for the discontinuous users and nonusers, respectively. After adjusting for age, sex and race, the hazard ratio for lymphoma risk for continuous users, relative to discontinuous users or nonusers, was 3.2 (95% confidence interval, 1.6-6.0). The vast majority of lymphomas were non-Hodgkin, with only 2% of cases representing Hodgkin lymphoma, reported investigator Ali Abbas, MD, MPH, at the annual meeting of the American College of Gastroenterology.

Echoes of Earlier Trials Previous studies have suggested that immunosuppressive drugs, particularly those used in inflammatory bowel disease (IBD), increase the risk for lymphoma. In a 2010 literature review, a team from the United Kingdom concluded that the relative risk for lymphoma from thiopurines in patients with IBD may be increased four- or fivefold relative to those with no exposure to thiopurines ((Aliment Pharmacol Ther 2010;32:119130), but they also noted that the absolute risk remained low; they estimated one additional lymphoma for every 300 to 1,400 years of thiopurine treatment.

Dr. Bousvaros pointed out that the data presented by Dr. Abbas and his coinvestigators are consistent with other published data, including a recent study

by Ashworth et al ((Inflamm Bowel Dis 2012;18:838-843) and an earlier study by Beaugerie et al ((Lancett 2009;374:16171625). Based on the preponderance of

these data, he said that it is now fair to conclude that “thiopurine use is associated with a small but real risk for the development of non-Hodgkin’s lymphoma.”

In regard to this particular study, he noted that one “novel piece of information is that discontinuous use (or discontinuation of the medication) may reduce the risk” for the malignancy.

Still, he re-emphasized, changes in practice are not yet warranted, given the low absolute risk for cancer seen in the trial. A more reasonable intervention, he noted, would be to “consider other options in patients who have not seen benefit from thiopurine treatment after a reasonable [period],” which he defined as a few months of thiopurines administered at a therapeutic level.

—Ted Bosworth Drs. Abbas and Bousvaros reported no relevant financial conflicts of interest.

ABELCET saves time.

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With invasive fungal infections (IFIs) being a leading cause of morbidity and mortality in the most vulnerable immunocompromised patients, polyenes offer effective fungicidal therapy.1,2,3 Abelcet is a key treatment for patients with IFIs who are refractory to, or intolerant of conventional amphotericin B (CAB) therapy. With its single-use vial,4 Abelcet is the only amphotericin B product5,6,7 that does not require reconstitution, saving preparation time and resources. And Abelcet is a cost-effective treatment option that may save you money based on 2012 versus 2013 price offerings.

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1

Fridkin SK. The changing face of fungal infections in health care settings. Clin Infect Dis. 2005;41:1455-1460.

Manavathu EK, Ramesh MS, Baskaran I, Ganesan LT, Chandrasekar PH. A comparative study of the postantifungal effect (PAFE) of amphotericin B, triazoles and echinocandins on Aspergillus fumigatus and Candida albicans. J Antimicrob Chemother. 2004; 53:386-389.

3 Moosa MYS, Alangaden GJ, Manavathu E, Chandrasekar PH. Resistance to amphotericin B does not emerge during treatment for invasive aspergillosis. J Antimicrob Chemother. 2002;49:209-213.

4 Abelcet® Prescribing Information. Gaithersburg, MD: Sigma-Tau Pharmaceuticals, Inc; 2010.

5 Amphocin® Prescribing Information. New York, NY: Pfizer, Inc. 6 AmBisome® Prescribing Information. Deerfield, IL: Astellas Pharma US. 7 Amphotec® Prescribing Information. Warrendale, PA: Three Rivers Pharmaceuticals, LLC. US.

2

abelcet.com

Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs (<0.1% incidence rate with Abelcet). Despite generally less nephrotoxicity of Abelcet observed at a dose of 5 mg/kg/d compared with CAB therapy at a dose range of 0.6 mg/kg/d to 1 mg/kg/d, dose-limiting renal toxicity may still be observed with Abelcet. Renal toxicity of doses greater than 5 mg/kg/d of Abelcet has not been formally studied.

The adverse events most commonly reported with Abelcet are transient chills and/or fever during infusion of the drug.

© 2013 Sigma-Tau Pharmaceuticals, Inc.

ABL-164-0413

24 Clinical

Pharmacy Practice News • June 2013

Hepatology

Hepatitis C Triple Therapy Scores in Large Clinical Trial

P

atients with the most prevalent type of hepatitis C virus (HCV) infection have a substantially higher likelihood of achieving a sustained virologic response (SVR) with a triple therapy that includes an HCV protease inhibitor, a recent report confirmed. The findings validate triple therapy as the first-line treatment for genotype 1 hepatitis C ((Ann Intern Med 2013;158:114-123).

Donald M. Jensen, MD, a professor of medicine and the director of the Center for Liver Diseases at the University of Chicago Medicine, said that the Annals study confirms previous research and an FDA review. “Triple therapy with a protease inhibitor is the current standard of care,” Dr. Jensen said.

After the drugs were approved in 2011, triple therapy quickly became the general practice in urban centers

I-101-41-US-N ®

ABELCETT (Amphotericin B Lipid Complex Injection) BRIEF SUMMARY (SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION) INDICATIONS AND USAGE ABELCETT® is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open-label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy (See DESCRIPTION OF CLINICAL STUDIES IN FULL P.I.).

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functional properrties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipidcomplexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products.

DOSAGE AND ADMINISTRATION The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion. ABELCETT® should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours.

Renal toxicity of ABELCETT®, as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient.

Preparation of Admixture for Infusion: Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of ABELCETT® from the required number of vials into one or more sterile syringes using an 18-gauge needle. Remove the needle from each syringe filled with ABELCET® and replace with the 5-micron filter needle supplied with each vial. Each filter needle may be used to filter the contents of up to four 100 mg vials. Insert the filter needle of the syringe into an IV bag containing 5% Dextrose Injection USP, and empty the contents of the syringe into the bag. The final infusion concentration should be 1 mg/mL. For pediatric patients and patients with cardiovascular disease the drug may be diluted with 5% Dextrose Injection to a final infusion concentration of 2 mg/mL. Before infusion, shake the bag until the contents are thoroughly mixed. Do not use the admixture after dilution with 5% Dextrose Injection if there is any evidence of foreign matter. Vials are for single use. Unused material should be discarded. Aseptic technique must be strictly observed throughout handling of ABELCETT®, since no bacteriostatic agent or preservative is present.

DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of ABELCET® with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of ABELCETT®, or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER. The diluted ready-for-use admixture is stable for up to 48 hours at 2$ to 8$C (36$ to 46$F) and an additional 6 hours at room temperature.

CONTRAINDICATIONS ABELCETT® is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation.

WARNINGS Anaphylaxis has been reported with amphotericin B desoxycholate and other amphotericin B-containing drugs. Anaphylaxis has been reported with ABELCETT® with an incidence rate of <0.1%. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of ABELCETT®.

PRECAUTIONS General: As with any amphotericin B-containing product, during the initial dosing of ABELCETT®, the drug should be administered under close clinical observation by medically trained personnel.

Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of ABELCETT®.

These reactions are usually more common with the first few doses of ABELCETT® and generally diminish with subsequent doses. Infusion has been rarely associated with hypotension, bronchospasm, arrhythmias, and shock.

Laboratory Tests: Serum creatinine should be monitored frequently during ABELCETT® therapy (see ADVERSE REACTIONS).

It is also advisable to regularly monitor liver function, serum electrolytes (particularly magnesium and potassium), and complete blood counts.

Drug Interactions: No formal clinical studies of drug interactions have been conducted with ABELCET®. However, when administered concomitantly, the following drugs are known to interact with amphotericin B; therefore, the following drugs may interact with ABELCETT®: Antineoplastic agents: Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with ABELCET® with great caution.

Corticosteroids and corticotropin (ACTH): Concurrent use of corticosteroids and corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could predispose the patient to cardiac dysfunction. If used concomitantly with ABELCETT®, serum electrolytes and cardiac function should be closely monitored.

Cyclosporin A: Data from a prospective study of prophylactic ABELCETT® in 22 patients undergoing bone marrow transplantation suggested that concurrent initiation of cyclosporin A and ABELCETT® within several days of bone marrow ablation may be associated with increased nephrotoxicity.

Digitalis glycosides: Concurrent use of amphotericin B may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly with ABELCETT®, serum potassium levels should be closely monitored.

Flucytosine: Concurrent use of flucytosine with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with ABELCETT® with caution.

Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.): Antagonism between amphotericin B and imidazole derivatives such as miconazole and ketoconazole, which inhibit ergosterol synthesis, has been reported in both in vitroo and in vivoo animal studies. The clinical significance of these findings has not been determined.

Leukocyte transfusions: Acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte transfusions and ABELCETT® should not be given concurrently.

Other nephrotoxic medications: Concurrent use of amphotericin B and agents such as aminoglycosides and pentamidine may enhance the potential for drug-induced renal toxicity. Aminoglycosides and pentamidine should be used concomitantly with ABELCETT® only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications.

Skeletal muscle relaxants:: Amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g., tubocurarine) due to hypokalemia. When administered concomitantly with ABELCETT®, serum potassium levels should be closely monitored.

Zidovudine:: Increased myelotoxicity and nephrotoxicity were observed in dogs when either ABELCET® (at doses 0.16 or 0.5 times the recommended human dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose) were administered concomitantly with zidovudine for 30 days. If zidovudine is used concomitantly with ABELCETT®, renal and hematologic function should be closely monitored.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:: No long-term studies in animals have been performed to evaluate the carcinogenic potential of ABELCETT®. The following in vitroo (with and without metabolic activation) and in vivo studies to assess ABELCETT® for mutagenic potential were conducted: bacterial reverse mutation assay, mouse lymphoma forward mutation assay, chromosomal aberration assay in CHO cells, and in vivoo mouse micronucleus assay. ABELCETT® was found to be without mutagenic effects in all assay systems. Studies demonstrated that ABELCET® had no impact on fertility in male and female rats at doses up to 0.32 times the recommended human dose (based on body surface area considerations).

throughout the United States and the regimen has been adopted slowly as standard treatment throughout the rest of the country, added Paul Pockros, MD, the director, Center for Liver Diseases, Scripps Clinic, San Diego. “I think [triple therapy] is widely adopted now,” said Dr. Pockros, who was not involved in the study.

In the report, lead author Roger Chou, MD, from the Division of Gen-

ADVERSE REACTIONS The total safety data base is composed of 921 patients treated with ABELCETT® (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were ADVERSE EVENTSa WITH AN INCIDENCE OF *3% (N=556) treated in open-label, non-comparative studies; and 556 patients were treated Adverse Event Percentage (%) of Patients in an open-label, emergency-use Chills 18 program. Most had underlying hemaFever 14 tologic neoplasms, and many were reIncreased Serum Creatinine 11 ceiving multiple concomitant medicaMultiple p Organ g Failure 11 tions. Of the 556 patients treated with Nausea 9 ABELCETT®, 9% discontinued treatment Hypotension yp 8 due to adverse events regardless of Respiratory p y Failure 8 presumed relationship to study drug.

Vomitingg 8 In general, the adverse events most Dyspnea yp 7 commonly reported with ABELCETT® Sepsis p 7 were transient chills and/or fever durrDiarrhea 6 ing infusion of the drug.

Headache 6 Cardiac Arrest Hypertension yp Hypokalemia yp Infection Kidneyy Failure Pain Thrombocytopenia y p Abdominal Pain Anemia Hyperbilirubinemia yp Gastrointestinal Hemorrhage g Leukopenia p Rash Respiratory p y Disorder Chest Pain Nausea and Vomitingg

6 5 5 5 5 5 5 4 4 4 4 4 4 4 3 3

The following adverse events have also been reported in patients using ABELCETT® in open-label, uncontrolled clinical studies. The causal association between these adverse events and ABELCETT® is uncertain.

Body as a whole:: malaise, weight loss, deafness, injection site reaction including inflammation Allergic:: bronchospasm, wheezing, asthma, anaphylactoid, and other allergic reactions a The causal association between these adverse events and ABELCET® is Cardiopulmonary:: cardiac failure, uncertain. pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular fibrillation Dermatological:: maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme Gastrointestinal:: acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, venoocclusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis Hematologic:: coagulation defects, leukocytosis, blood dyscrasias including eosinophilia Musculoskeletal:: myasthenia, including bone, muscle, and joint pains Neurologic:: convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms Urogenital:: oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria Serum electrolyte abnormalities:: hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia Liver function test abnormalities:: increased AST, ALT, alkaline phosphatase, LDH Renal function test abnormalities:: increased BUN Other test abnormalities:: acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau Pharmaceuticals, Inc., at 1-888-393-4584 or by email at drugsafety@sigmatau.com or contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

Special Populations Hepatic Impairment:: The effect of hepatic impairment on the disposition of ABELCETT® is not known.

Renal Impairment:: The effect of renal impairment on the disposition of ABELCETT® is not known. The effect of dialysis on the elimination of ABELCETT® has not been studied; however, amphotericin B is not removed by hemodialysis when administered as amphotericin B desoxycholate.

Pediatric and Elderly Patients: The pharmacokinetics and pharmacodynamics of pediatric patients ()16 years of age) and elderly patients (*65 years of age) have not been studied.

Pregnancy:: There are no reports of pregnant women having been treated with ABELCETT®. Teratogenic Effects. Pregnancy Category B: Reproductive studies in rats and rabbits at doses of ABELCETT® up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, ABELCETT® should be used during pregnancy only after taking into account the importance of the drug to the mother.

Nursing Mothers:: It is not known whether ABELCETT® is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from ABELCET®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:: One hundred eleven children (2 were enrolled twice and counted as separate patients), age 16 years and under, of whom 11 were less than 1 year, have been treated with ABELCET® at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. In one single-center study, 5 children with hepatosplenic candidiasis were effectively treated with 2.5 mg/kg/day of ABELCETT®. No serious unexpected adverse events have been reported.

Geriatric Use:: Forty-nine elderly patients, age 65 years or over, have been treated with ABELCET® at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. No serious unexpected adverse events have been reported.

OVERDOSAGE Amphotericin B desoxycholate overdose has been reported to result in cardio-respiratory arrest. Fifteen patients have been reported to have received one or more doses of ABELCETT® between 7-13 mg/kg. None of these patients had a serious acute reaction to ABELCETT®. If an overdose is suspected, discontinue therapy, monitor the patient’s clinical status, and administer supportive therapy as required. ABELCETT® is not hemodialyzable.

I-101-41-US-N

Manufactured by Sigma-Tau PharmaSource, Inc., Indianapolis, IN 46268.

Distributed by Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD 20878.

eral Internal Medicine and Geriatrics at Oregon Health & Science University, in Portland, and his colleagues assessed 379 studies identified by searching multiple databases dating between 1947 and August 2012. Their analysis revealed that, for HCV genotype 1 infection, “fair-quality trials” demonstrated that triple therapy with pegylated interferon (PEG-IFN), ribavirin and either boceprevir or telaprevir increases the likelihood for achieving SVR by between 22% and 31% compared with dual therapy not including a protease inhibitor.

Triple therapy for HCV genotype 1 infection also was associated with a shorter duration of treatment, “an important consideration given the high frequency of adverse effects associated with interferon-based therapy,” the authors said.

Their findings also confirm the welldocumented increase in adverse events (AEs) for triple-therapy regimens.

Compared with dual therapy, triple therapy including boceprevir was associated with a greater risk for hematologic AEs, and triple therapy including telaprevir was linked to higher rates of anemia and rash.

The authors said their findings have important implications for treatment as well as screening because “screening benefits depend in part on the effectiveness of available treatments.”

Precedent-Setting Further reviewing the trial results, the investigators reported that no study in

Clinical 25

Pharmacy Practice News • June 2013

Hepatology ‘This has been an area of controversy in the field for a number of years. With the slow natural history of hepatitis C, it was difficult to demonstrate the benefits in accepted clinical outcomes.’

—Andrew J. Muir, MD, MHS the past 70 years has focused on longterm clinical outcomes after treatment.

Instead, studies rely on SVR as the primary outcome measure. The authors said that it is difficult to evaluate longterm clinical outcomes other than SVR because HCV infections develop over many years.”

50% Mortality Risk Reduction However, the authors said evidence suggested that SVR is associated with a lower risk for all-cause mortality.

The strongest evidence comes from a cohort study published in 2011 that showed SVR was associated with a 30% to 50% reduction in mortality risk, after adjusting for confounders (Clin Gastroenterol Hepatol 2011;9:509-516). Dr. Chou and his colleagues said the study provides “strong evidence” that virologic and clinical outcomes are linked.

That may be the most important finding in the report, commented Andrew J. Muir, MD, MHS, the clinical director of hepatology, Department of Medicine at Duke University in Durham, N.C. “This has been an area of controversy in the field for a number of years,” Dr. Muir said. “With the slow natural history of hepatitis C, it was difficult to demonstrate the benefits in accepted clinical outcomes. The lack of clear clinical benefit also kept some [practitioners] from accepting the value of hepatitis C treatment.”

The investigators also reported that dual therapy with PEG-IFN alfa-2b was associated with a reduced rate of SVR by about 8% compared with PEG-IFN alfa-2a. However, PEG-IFN alfa-2b was associated with a lower risk for serious AEs, “suggesting potential trade-offs

standard doses, according to evidence from two to four fair-quality trials.

Across all regimens, absolute SVR rates were lower in older patients, black patients, patients with more advanced fibrosis and patients with higher viral load, the researchers noted.

between benefits and harms,” said the authors. For patients with HCV genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood for achieving SVR than was therapy for 24 weeks, and lower doses of PEG-IFN alfa-2b were less effective than

—Christina Frangou The study was supported by the Agency for Healthcare Research and Quality.

The authors reported no relevant conflicts of interest.

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26 Clinical

Pharmacy Practice News • June 2013

Bleeding Management

A Fix for Filling the Oral Anticoagulant Evidence Gap Lack of guidance prompts Virginia center to develop coagulopathy protocol

T

he use of new oral anticoagulants has been increasing, but clinicians have little guidance for the management of bleeding in patients receiving these agents. At Riverside Medical Center, in Newport News, Va., clinicians took matters into their own hands and developed recommendations based on the very limited data available on this subject.

The uncertainty about how to manage bleeding in patients receiving the newer oral anticoagulants prompted Larry Davis, PharmD, the system clinical manager in the Medical Center’s Department of Pharmacy, to assemble a task force composed of medical, administrative, laboratory and pharmacy staff to review the existing literature on the topic and develop a protocol.

The paucity of research left the team to base their recommendations on two sources: the ninth edition of the American College of Chest Physicians’ Chest Guidelines (Chest 2012;141[2 suppl]) and what was, at the time, the only study evaluating the efficacy of prothrombin complex concentrate (PCC) as a reversal agent for the new oral anticoagulants (Circulation 2011;124:1573-1579).

The task force’s review found insufficient evidence to support the use of PCC as a reversal agent for dabigatran (Pradaxa, Boehringer Ingelheim).

Instead, they recommended transfusion of fresh frozen plasma (FFP) for

serious dabigatran-related bleeding and hemodialysis for cases of lifethreatening bleeding.

They did, however, find evidence to support the use of PCC for reversal of rivaroxaban (Xarelto, Janssen) anticoagulation in cases of life-threatening bleeding and recommended a dose of 50 units per kilogram administered intravenously. For serious but non– life-threatening bleeding, they recommended FFP. For newly FDA-approved apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), Dr. Davis said he plans to amend the protocol to specify following the same treatment approach as that used for rivaroxaban.

Dr. Davis, who presented the protocol at the American Society of Health-System Pharmacists 2012 Midyear Clinical Meeting (poster 5-025) in Las Vegas, also said some clinicians had been using recombinant Factor VIIa (rFVIIa; NovoSeven, Novo Nordisk) for warfarin-related bleeding, “although the [protocol] guidelines now do not recommend it.”

To address this, Dr. Davis’ group included a recommendation that rFVIIa be used for warfarin reversal only in cases of life-threatening intracranial hemorrhage that is refractory to treatment with PCC, FFP and vitamin K. For serious but not life-threatening warfarinrelated bleeding, they recommended

‘We are operating in an evidence vacuum when it comes to management of bleeding in patients receiving novel oral anticoagulants ….’

—Nathan Clark, PharmD

infusion of 10 mg of vitamin K, followed by a 5-mg infusion after 12 hours if the initial dose is ineffective.

“The protocol provides a reasonable approach to management of lifethreatening bleeding, but I would be more conservative in managing serious but not life-threatening bleeding,” said Nathan Clark, PharmD, the supervisor of the Clinical Pharmacy Anticoagulation and Anemia Service at Kaiser Permanente, in Aurora, Colo., who was not involved in the development of the protocol. “Obviously, there needs to be a detailed clinical assessment of each patient, but in many cases I would prefer to not actively reverse the agent and risk exposure to blood products that are unlikely to work,” he said.

Dr. Clark added that the protocol recommends coagulation testing for riva-

roxaban and dabigatran, but does not define treatment targets. “This is likely because their role has yet to be defined in the context of clinical trials,” he explained. “Until that is determined, it remains unclear how clinicians should integrate available coagulation testing into the care of a patient with bleeding due to novel oral anticoagulants.”

Those caveats aside, Dr. Clark said he understood the effort behind the protocol. “We are operating in an evidence vacuum when it comes to management of bleeding in patients receiving novel oral anticoagulants, and so the clinical need for an evidence-based protocol is difficult to overstate.”

—David Wild Drs. Clark and Davis reported no relevant financial conflicts of interest.

Pharmacist-Driven Program Improves Compliance

T

o ensure compliance with national anticoagulation patient safety goals and better position their health system to be eligible for federal financial incentives, a team at the University of North Carolina (UNC) Health Care, in Chapel Hill, evaluated a pharmacist-driven discharge process to improve outcomes of patients receiving anticoagulation therapy.

The pharmacist-driven discharge counseling process resulted in a 20% increase in institutional compliance with the Joint Commission’s National Patient Safety Goals (NPSG) and the Centers for Medicare & Medicaid Services’ (CMS) meaningful use requirements, noted Brett Crisp, PharmD, the clinical manager of the Department of Pharmacy.

Dr. Crisp said UNC’s Department of Pharmacy targeted patients requiring anticoagulation discharge counseling, then worked collaboratively with the university’s Information Security Department to develop a compliance report that would accurately reflect rates of completion of discharge counseling documenta-

tion. A committee of pharmacists also standardized educational materials and developed procedures for identifying, counseling and documenting the process.

After a two-week pilot in August 2011, the Department of Pharmacy began to take responsibility for anticoagulation discharge counseling in a phased approach over an eight-week period. After the transition, the team compared compliance rates to assess the effect of pharmacist intervention on the discharge process.

The team tracked compliance rates monthly beginning Jan. 1, 2010. From that time until the pilot period, the average monthly compliance rate was 55.5%.

From the time the study began in August 2011 through March 2012, the average monthly compliance rate increased to 76%—an improvement of 20%.

A ‘Culture Shift’ in Discharging Patients Dr. Crisp said the study showed that the pharmacist’s role in the discharge process, which he called a “culture

shift,” enhanced his institution’s compliance and helped to position it to receive governmental financial incentives by demonstrating meaningful use of electronic health record technology.

Pointing to some of the challenges that the team faced, Dr. Crisp said putting together the automated compliance report, with a checklist for clinicians to use during patient counseling sessions, wasn’t easy. “It was the toughest part. It took nearly six months of working with the Information Security Department and the pharmacists’ group to create a reliable, standard process so that documentation would be consistent,” he said.

To gain acceptance among staff, Dr. Crisp employed the “bottom-up” approach. A task force of departmental managers and front-line clinicians— specialist and generalist pharmacists— helped design the form. “That way, when we rolled it out, surprises were minimized. We were successful because everyone was invested and willing to help out on behalf of patients,” noted

Dr, Crisp, who presented the study at the American Society of Health-System Pharmacists 2012 Midyear Clinical Meeting in Las Vegas.

The study results prove that pharmacists play a unique role in successfully managing patients on anticoagulant therapy, according to William E. Dager, PharmD, a pharmacist specialist at the University of California, Davis Medical Center. “This is important because this in-depth [research] shows that health systems should turn to pharmacy departments to improve the outcomes of patients on anticoagulants,” he said.

“Pharmacists have the training to give more individualized answers to patients’ questions. They understand drug interactions and can describe the entire anticoagulation therapy plan to patients. It intuitively makes good sense.”

—Dana Hawkins-Simons Drs. Crisp and Dager reported no relevant financial conflicts of interest.

Clinical 27

Pharmacy Practice News • June 2013

Critical Care

ICU Checklist May Help Avoid Unplanned Readmissions

W

hen used correctly, a checklist to guide the transfer of patients between the operating room, the ICU and other areas of care can help eliminate unplanned readmissions, Minnesota researchers have found.

In a small quality improvement project, Nathan Smischney, MD, a Mayo Clinic Scholar in the Department of Anesthesiology at the Rochester institution, and his colleagues set out to develop a tool to address the communication gap between the surgical ICU and the wards. They reviewed medical records from June to October 2011, identifying risk factors for ICU readmission and queried surgical teams in the ICU and receiving teams on the orthopedic, vascular and thoracic services about what they would like to know about incoming patients.

The researchers developed a checklist and incorporated it into daily rounds.

The checklist featured seven items addressing the clinical plans for pain, delirium, arrhythmias, respiratory support, antibiotics, diuretics, blood products, anticoagulation, antihypertensive management and any nursing concerns.

The template was placed in charts accompanying patients to their new units. Dr. Smischney’s team then monitored use of the tool over a five-week period in 2012 and distributed surveys to the receiving hospital floor services to measure the quality of sign-out.

The tool was used for 42 of the 141 dismissals during that period (a 30% compliance rate), the investigators noted at the 2013 Annual Congress of the Society of Critical Care Medicine (abstract 163). They identified 17 unplanned readmissions; in none of these cases did the team use the checklist. A preimplementation survey indicated a fairly high understanding of the care plan; a postimplementation survey demonstrated improved communication when the checklist was used.

“It could be considered statistically significant and clinically important regarding a meaningful outcome benefit; however, a cause-and-effect relationship is hard to ascertain due to the small sample size and low compliance rate,” Dr. Smischney said. The low compliance resulted mainly because residents thought it was too long, he noted.

Still, “the surgical teams were very excited about it, as were we,” Dr. Smischney said. “It created a lot of enthusiasm in the ICU and in the surgery department, and that’s the reason for continuing its use.”

The checklist is being revised by a group of fellows to shorten it to the most essential components for ICU staff and receiving surgical teams, he said.

Eugenie Heitmilller, MD, an associaate professor of anestthesiology and pediaatrics, and the vice chair for f clinical affairs at Joh hns Hopkins School of M Medicine, in Baltimore, called the t checklist a “helpful commu unication tool” despite its inconsisstent use. “If they study the checklist st on a larger scale

with a llarger sample size, it mayy very well be shown to be eeffective.”

Dr. Heitmiller, a panelist in a workshop on o implementing checklists at the Society for Pediatric Aneesthesia’s 2012 annual meetting, said that to fullly implement a checklist, physicians and

nurses who will use it most must embrace the document. It must be user-friendly, easily available and widely disseminated.

“If someone sees this as [flawed], they won’t use it,” she said.

“Checklists are good reminders,” Dr. Heitmiller added. “Even when you do the same thing over and over, you can forget something or get distracted. But you have to have it handy.”

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28 Operations & Management

Pharmacy Practice News • June 2013

Reimbursement

Parkview Cuts Readmissions, Keeps CMS at Bay comprehensive care transitions program implemented by Parkview Health in Fort Wayne, Ind., has reduced 30-day readmission rates for its eight hospitals by nearly 35%, from 11.2% in 2008 to 7.3% in 2011 even as patient enrollment increased.

The program’s success has so far kept Parkview out of the crosshairs of the Centers for Medicare & Medicaid Services (CMS), which last year began cutting Medicare payments to hospitals whose readmission rates for certain conditions exceeded specified targets. Indeed, in 2012, CMS reduced Medicare payments by up to 1%, totaling $280 million, to more than 2,000 hospitals that failed to stay under the readmissions ceiling.

That potential financial hit is a huge driver for change—and a compelling reason for starting the Parkview initiative as early as possible in the patient care cycle, noted Greg Johnson, DO, the system’s chief medical officer.

“Reducing readmissions starts at admission,” Dr. Johnson said during a recent webcast conducted by HealthLeaders Media. He explained that Parkview’s program begins by identifying incoming patients who might be at risk for readmission from congestive heart failure, diabetes, pneumonia, acute myocardial infarction or chronic obstructive pulmonary disease (COPD). Other highrisk indicators include patients who had been admitted during the previous 30 days, those with multiple admissions during the past six to 12 months, or those presenting with other high-risk demographic and clinical indicators.

‘No Unhappy Returns’ Once such a high-risk patient has been identified, care transition nurses are alerted and meet with the patient within 24 hours of admission. These nurses, who are former home health care RNs, seek to establish a trusting relationship with the patient and family or caregiver.

“As you assess the patient, you can see all of the things that you could maybe do for this patient to prevent the readmission,” said Joni Hissong, Parkview’s director of care coordination. “Maybe they don’t have transportation back to their follow-up appointment. Maybe they really couldn’t afford the medication [they need] because they don’t have prescription coverage.”

During the hospital stay, the transition care nurses join a collaborative care team with a hospitalist or cardiologist, inpatient case manager and the bedside nurse. Depending on the patient’s needs and condition, other specialists may join the team, such as a dietitian, pharmacist or behavioral health clinician. Team members make the rounds together to

ensure everyone shares the same understanding of the patient’s needs and nothing slips through the cracks.

Tara Jellison, PharmD, Parkview’s clinical pharmacy manager, said pharmacists on collaborative care teams may help select antibiotics and often adjust medication dosing requirements. “They help make sure that all the pieces of the puzzle are in place for the best care of the patient,” she told Pharmacy Practice News.

from the hospital to the home occur seamlessly, preventing hospital readmissions,” she said.

During the hospital stay, Parkview’s transition care nurses screen for patients who might benefit from AIHS’ services and request patient and family approval. If granted, AIHS coaches then visit the patient and family in the hospital to review the transition and followup plans. Within 48 hours of discharge, the coaches visit the patient at home

‘Early, consistent contact helps build what has been missing in preventing readmissions—relationships with the patient.’

—Greg Johnson, DO Such an approach is a major upgrade compared with earlier procedures, Dr. Johnson noted. In the past, patients being discharged from the hospital were simply given a list of doctors to see and were wished good luck, he said. “Well, luck isn’t a great way to manage patients, so we try to make that handoff as seamless as possible,” he explained. For example, by the time of discharge, the transition care nurses will have discussed with the patient and family issues they will likely face at home. They also ensure that follow-up physicians, home health agencies and other caregivers receive the same information. More than a “static” approach to disseminating information, the nurses employ a “teach-back” technique and have the patient and family explain the transition plan in their own words to ensure understanding.

The transition staff also works to identify barriers to obtaining necessary follow-up care, such as lack of transportation or impeding social or behavioral issues. They confirm that follow-up doctor appointments have been made and that the necessary medical information has been sent to and received by those physicians.

and stay in touch by telephone for 30 days. Typically, such coaching services include managing medications; recognizing and responding to “red flags” that could indicate a worsening condition, such as fever onset; and helping the patient take ownership of a core set of personal health information.

“Improving care transitions and reducing hospital readmissions is a team sport,” said Eric A. Coleman, MD, MPH, the director of the care transitions program at the University of Colorado, Denver. “The program at Parkview Health clearly illustrates that by reaching out to community providers such as Aging & In-Home Services of Northeast Indiana, the team is not only strengthened but has the capacity to address the myriad medical and social contributors that drive

‘I can’t emphasize enough the importance of using pharmacists in the discharge process.’

—Deborah Hauser, RPh, MHA

Community Partners Since 2010, Parkview has been partnering with Aging & In-Home Services of Northeast Indiana Inc. (AIHS), a private, nonprofit social service organization in Fort Wayne that has been providing nutrition and counseling services to seniors and the disabled community since 1974. Connie Benton Wolfe, AIHS president and chief executive, said the organization had been helping elderly people understand their options for community services, had been working with family caregivers and had been providing case management services for many years. “However, we weren’t doing any of those things specifically with the intent of helping transitions

15 12

Rate (%)

A

11.2

9

7.3

6 3 0

2008

2011

Figure. Effect of Parkview Health initiative to reduce 30-day hospital readmissions.

readmission,” Dr. Coleman said.

Dr. Coleman, who w was not involved in the webinar, pioneered and developed Care Transitions Interven-tion, a validated model used by more than 700 organizations nationwide, including AIHS. “When it comes to reducing readmission, there is no single solution or magic bullet,” Dr. Coleman continued. “Complex problems often require complex solutions and, as Parkview Health demonstrates, engaging patients and families in self-care is at the center of the solutions.”

Recently, Parkview and AIHS participated in a pilot project with Medicare to assess the effectiveness of the partnership. In the pilot, two part-time AIHS coaches worked with 95 patients who were dually eligible for Medicare and Medicaid and were at risk for heart failure, pneumonia or COPD. The coaches did not perform clinical duties but helped the patients stay on their medication and keep their medical appointments, among other things. The readmission rates for these patients fell by 5% to 7%, a significant reduction given their high-risk status, Dr. Johnson said.

Costly and Harmful Not all health systems are as proactive as Parkview in improving their hospital readmission rates—a fact that is underscored by the millions of dollars in Medicare payment cuts levied by CMS to date. Those penalties are expected to increase because the Affordable Care Act allows CMS to levy fines of up to 2% this year and 3% in 2014. Moreover, in 2015, additional conditions will be added to the list of conditions on CMS’ radar, and likely will include COPD, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty procedures and other vascular procedures, according to the American College of Emergency Physicians.

If hospitals fail to rise en masse to that challenge, there already are data pointing to the economic toll one can expect from such a failure. According to a recent study, inadequate care coordination, including care transitions, led to $25 to $45 billion in wasteful health care spending in 2011 due to unnecessary hospital readmissions and avoidable complications ((JAMA 2012;307:15131516). CMS estimates that hospital readmissions involving Medicare patients alone total $26 billion annually, with more than $17 billion of it potentially preventable, especially if care transitions were to be improved.

•

see READMISSIONS, page 31

LEVETIRACETAM INJECTION

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IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS There ere are no contraindications contr co ntrain aindic dicati ations ons to Le Levet Levetiracetam vetira iracet cetam am Injection Inject Inj ection io for intravenous intrav use.

WARNINGS AND PRECAUTIONS Neuropsychiatric Adverse Reactions Parttial Onset Seiz eizure uress In some adults experiencing partial onset seizures, levetiracetam causes the occurrence of central nervous vous ssystem em adverse reac reactions ctions that cann be classified into the following fo categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnorma abnormalities.

Myooclonic Seizures During ing 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 juvenile myoclonic epilepsy (JME).

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.

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 (â&#x2030;¤2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (â&#x2030;¤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.

Laboratory Tests Although most laboratory tests are not systematically altered with levetiracetam treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.

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Adverse Reactions 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.

Partial Onset Seizures In 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 Seizures In 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 Seizures In the well-controlled clinical study that included patients 4 years of age and older with prima mary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse reaction assoc sociiated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequ equencyy among placebo-treated patients, was nasopharyngitis.

In addition to the adverse reactions listed above, the following adverse events have beenn reportedd in patients receiving marketed levetiracetam worldwide. The listing is alphabetized: ab abnormall liliver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopeeniaa (withh bone marrow suppression identified in some of these cases), thrombocytopenia and weigh ghtt loss os . Alopecia has been reported with levetiracetam use; recovery was observed in majorrity ty of ca c ses where levetiracetam was discontinued. There have been reports of suicidal behavior (in including ing compl c p eted suicide, suicide attempt and suicidal ideation) with marketed levetiracetam.

SPECIFIC POPULATIONS udies in preegna gnantt women. In Pregnancy Category C: There are no adequate and well-controlled stud animal studies, levetiracetam produced evidence of developmentall toxi t x city, incclu luding ng teratogenic effects, at doses similar to or greater than human therapeutic dosses es. Levetiraacet etam sho sh uld be used during pregnancy only if the potential benefit justifies the potentiaal risk s to thhe fet etus.

The effect of levetiracetam on labor and delivery in humans is unknown.

Levetiracetam is excreted in breast milk. Because of thee potent e ial for serious adverse reactions in nursing infants from levetiracetam, a decision shouldd be made whet hethher to discontinue nursing or discontinue the drug, taking into account the importan ance of the drug ug to the mother.

Pediatric Use Safety and effectiveness of levetiracetam injection i inn patie patients below the age of 16 years have not been established.

Geriatric Use Of 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.

Levetitracetam 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 o , care ar should be taken in dose selection, and it may be useful to monitor renal function.

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LEVETIRACETAM INJECTION, USP Rx Only INDICATIONS 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 Epilepsyy - Levetiracetam is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy.

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

CONTRAINDICATIONSS - None WARNINGS AND PRECAUTIONS Neuropsychiatric 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 levetiracetamtreated 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 treatmentt 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 Seizuress - 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 too 0% of placebo patients. Nonpsychotic 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 wass 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 doubleblind, 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 Seizuress - Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.

Hematologic Abnormalitiess - 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 Epilepsyy -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 Abnormalitiess - 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 REACTIONS Clinical Studies Experiencee - 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 Headache Infection Pain Digestive System Anorexia Nervous System Somnolence Dizziness Depression Nervousness Ataxia Vertigo Amnesia Anxiety Hostility Paresthesia Emotional Lability

15 14 13 7

9 13 8 6

3

2

15 9 4 4 3 3 2 2 2 2 2

8 4 2 2 1 1 1 1 1 1 0

Respiratory System Pharyngitis Rhinitis Cough Increased Sinusitis Special Senses

6 4 2 2

4 3 1 1

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 Myoclonicc 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 disorderss Vertigo Infections and infestations

5

3

Pharyngitis Influenza Musculoskeletal and connective tissue disorders

7 5

0 2

Neck pain Nervous system disorders

8

2

Somnolence Psychiatric disorders

12

2

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 Agee 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 General disorders and administration site conditionss

8

7

Fatigue Infections and infestations

10

8

Nasopharyngitis Psychiatric disorders

14

5

Irritability 6 2 Mood swings 5 1 DRUG INTERACTIONS In vitroo 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 nott 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 Pregnancyy - 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 Deliveryy - The effect of levetiracetam on labor and delivery in humans is unknown.

Nursing Motherss - 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 Usee - Safety and effectiveness of levetiracetam injection in patients below the age of 16 years have not been established.

Geriatric Usee - Of the total number of subjects in clinical studies of levetiracetam, 347 were 65 and over. No overall differences in safetyy 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 twicedaily 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 a 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 off consciousness, respiratory depression and coma were observed with levetiracetam overdoses in postmarketing use.

Treatment or Management of Overdosee - 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.

Storagee - 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

Operations & Management 31

Pharmacy Practice News • June 2013

ACCREDITATION continued from page 1

National Association of Boards of Pharmacy (NABP) and the American Society of Health-System Pharmacists (ASHP).

A Strong Base of Support Lynnae Mahaney, BSPharm, MBA, FASHP, CPPA’s executive director, said members of her organization felt a strong need to establish professional standards for community pharmacy practice that come from within the pharmacy profession. “We have direct access to the professionals who have the best knowledge about how services should be provided—that’s one of our distinguishing factors,” Ms. Mahaney said. “CPPA’s standards were developed and vetted by the major stakeholders in community pharmacy practice.”

The importance of instituting a community pharmacy accreditation program reflects the ongoing shift from a dispensing mode of practice to one that is more focused on clinical services and improving patient outcomes, Ms. Mahaney said. Many pharmacy practices are providing services and programs that CPPA wants to see grow, such as immunization, patient adherence and smoking cessation.

“What we’re doing matches up with what’s going on in the U.S. health care environment,” she said. “There’s a huge demand and need for the type of costeffective quality care that pharmacists can provide.”

In order to help pharmacies through the accreditation process, Ms. Mahaney said she’s willing to speak at state association meetings and talk with group purchasing organizations and community pharmacy alliances. CPPA’s website,

READMISSIONS continued from page 28

With the financial and patient care stakes so high, it’s not surprising that although there are laggards, several hospitals are aggressively targeting 30-day readmission rates. Einstein Medical Center, in Philadelphia, for example, generated lots of recent social media buzz for a program that enabled them to slash readmission rates by 50%, as reported in a May 5 Philadephia Inquirer article. John Poikonen, PharmD, an informatics expert and Twitter presence (@poikonen), posted this reaction to the Inquirer article: “50% [reduction]! YIKES.” Pharmacy Practice News covered the Einstein initiative in May 2012, when program developers reported slightly lower reductions in readmissions—approximately 42%. In a follow-up interview, Deborah Hauser, RPh, MHA, the network

‘Accreditation certainly is an administrative burden, and we’re mindful of that. But we firmly believe [it] is the right thing to do, because our first obligation is to take care of patients.’

—Lynnae Mahaney, BSPharm, MBA, FASHP which is under development, expects to go live in early July. Ms. Mahaney said the site will provide information on continuous quality improvement tools, best practices and literature references.

The group also plans to add instructional offerings such as webinars to the website.

URAC an Established Player URAC, a health care accreditation, education and measurement organization, is also developing community pharmacy standards. Terri Smith Moore, PhD, RPh, senior manager of product development at URAC, explained what she sees as the distinguishing factor between her group and CPPA. “We don’t align with one particular segment. We represent and work with [a cross-section] of stakeholders because community pharmacies touch a variety of players—consumers to payers, Ms. Moore said. “Is that an advantage?

Let the marketplace decide.”

Ms. Moore also pointed to URAC’S experience in the field of health care accreditation. “URAC historically has tremendous experience in the accreditation space, developing standards and operational processes that truly meet the needs of an organization,” she said.

“We have a longstanding track record in [this martket] with our pharmacy benefit management, specialty pharmacy and mail service pharmacy accreditations.”

Ms. Moore said most of URAC’s proposed standards focus on the patient care services that community pharma-

cies should provide, such as comprehensive medication management, adherence consultations, immunizations, wellness and health screenings, and chronic disease management.

However, some community pharmacy groups, such as the National Community Pharmacists Association (NCPA), oppose CPPA and URAC’s push to establish accreditation programs. The NCPA sent letters outlining its concerns about the programs to both organizations. The group argues that the programs are costly; duplicative of current state and federal laws and regulations; and rely largely on documentation of policy and procedures instead of actual practice improvements.

The NCPA also believes the standards are focused on subjective procedures and goals—which leaves members to wonder how compliance with the draft standards will be measured. Yet another concern is that although accreditation is voluntary at this point, it may become a requirement in the future. “Ultimately, NCPA is concerned that (accreditation) would become a carrot for larger entities, but a stick for smaller independent businesses,” the letter sated.

Douglas J. Scheckelhoff, MS, vice president of ASHP’s Office of Professional Development, agreed that, over time, payers are likely to look to accreditation to verify that the level of services offered meets their standards. “There comes a point where it becomes the market standard to have accreditation status,” Mr.

‘Complex problems often require complex solutions and, as Parkview Health demonstrates, engaging patients and families in self-care is at the center of the solutions.’

—Eric A. Coleman, MD, MPH pharmacy director at Einstein, said the hospital’s readmissions reduction efforts have expanded significantly since the earlier data collection was done. “We’ve hired a dedicated pharmacist with transitions of care expertise who primarily focuses on the Medicare elderly population,” she noted. “We also have a lead pharmacy technician role called APPLE (ambulatory pharmacy patient liaison empowerment), which focuses primarily on access-to-care issues. (An APPLE a day keeps the readmission/doctor away.)

We were one of 47 hospitals that received a CMS community care transitions pro-

gram grant which enabled us to expand and grow our program. And we have increased our collaboration with other community organizations, including the Philadelphia Corporation for Aging.”

Due in part to these expanded efforts, readmissions reductions at Einstein are now approaching 60%, Ms. Hauser said.

But she stressed that the hospital’s recent successes also can be attributed to a core component of the progam that remains from the early days of the initiative, which launched in fall 2010. Called Medication REACH (validate medication Reconciliation; deliver patient-centered Education;

Reimbursement Scheckelhoff said. “If I’m going to use a pharmacy, I want one that’s meeting a high standard. It’s the same as choosing a cardiologist, a hospital or any other medical service. I would want the one that has passed the test of an external review.”

In the meantime, CPPA and URAC are moving forward with their accreditation programs. URAC is doing more testing and validation before it releases its standards. “We don’t have a specific launch date, but we’re aggressively ... working on our program,” Ms. Moore said.

CPPA’s accreditation program documents are drafted, and Ms. Mahaney said she anticipates opening application for accreditation in June or July.

Both organizations understand that some community pharmacies believe that the accreditation process can be overly taxing and provides no guidance.

But Ms. Moore said URAC takes an educational and interactive approach to the process that can be transformational.

“Accreditation allows organizations to step back and look at themselves more deeply. It allows them to get recognition from payers or those that look closely at quality,” she said. “We want organizations to benefit from the experience and find the process rewarding and helpful.”

Ms. Mahaney agreed that “accreditation can be an administrative burden, and we’re mindful of that by harmonizing our standards with existing quality standards and other accreditation standards such as the ASHP community pharmacy residency. But we firmly believe accreditation is the right thing to do, because our first obligation is to take care of patients.”

—Dana Hawkins-Simons Ms. Mahaney, Ms. Moore and Mr. Scheckelhoff declared no relevant financial conflicts of interest.

resolve medication Access issues during transition; coordinate a comprehensive Counseling approach; Healthy, compliant patient at home), the program’s primary objective is to create a smooth transition for patients between the hospital and home, with an emphasis on safe medication management. Taken together, the discharge services currently offered at Einstein are very robust, Ms. Hauser noted, and include face-to-face education sessions, where patients are given a toolkit that includes pictorial medication cards and medication organizers; dose optimization; stopping unnecessary therapy or adding new ones.

“I can’t emphasize enough the important of using pharmacists in the discharge process,” Ms. Hauser stressed.

“This has made a huge difference.”

—Ted Agres, with additional reporting by David Bronstein

32 Policy

Pharmacy Practice News • June 2013

Compounding ‘We are kicking the can down the road and not truly solving this problem.’

HELP BILL continued from page 1

During a May 9, 2013, HELP committee hearing, Kasey Thompson, ASHP’s vice president of policy, planning and communications, offered a far more positive view. “Simply put, we believe the committee got it right with this proposed legislation,” he said. “It is critical to make the distinction between health systems—which are fully accountable for the comprehensive care of the patient—and a ‘compounding manufacturer’ that prepares and sells its products across state lines without a prescription or knowledge of the patient to a third party for administration.”

Mr. Thompson also suggested that the exemption should be extended to include ambulatory clinics and infusion centers under a health system’s control.

The Bill in Detail The “compounding manufacturer” category that Mr. Thompson cited in his testimony is at the heart of the new legislation. Known as the “Pharmaceutical Compounding Quality and Accountability Act,” (S 959), it is one of several bills introduced following last year’s illnesses and deaths associated with the New England Compounding Center (NECC). The new bill would give the FDA authority to oversee compounding manufacturers as a new category that would include companies that prepare sterile products without, or far in advance of, patient-specific requests from prescribers and then ship the products across state lines. Currently, state pharmacy boards oversee such facilities, in addition to smaller and hospital-based compounding entities.

Hospital and health-system pharmacies, regardless of their size, would be exempt from being considered to be compounding manufacturers, even if they do ship products to their affiliates in other states. In contrast, entities (other than a hospital or health system) that pool sterile products, or that repackage sterile, single-use, preservative-free vials, would be categorized as compounding manufacturers and thus fall under the regulatory eye of the FDA. And such manufacturers could not be licensed as pharmacies in any state.

Among other requirements of the legislation, compounding manufacturers must register with the FDA and be inspected according to a risk-based schedule; prepare products under a state-licensed pharmacist’s oversight and in compliance with current good manufacturing practices; file reports with the FDA every six months; and report adverse events within 15 days and do follow-up investigations and label their products as being compounded and not for resale. These companies also would pay an annual $15,000 “establish-

—Eric Kastango, RPh, MBA ment fee” to help defray the costs of FDA inspections and regulation. (Companies with no more than $1 million in annual gross sales would pay $5,000.)

The new legislation “is a significant step forward in protecting the public from unsafe compounded products,” said HELP committee chairman Sen. Tom Harkin (D-IA). “By clarifying FDA authority over high-risk compounding practices, this bill will enhance protections for patients taking compounded drugs and help prevent crises like last year’s tragic meningitis outbreak,” Mr. Harkin said during the committee hearing. Other bill sponsors include ranking committee member Lamar Alexander (R-TN) along with committee members Al Franken (D-MN), Barbara Mikulsi (D-MN), Pat Roberts (R-KS), and Elizabeth Warren (D-MA).

IACP Not a Fan The International Academy of Compounding Pharmacists (IACP) strongly disagreed that health-system pharmacies should be exempt from rules preventing batch preparation. “We would note that health systems were the primary client of NECC and they purchased these injections in large quantities without a patient script and without a doctor’s order,” said David G. Miller, IACP’s executive vice president and chief executive.

“All legislation or regulation pertaining to compounding should cover all pharmacy practices, whether they are freestanding or located within a hospital or health care facility.” The exemption is “especially questionable in light of the volume and types of compounding done in hospital pharmacies, a substantial amount of which includes sterile compounded preparations,” he said in written testimony.

Mr. Miller expressed concern over specific restrictions and prohibitions on compounding that he noted were included at the behest of large pharmaceutical companies. These include restrictions on dosage variations; a prohibition on compounding FDA-approved drugs even after they have been discontinued by manufacturers because of limited patient populations; a prohibition on repackaging of sterile preservative-free single-dose vials in physician offices, which would categorize doctors as compounding manufacturers; and the prohibition on the pooling of sterile drugs, which would implicate many home infusion pharmacies that administer parenteral therapies.

“It is not the time to attack compounding pharmacies from a commercial perspective as a result of other [monetary] motives,” Mr. Miller said. “Safety should remain the objective of this bill.”

The National Association of Boards of Pharmacy (NABP) supported the legislation but expressed concern that the FDA would have access to records of traditional compounding pharmacies under state regulation. This could “create jurisdictional conflicts with the states and impede the states from investigating or prosecuting a case because the FDA has seized evidence or information,” said NABP executive director Carmen Catizone, MS, RPh, DPh. What is needed instead is increased communication between the states and FDA, he stressed.

Dr. Catizone also expressed concern that only interstate and not intrastate distribution of non–patient-specific sterile compounded products could trigger compounding manufacturing status. Large compounding manufacturers could use this loophole to circumvent FDA scrutiny.

“In fact, some intrastate operations are as large and larger than interstate distributors,” Dr. Catizone told the Senate panel.

Allowing this distinction could unintentionally create a “safe haven” for those “who have the intent to simply avoid the different and federal-based requirements for interstate activities.”

Other Gaps in Oversight Remain Mr. Kastango stressed that the draft legislation does not address all of the issues facing compounding pharmacies. In addition to his concerns over the exemptions for health systems, “I’m not sure how the FDA is going to regulate these compounding manufacturers who are technically creating a new class of drugs that won’t go through the same rigorous NDA [New Drug Application] or ANDA [Abbreviated New Drug Application] review process as does Big Pharma.”

Additionally, many states continue to struggle with budget shortfalls and with getting their inspectors up to speed to survey compounding pharmacies, Mr. Kastango noted, adding that some state boards don’t routinely inspect hospitals because they come under the purview of state health departments, which also lack training and funding. “There also is a lack of commitment from hospital leadership to invest in people, and facilities don’t use robust and scientifically sound qualityrelease checks and tests,” he said. “We are kicking the can down the road and not truly solving this problem.”

Since December 2012, the NABP has been ramping up investigations of compounding pharmacies in conjunction with state pharmacy boards ((Pharmacy Practice News January 2013, p. 1). “Our initial inspections confirmed that what occurred at NECC also was occurring at other facilities in other states,” i.e., the production of drugs in large quantities

and/or without a specific prescription, Dr. Catizone told the Senate panel. He later told Pharmacy Practice News that as long as state boards are permitted to retain the licensure and registration fees that they collect, states “can and will follow through on needed inspections.”

If, on the other hand, the present policy of incorporating those fees into states’ general funds continues, the resulting shortfall in revenue will result in only a small percentage of states being able to complete the inspections, Dr. Catizone noted. “Recognizing that scenario 2 is the more likely to occur, NABP and the states are working collaboratively to share resources,” he said. “ [This] is already being implemented.”

Another Favorable View Tom Van Hassel, RPh, MPA, the director of pharmacy at the Yuma (Arizona) Regional Medical Center and the president of the Arizona State Board of Pharmacy, said he welcomes the new collaborative efforts to improve compounding safety. “The FDA and state boards of pharmacy are working diligently to put in place policies and practices that will ensure that the highest standards will be met,” Mr. Van Hassel said. But he did add an important caveat: “For this to be accomplished requires significant policy and procedure changes as well as welltrained staff and equally well-trained inspectors to make sure that those policies are complete and actually being followed at an individual site.”

“This is the right thing to do,” he said, “and it’s the lack of these oversight steps that led us into the meningitis issue, as well as other compounding and manufacturing issues that have arisen in the past few years.”

Public Citizen Blasts Bill Not all stakeholders are so sanguine about this new regulatory landscape.

In mid-May, Public Citizen blasted the proposed HELP legislation, calling it “a major step backward for U.S. drug safety.” The group focused most of its concerns on the bill’s creation of the compounding manufacturers category, which it sees as “a new regulatory class of drug manufacturers ... that would be exempt from federal premarket approval and related labeling requirements.”

The compounders will be able “to massproduce new drugs without testing for safety and efficacy and undergo inspections only after a drug is on the market.”

The effect of such lax oversight, Public Citizen noted, would be to encourage “the further growth of substandard— and what is currently illegal—drug manufacturing that has been allowed to thrive under the guise of pharmacy compounding. The American public deserves much better.”

—Ted Agres

Policy 33

Pharmacy Practice News • June 2013

Pain Medicine

FDA Changes Tune On Need For Opioid Abuse Deterrence

W

hen in April, the FDA granted approval to Purdue Pharma’s supplemental new drug application (NDA) for its reformulated, abuse-deterrent version of controlled-release oxycodone hydrochloride (OxyContin), many in the field of pain medicine, as well as political and media pundits, surmised that they had figured out a method to the FDA’s madness regarding the development of abuse-deterrent formulations of opioids. By agreeing with the principles of Purdue’s Citizen Petition, namely that the original version of OxyContin was removed from the market because of safety and efficacy reasons, and that the new abuse-deterrent version was superior in terms of risks and benefits, the agency set a new benchmark that all generic versions of OxyContin would be required to meet. This, many decided, was how the FDA was going to handle the prickly issue of generic opioids, which given their lack of abusedeterrent properties, likely would make them a target for abusers, misusers and diverters of opioid analgesics.

Then, on May 10, Endo Pharmaceuticals, the maker of Opana ER (oxymorphone HCl), which also was reformulated with abuse-deterrent properties that made it crush resistant, received a denial for its own Citizen Petition. That petition made many of the same arguments for Opana ER that were made for OxyContin—specifically, that the non–abuse-deterrent formulation was withdrawn from the market for reasons of safety, and the new abuse-deterrent version was therefore safer and should be the measuring stick used for all potential generic versions. This time, however, the FDA did not agree.

At First, Clarity …

The April FDA decision on OxyContin set the stage for this debate, when the agency approved updated labeling for reformulated OxyContin (oxycodone hydrochloride controlled-release) tablets. The new labeling states that reformulated OxyContin is imbued with “physical and chemical properties that are expected to make abuse via injection difficult and to reduce abuse via the intranasal route (snorting),” according to a press release from the FDA, announcing the approval.

The FDA further noted that the reformulated OxyContin is therapeutically equivalent to original OxyContin, which ceased delivery to pharmacies in August 2010, because of safety concerns. (The abuse-deterrent version of the agent was introduced in April 2010.) The

agency added that given the original version’s higher risk for some forms of abuse and misuse, “the FDA has determined that the benefits of original OxyContin no longer outweigh its risks and that original OxyContin was withdrawn from sale for reasons of safety or effectiveness.” Thus, the FDA stated at the time of the new approved labeling that it would not consider for approval new drug applications for generic opioids based on the approval of the original, discontinued version of OxyContin. The original formulation of OxyContin was approved by the FDA in 1995.

“Purdue Pharma is pleased with the FDA’s approval of this new language for the OxyContin label, which will provide important information to health care professionals,” said Gary L. Stiles, MD, senior vice president of research and development at Purdue Pharma.

He added, “Prescriber and patient education remains critically important to ensuring the proper use of opioid analgesics. We strongly encourage prescribers to take advantage of the professional education resources developed as part of the Risk Evaluation and Mitigation Strategies (REMS) for extendedrelease and long-acting opioids.”

Clinicians count on you for accuracy.

Count on CLSI’s AST standards to help you deliver reliable results. new for 2013 Find New or Revised Breakpoints and QC Ranges M100-S23 Vol. 33, No. 1 Replaces M100-S22 Vol. 31 No. 1

M100-S23 Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement

This document provides updated tables for the Clinical and Laboratory Standards Institute antimicrobial susceptibility testing standards M02-A11, M07-A9, and M11-A8.

… Then Confusion Pain management stakeholders were much less sanguine when the Opana decision came down from FDA. “We are extremely disappointed and disagree with [the] decision, and believe that the approval of non–abuse-deterrent formulations of long-acting opioids will contribute to a significant increase in prescription drug abuse,” said Rajiv De Silva, president and CEO of Endo Health Solutions.”

Endo made that case, in part, by citing ongoing epidemiologic research that supports the abuse deterrence of the crush-resistant version of Opana ER. That research showed that 30-day abuse rates for the crush-resistant formulation per 100,000 prescriptions was 79% lower than for generic, non–abuse-deterrent versions of oxymorphone, the company noted in a press release. Based on those data, Endo asked the FDA to reject any abbreviated NDAs for generic versions of oxymorphone that referenced the non– abuse-deterrent version of Opana ER. Furthermore, it requested the suspension of any approved generic formulations of Opana ER currently on the market. Both requests were turned down by the FDA. According to Endo, the FDA decided that the original formulation of Opana

•

M100-S23 | Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement This document provides updated tables for CLSI AST standards M02-A11, M07-A9, and M11-A8.

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34 Policy

Pharmacy Practice News • June 2013

FDA Watch

Kcentra Approved for Urgent Anticoagulation Reversal

O

n April 29, the FDA approved Kcentra (Prothrombin Complex Concentrate, Human) for urgent reversal of acquired coagulation factor deficiency induced by warfarin or other vitamin K antagonists (VKAs) in adults with acute major bleeding, according to the FDA and Kcentra’s manufacturer, CSL Behring.

The only other product approved for this use in the United States is plasma. Made from pooled plasma, Kcentra contains four vitamin K-dependent factors—factor II (prothrombin), factor VII, factor IX and factor X—as well as the antithrombotic proteins C and S. “The FDA’s approval of this new product gives physicians a choice when

deciding how to treat patients requiring urgent reversal of VKA anticoagulation,” said Karen Midthun, MD, the director, Center for Biologics Evaluation and Research, FDA, in a statement. “Kcentra is administered in a significantly lower volume than plasma at recommended doses, providing an alternative for those patients who may not tolerate the volume of plasma required to reverse VKA anticoagulation.” The FDA also stated that, unlike plasma, Kcentra does not require blood group typing or thawing, so it can be administered more quickly.

FDA approval of Kcentra was based on a Phase IIIb trial of 212 evaluable patients comparing the newly approved

drug to plasma for urgent warfarin reversal in acute major bleeding, according to the FDA and CSL Behring.

Kcentra proved similar to plasma in its ability to stop acute major bleeding, with a duration of infusion that was seven times faster than plasma (24 min-

utes vs. nearly three hours). International normalized ratio reduction (≤1.3) at 30 minutes post-treatment occurred in 62.2% of patients receiving Kcentra compared with 9.6% receiving plasma.

Common adverse events in patients receiving Kcentra were headache, nausea/vomiting, arthralgia and hypotension. Because both fatal and nonfatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and postmarketing surveillance, the product carries a boxed warning stating that patients receiving Kcentra should be monitored for signs and symptoms of thromboembolic events.

—George Ochoa

Amitza Gets sNDA for Opioid-Induced Constipation

T

he FDA has approved a supplemental new drug application (sNDA) for lubiprostone (Amitza, Sucampo and Takeda) 24 mcg twice daily as the first oral medication for the treatment of opioid-induced constipation (OIC) in adult patients with chronic noncancer pain (CNCP). The effectiveness of lubiprostone in the treatment of OIC in patients taking diphenylheptane opioids (e.g., methadone) has not been established.

Lubiprostone also is approved in the United States for the treatment of chronic idiopathic constipation in

adults and irritable bowel syndrome with constipation in adult women.

Binding of opioids to peripheral opioid receptors in the gastrointestinal (GI) tract results in absorption of electrolytes, such as chloride, and subsequent reduction in small intestinal fluid. Additionally, activation of enteric opioid receptors results in abnormal GI motility. Together, these processes result in OIC, which is characterized by infrequent and incomplete evacuation of stool, hard stool consistency and straining associated with bowel movements. Approximate-

ly 40% to 80% of patients taking opioids for CNCP report constipation.

Some patients may discontinue opioid therapy and thereby endure pain rather than suffer from the constipation caused by opioids.

Lubiprostone is a specific activator of ClC-2 chloride channels in the intestinal epithelium. Via activation of apical ClC-2 channels in the intestinal epithelium, lubiprostone bypasses the antisecretory action of opiates.

This approval is based on results from Phase III, well-controlled studies of 12 weeks’ duration in patients tak-

ing opioids (among them, morphine, oxycodone and fentanyl) for CNCP, as well as a long-term, open-label safety study, which provides additional support for use in this population. Two of the Phase III studies met their overall efficacy end point, whereas a third Phase II study did not.

In clinical trials of lubiprostone versus placebo, the most common adverse reactions were nausea and diarrhea.

Full prescribing information can be found at www.sucampo.com/products.

—Staff

FDA Approves Breo Ellipta for COPD

T

he FDA has approved Breo Ellipta for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

The approval, which also includes an indication for reducing exacerbations of COPD in patients with a history of flare-ups, follows an April advisory committee recommendation that the drug be approved for the lung disease.

“COPD is a serious [disorder],” said Curtis Rosebraugh, MD, MPH, the director of the FDA’s Office of Drug Evaluation II, Center for Drug Evaluation and Research, Silver Spring, Md. “The availability of new long-term maintenance medications provides additional treatment options for the millions of Americans who suffer with COPD.” Breo Ellipta contains a combination of fluticasone furoate, an inhaled corticosteroid, and vilanterol, a long-

acting β 2-adrenergic agonist (LABA). The drug’s approval was based on a study of 7,700 patients with a clinical diagnosis of COPD. Patients who were treated with the new medication experienced significantly improved lung function and fewer exacerbations compared with placebo.

According to the FDA, Breo Ellipta labeling will include a boxed warning indicating that LABAs, such as vilanterol, are associated with an increased risk for asthma-related death. The agency added that Breo Ellipta’s safety and efficacy in asthma patients have not been established, and thus the new medication is not approved for the treatment of asthma. The drug should not be used as a rescue therapy to treat acute bronchospasm and is not

recommended for people younger than 18 years of age, the agency added.

Clinical studies indicate that Breo Ellipta may cause other potentially serious side effects, including an increased risk for pneumonia (some fatal cases) and bone fractures, according to a press release from San Francisco-based Theravance, which developed the drug in collaboration with GlaxoSmithKline.

The most common adverse reactions (>3%) reported by patients using Breo Ellipta included nasopharyngitis, upper respiratory tract infection, headache and oral candidiasis.

The product will be available in the United States in the third quarter of this year, according to Theravance.

—Staff

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Policy 35

Pharmacy Practice News • June 2013

FDA Watch

Invokana Approved For Type 2 Diabetes

T

he FDA has approved canagliflozin (Invokana, Johnson & Johnson) tablets, used with diet and exercise, to improve glycemic control in adults with type 2 diabetes.

Canagliflozin works by blocking the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels in people with diabetes in whom these levels are high.

Its safety and efficacy were evaluated in nine clinical trials involving more than 10,285 patients with type 2 diabetes. Trial results showed improvement in hemoglobin A1c and fasting plasma glucose levels, according to an FDA press release.

The FDA said it is requiring five postmarketing studies for canagliflozin, including a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities and adverse pregnancy outcomes; and two pediatric safety and efficacy studies.

Canagliflozin has been studied as a stand-alone therapy and in combination with other therapies for type 2 diabetes, including metformin, sulfonylurea, pioglitazone and insulin. The newly approved medication should not be used to treat people with type 1 diabetes; those who have increased ketones in their blood or urine; or those with severe renal impairment, end-stage renal disease or in patients on dialysis, according to the FDA. —Staff

Ilaris Gets FDA Nod For Rare Arthritis

T

he FDA has approved canakinumab (Ilaris, Novartis) for treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and older.

Administered as a once-monthly subcutaneous injection, canakinumab is the first interleukin-1 beta (IL-1β) β inhibitor approved for SJIA, according to Novartis. Tocilizumab (Actemra, Roche), an IL-6 inhibitor, is also approved for SJIA, but is administered twice a month as an hour-long IV infusion.

Canakinumab’s approval is based on two Phase III trials in SJIA patients, aged 2 to 19 years, according to a press release from Novartis. In a randomized, double-blind study, 84% of patients treated with one dose of canakinumab (n=43) achieved the primary end point of the adapted pediatric American College of Rheumatology 30 (ACR30) at day 15 compared with 10% (n=41) of patients who received a placebo injection.

The second study, which included

both open and randomized stages, found that patients who received canakinumab were more likely to reduce or discontinue their use of corticosteroids, and to experience fewer arthritis flares, than patients given sham injections.

“The efficacy of Ilaris, along with its monthly subcutaneous dosing, make it an exciting new option for children who are living with this debilitating disease,” said study investigator Daniel Lovell, MD, MPH, of Cincinnati Children’s Hospital Medical Center, in a statement.

“Additionally, the potential to reduce

corticosteroid use is particularly beneficial in this patient population given the side effects associated with long-term use of corticosteroids in children.”

SJIA is the second indication for canakinumab, which also is indicated for cryopyrin-associated periodic syndromes. Canakinumab acts by inhibiting IL-1β, an immune system component that is excessively produced in certain inflammatory diseases.

Canakinumab may interfere with immune response to infection, increasing the risk for serious infections and

malignancies, according to Novartis. Physicians should use caution when administering canakinumab to patients with infections, a history of recurring infections or underlying conditions that may predispose to infection. The most common adverse events are cold symptoms (including runny nose and sore throat), upper respiratory tract infection, pneumonia, urinary tract infection, gastroenteritis, stomach pain and injection site reactions, the company said.

—George Ochoa

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36 Policy

Pharmacy Practice News • June 2013

Pain Medicine

DETERRENCE

ER better resisted attempts to crush it than the older version, “study data show that the reformulated version’s extended-release features can be compromised when subjected to other forms of manipulation, such as cutting, grinding or chewing, followed by swallowing.” The agency also maintained that reformulated Opana ER could still be manipulated easily for injection, “despite Endo’s claim that these tablets have ‘resistance to aqueous extraction (i.e., poor syringeability).’” The FDA added that the reformulated drug “can

continued from page 33

ER was not withdrawn from the market for safety or effectiveness reasons.

Because of this, the agency will continue to allow existing generic versions of the original formulation of oxymorphone to remain on the market and allow new products to be submitted for FDA approval.

In a statement regarding the rejection of Endo’s petition, the FDA stated that while the new version of Opana

be prepared for snorting using commonly available tools and methods.”

A Tale of Two Rulings News of the two rulings was met with confused reactions by several thought leaders in pain medicine.

“The OxyContin approval sends a very positive message for developers of other [potential] oxycodone extendedrelease abuse-deterrent formulations,” said Joseph Pergolizzi, Jr, MD, senior partner in the Naples Anesthesia and Physician Associates Group, in

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Volu ume 40 • Number 4 • April 2013

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in this issue CLINICAL

3 12

Safety, quality pearls: collaboration a key to successs.

E-alerts boost venous thromboembolism prevention.

TECHNOLOGY

16 23

Health IT pearls: telepharmacy, smarter IV pumps and more.

When the carousel stops: a plan for drug dispensing.

POLICY

26

IOM urges trackand-trace system for protecting drug supply

OPERATIONS & MGMT

30

The case against overuse of proton pump inhibitors.

EDUCATIONAL REVIEW

Medication Errors: A Year in Review See insert after page 8.

REPORT Teflaro® (ceftaroline fosamil) for the Treatment of Acute Bacterial Skin and Skin Structure Infections Caused by Designated Susceptible Bacteria See insert after page 16.

OIG Says REMS Program Falling Short Of Goals

A

fter four years, the effectiveness of the FDA’s mandatory Risk Evaluation and Mitigation Strategies (REMS) program remains open to question because drug companies have failed to comply with key reporting requirements and the agency lacks adequate enforcement authority to take action against them, according to a report by the Department of Health and Human Services’ Office of Inspector General (OIG).

Nearly one-fourth of the drug companies 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

•

H

ospital pharmacists face several ral challenges in h helping l i manage antibiotic-resistant, gram-negative superbugs that produce carbapen nemases.

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

A report in the March issue off Infection Control and Hospital Epiidemiology (2013;34:259-268) foun nd that the proportion of K. pneumon niae cases resistant to carbapenems increa creaased d from 0.1% in 2001 to 4.5% in 2010 0. ““That is huge,” said Robert Rapp, PhaarmD, D a professor of pharmacy and sur-gery emeritus at the University of Kentucky Medical Center in Lexington, who is one of manyy pharmacists concerned about KPC C. Those concerns were compound ded by a Centers for Disease Control aand Prevention’s report on the rising prrevalence of carbapenem-resistant en nterobacteriaceae (CRE). According to the h report, in the last decade, hospitals have seen a fourfold increase in CRE, with most of the increase attrib-utable to Klebsiella species (MMWR ( 2013;62:1-6).

•

see REMS, page 24

Addiction Cited As Powerful Diversion Driver

C

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

•

In Ranking of Superbugs, Klebsiella Takes the Lead

see CHALLENGE, page 20

t

A Pharmacist’s Take

see SUPERBUGS, pag ge 6

Shifting the Main Focus off Acid id Suppression to the Critically Ill Las Vegas—A San Antonio health care system 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, researchers 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-

9

Naples, Fla. The approval “is a great win for public health policy,” he said.

“Unfortunately, the negative ruling on Endo’s Citizen Petition related to Opana ER with Intac technology is somewhat concerning, because now non–[abuse-deterrent formulations] of this potent opioid analgesic could be more readily available.”

American Academy of Pain Medicine (AAPM) President Lynn Webster, MD, said pushing for extending tamper-resistant requirements for all opioid analgesic drugs is a chief focus of the AAPM for 2013. “It would be ironic and counterproductive if the FDA allows generics without tamper-resistant properties to compete with branded tamper-resistant formulations since they also have mandated a comprehensive REMS for the same long-acting/extended-release opioid formulations,” Dr. Webster told Pharmacy Practice News. “Since abusedeterrent technology is now available, all new formulations should be required to have abuse-deterrent properties.

Failure to require abuse-deterrent properties in new formulations or generics would be a setback in the battle to fight prescription drug abuse and unintentional overdose deaths.”

ber 2012 Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP), were undertaken to address persistent inappropriate 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-receptor agonists constantly, and

•

see STRESS ULCERS, page 30

New Products GlucoCareTM IGC System insulin dosing calculator.

A new medication safety initiative from Medi-Dose®, Inc./ EPS®, Inc.

See page 19.

See page 27.

David Craig, PharmD, BCPS, the director of the Pain and Palliative Care Specialty Residency at the H. Lee Moffitt Cancer Center and Research Institute, in Tampa, Fla., commented that the FDA “is giving mixed messages to patients and health-care professionals with their recent decision to not require Oxymorphone ER generics to contain abuse-deterrent technology.” However, “I don’t agree that alll ER/LA opioids must contain some form of abuse-deterrence, because they are not completely ‘abuse-resistant.’ Anyone wishing to abuse something sooner or later will find a way around the well-intended technology, and to my knowledge nothing exists to prevent someone taking more of these medications than prescribed.”

In terms of next steps, “the FDA should provide more information to manufacturers on why this decision was made and how future [abuse deterrence] technologies should be developed to meet their criteria,” Dr. Craig said. “We should also not forget that opioid overdose deaths in the United States are often caused by multiple medications. Thus, focusing solely on abuse deterrent-technologies for ER/ LA opioids while ignoring all of the immediate-release opioids and other potentially lethal product combinations (e.g., benzodiazepines, barbiturates, alcohol, heroin) is a very nearsighted approach to this problem.”

—Donald M. Pizzi

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2013 Oncology Pharmacy Preparatory Review Course for Home Study

ACCP July 1, 2013 This course is designed to help oncology pharmacy practitioners prepare for the Board of Pharmacy Specialties Oncology Pharmacy Specialty Certification examination, and obtain a broad and detailed update to their knowledge in oncology.

2

Aulton’s Pharmaceutics: The Design and Manufacture of Medicines: Fourth Edition

Michael E. Aulton July 12, 2013 An understanding of pharmaceutics is therefore vital for all pharmacists and those pharmaceutical scientists who are involved with converting a drug or a potential drug into a medicine that can be delivered safely, effectively and conveniently to the patient.

3

Basic Skills in Interpreting Laboratory Data: Fifth Edition

Mary Lee May 20, 2013 The book enhances the skills pharmacists need by providing essential information on common laboratory tests used to screen for or diagnose diseases and monitor the effectiveness and safety of treatment and disease severity. Students will find this guide a clear and useful introduction to the fundamentals of interpreting laboratory test results.

4

Lange Pharmacology Flash Cards, Third Edition

Suzanne Baron, Christoph Lee April 22, 2013 These 230 cards deliver a fun, fast, high-yield review for the USMLE Step 1. With these cards, you’ll be able to focus on must-know information for the boards, compare and contrast drugs, understand the basic principles of drug classes that are board-relevant, mechanisms of action, c ca uses and clinical a d side s de effects e ects and a d review e e the t e clinical c ca aspects of o disease. d sease

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Mosby’s Drug Reference for Health Professions

Mosby April 15, 2013 This reference is the must-have portable drug handbook for every curr rent or aspiring health professional in the field today. This updated edition features concise, reliable information that is easy to navigate, with alphabetically listed monographs for more than 900 generic drugs, including 4,500 trade-name drugs for both the U.S. and Canada.

6

Pediatric Injectable Drugs

Stephanie J. Phelps June 25, 2013 The 10th edition of this invaluable reference has grown to cover 238 drugs commonly used in the treatment of infants and children, including 20 new to this edition. The book covers neonates through adolescents, with age-specific dosing and administration guidelines throughout.

7

Pharmacotherapy Self-Assessment Program (PSAP): 2013 Book 1 Cardiology/Endocrinology

ACCP January 15, 2013 ACCP’s premier home study series provides clinical pharmacists with pertinent therapeutic updates to enhance and assess their practice skills and improve patient outcomes. Now updated with features such as enhanced online access, summary graphics and multimedia elements, this is an excellent home study tool for the pharmacotherapy specialist.

8

The Textbook of Pharmaceutical Medicine: Seventh Edition

John P. Griffin; John Posner; Geoffrey R. Barker May 28, 2013 This new edition reflects the enormous changes in the environment in which the pharmaceutical industry and the pharmaceutical physician operate, many of which have occurred since the last edition was published. More consideration is given to ethical issues across all areas of t e book. the boo PPN0613

38 Policy

Pharmacy Practice News • June 2013

Supply Chain

Some MDs Blame GPOs for Chronic Drug Shortages F

rustrated with ongoing shortages of key drugs, a new grassroots group is calling for the repeal of federal legislation that permits group purchasing organizations (GPOs) to engage in what they call collusive and anticompetitive activities. Several senior U.S. lawmakers have asked the Government Accountability Office (GAO), the investigative arm of Congress, to look into the allegations that GPOs aree at least partly responsible for th he nation’s drug shortages.

“We are convinced that the anticompetitive contracting and pricing practices, kickbacks and self-dealing of hospital GPOs are the root cause of this public healtth emergency,” said anesthesio ologist Robert A. Campbell, MD, the co-chair of the new group, Physicians Against D Drug Sh Shortages (PADS) (PADS).

“We’re launching a national campaign to build public awareness of these anticompetitive practices and press Congress to halt them,” said Dr. Campbell, who also is the vice president of the Pennsylvania Society of Anesthesiologists and a state delegate to the American Society of Anesthesiologists (ASA).

‘We are convinced that the anticompetitive contracting and pricing practices, kickbacks and self-dealing of hospital GPOs are the root cause of this public health emergency.’

—Robert A. Campbell, MD Dr. Campbell described PADS as “a small group of physicians who met at the recent ASA meeting. After a totally unsatisfactory panel on drug shortages, we chose to exchange emails and explore an economic explanation for drug shortages. Our solution will save at first $35 billion per year in health care costs. Once competitive forces are restored in the health care supply chain, even more savings will be realized.”

Any attempt to link GPOs to drug shortages is an “irresponsible and dangerous distraction,” countered Curtis Rooney, the president of the Healthcare Supply Chain Association (HSCA), a trade association representing 14 GPOs, including the nation’s five largest. “The true cause of drug shortages is manufacturing problems, disruptions and barriers to entry in getting new suppliers online when there is a disruption in supply. The fact is that GPOs are taking a variety of creative and innovative steps to reduce drug shortages,” Mr. Rooney said.

GPOs negotiate contracts with manufacturers and vendors of pharmaceuticals and other medical products on behalf of their customers, typically hospital groups and other large health care organizations.

About 72% of all hospital purchases are made through GPO contracts. GPOs leverage their collective purchasing power in order to keep costs low for their custom-

ers. Vendors pay GPOs “administrative” fees, typically based on a percentage of sales and capped by law at 3%. GPOs have been allowed to collect these fees since 1986 through a “safe harbor” provision added to the Social Security Act’s Anti-Kickback statute, which would otherwise prohibit the practice.

“By exempting GPOs fr from criminal prosecution for taking kickbacks from vendors, [the exemption] has givven rise to monumental conflicts of interest and perverse incentives that p have undermined competition and innovation and inflated costs in the health care supplies, devices and generic drug marketplace—with tragic m co onsequences,” said Phillip L. Z Zweig, MBA, the executive i di director of PADS. Mr. Zweig worked for medical device companies between 1999 and 2008 but no longer has financial ties to the industry. His current work with PADS is pro bono, he said.

“Our goal is to end the generic drug shortage crisis by restoring integrity and free market competition to ... the entire U.S. health care supplies industry,” Mr. Zweig said. “To accomplish that, we’re pushing for the repeal of the Medicare anti-kickback safe harbor provision, which created the GPO ‘pay to play’ scheme in the first place. As a result of this misguided legislation, the GPOs now exert a stranglehold on the entire hospital supplies marketplace. They’ve rigged the market.

PADS intends to end their reign of terror.”

PADS, Mr. Zweig added, does not want to abolish GPOs, but rather return them to the pre–safe harbor system—“which worked fine from the early 1900s to the early 1990s.”

But Phil Johnson, MS, RPh, the oncology director at Premier Inc., the nation’s second largest GPO by purchasing volume, said the accusation that GPOs have eliminated free market forces is “uninformed and wrong.” In fact, “GPOs encourage the free market by competitive bidding and multiple rewards for the best supplier performance,” Mr. Johnson told Pharmacy Practice News. “Consider that Premier represents approximately 2,700 hospitals and more than 90,000 non-acute sites. Our members determine the acceptable drugs or medical supplies within a therapeutic category, and Premier obtains strong contracts ensuring multiple vendors and product choices. With GPOs, the best drugs within the category, as determined by our member providers—physicians and pharmacists—develop strong contracts with competitive pricing.”

But a June 2012 report by the House Committee on Oversight and Government Reform concluded that GPOs have contributed to the current shortage of generic injectable medications because of pressures that the purchasing organizations exert on manufacturers and suppliers. “Companies that cannot produce a drug at large enough output levels to take advantage of the economies of scale—often because they lack the guaranteed source of demand that GPOs provide—will stop producing the drug or will neglect to enter the market,” the House report stated.

The controversy surrounding GPOs is not new.

Over the years, hospital systems have claimed that GPOs have saved them billions of dollars annually

The accusation that GPOs have eliminated free market forces is ‘uninformed and wrong.’

—Phil Johnson, MS, RPh in purchasing costs, while lawmakers and others have worried about the anticompetitive or unethical practices of GPOs. The GPO industry has adopted voluntary codes of conduct and since 2005, many companies have participated in an annual survey of their contracting practices.

In November 2012, six senior members of the House of Representatives asked the GAO to investigate whether GPOs are a “driving cause” of drug shortages. The lawmakers—Democrats Edward J. Markey (Mass.), John Dingell (Mich.), Frank Pallone (N.J.), Diana DeGette (Colo.), and Henry A. Waxman and Anna G. Eschoo (Calif.)—also said that shortages of critical drugs have forced hospitals and other providers to rely on unregulated compounding pharmacies, such as the New England Compounding Center, the Framingham, Mass., firm that has been blamed for last year’s deadly outbreak of fungal meningitis and other infections caused by contaminated epidural steroid injections.

“As Congress fully investigates all the causes of the tragic meningitis outbreak in an effort to protect patients in the future, we need to look at the role GPOs play in the occurrence of drug shortages that could lead to increased reliance on compounding pharmacies,” Mr. Markey said in a statement.

Expert practitioners and academics concurred.

“This broken generic drug market, which is the direct consequence of unethical GPO drug purchasing contracts legalized by Congress, must be fixed immediately,” said Joel B. Zivot, MD, the medical director of the cardiothoracic intensive care unit at Emory University Hospital, in Atlanta, in a statement.

“GPOs are a major, if not the primary, contributor to the market distortions in the health care industry in the United States,” added S. Prakash Sethi, PhD, a university distinguished professor at Baruch College, in New York City. “Through exclusive contracting, which has given GPOs effective monopolistic control of this industry, they have contributed to product shortages and disincentives for legitimate producers to manufacture and stock essential drugs. At the same time, they have given rise to unscrupulous manufacturers to produce and market substandard drugs and thereby expose the patient population to serious health risks.”

But Thomas G. Moore, the president of Hospira Inc., blamed shortages of injectable drugs on manufacturing problems and disputes any link between drug shortages and the meningitis outbreak or between drug shortages and GPOs. “The practice of hospitals contracting with a GPO in order to aggregate their purchasing power is not a factor in drug shortages,” Mr. Moore wrote in a Nov. 19, 2012, letter to the lawmakers. “It has been Hospira’s experience that GPOs do not limit the manufacturers who can contract with the GPO, especially in the circumstance of a drug shortage.”

—Ted Agres

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

Horsham, Pennsylvania

T

he 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

KEY TO TABLES

be effective, they must become a priority.

1

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 mistakes 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 potentially hazardous drug-use situations; • Explore and understand the root causes of medication 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 prevent medication errors; • Respond to potentially hazardous situations before errors occur; and

Computerized 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 orderscreening capability.

2

Bar 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.

4

Automated dispensing cabinets (ADCs)—These are robust, point-ofuse dispensing systems. ADCs should be integrated with the health care facility’s information systems 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.

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P H A R M AC Y P R AC T I C E N E WS • J U N E 2 0 1 3

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Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Technology

Title

Problem/Discussion Point

Recommendation

Clear Care (CIBA Vision) contact lens cleaner still burning eyes

• People who wear contact lenses continue to be injured when using Clear Care as a multi-purpose solution for rinsing and soaking lenses.

• Clear Care solution contains 3% hydrogen peroxide, which should never come in contact with the eyes.

• People commonly miss the statement on the product label informing them to soak their lenses only in the special contact lens holder.

• ISMP has contacted the manufacturer and FDA for a labeling change to better distinguish Clear Care solution from other solutions.

• Outpatient pharmacies that carry Clear Care or generic equivalents should separate the product from soaking solutions or put it behind the counter so instructions can be communicated orally.

Concentrated EPINEPHrine mistaken as lidocaine with EPINEPHrine

• Mix-ups between a local injection of EPINEPHrine 1:1,000 and lidocaine with EPINEPHrine (1:100,000) continue to happen even though this resulted in the death of a child more than 15 years ago.

• Supply EPINEPHrine for topical use in a pour-bottle with an auxiliary label that states “TOPICAL.” • Or, replace the need for vials of topical EPINEPHrine with presoaked EPINEPHrine pledgets prepared in advance of procedures.

• Do not place medication meant for injection (eg, local anesthetic) in an open container (eg, bowl).

2

Confusion between EPIPEN (EPINEPHrine injection) training device and active pen

• EpiPens are only available in a 2-Pak containing 2 EpiPens and a nonfunctioning training pen.

• The training pen looks similar to the actual EpiPen. • An emergency department’s ADC was accidentally stocked with an EpiPen training device instead of the active pen.

• If hospitals store EpiPens on clinical units or in code carts, the pens should be removed from their carton and only the active pens should be stored in unit stock.

• Be sure staff members know about the risk for confusion between the training pens and actual pens.

2

How much insulin is in a 3-mL vial?

• Eli Lilly introduced insulin 100 units/mL, 3-mL vials in 2009.

• A nurse prepared an insulin drip (250 units/250 mL), reading the U-100 (100 units/mL designation) as 100 units per vial. She then used 2.5 vials of insulin (7.5 mL) instead of 2.5 mL, which resulted in the bag containing 750 units instead of 250 units.

• Fortunately, the solution was never administered to the patient because the order was discontinued before the infusion was started.

• ISMP recently communicated with Lilly and the FDA about this issue so each could further investigate whether or not the per-container amount should be listed.

• Whenever possible, pharmacy should prepare, label, and dispense all insulin infusions.

• If this is not possible, an independent doublecheck of the preparation should occur before the infusion is administered.

Important change with heparin labels

• The FDA announced that, effective May 1, 2013, heparin vial labels must express the strength per the entire container followed by the strength per mL in parentheses.

• Staff have mistaken the per mL strength as the total dose contained in a vial, which has led to heparin overdoses.

• There will be a transition period where both labeling styles will be on the market.

• To minimize the potential for medication errors, purchasers and pharmacy managers should strongly consider separating the supplies of “current” and “revised” heparin, using all of the “current” heparin products before using products with the “revised” label.

Inadvertent IV injection of EXPAREL (bupivacaine liposome suspension injection, Pacira Pharmaceuticals)

• Exparel, a local anesthetic intended for infiltration into a surgical wound to produce postoperative analgesia, looks a lot like propofol, a drug used for sedation.

• Both products are a milky white emulsion used in the operating room, so unlabeled syringes could result in misadministration, potentially resulting in a fatality.

• Separate the storage of these 2 drugs.

• Require proper labeling of all syringes that contain propofol or Exparel, even if the medication will be immediately used.

• Establish a routine double-check process to make sure that any unused medication in a syringe containing Exparel never leaves the sterile field without a label.

• See additional recommendations at www.ismp. org/NAN/files/NAN-20120318.pdf.

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Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Technology

Title

Problem/Discussion Point

Recommendation

Inappropriate use of PBPs of IV contrast media increases risk for infections

• Some staff members have been using PBPs of contrast media inappropriately as multidose containers for multiple patients in radiology, cardiac catheterization labs, and cardiac surgery locations.

• Staff may believe the PBP is a multidose container because some manufacturers refer to it as a “multipack” and some power injector manufacturers suggest such use.

• PBPs of contrast media do not contain preservatives to help prevent contamination and the spread of infection.

• The pharmacy should oversee purchase, distribution, storage, and use of IV contrast media for inpatients and outpatients.

• Staff should draw up doses of IV contrast media from single-dose vials or use prefilled single-use syringes from the pharmacy or manufacturers.

• The contents of PBPs should be transferred only to single-dose containers or syringes in the pharmacy under a laminar flow hood or other USP <797>–suitable environment within 4 to 10 hours of initial entry into the bag.

Look-alike vials of calcium gluconate (100 mg/mL) from APP Pharmaceuticals and cupric sulfate (4 mg/10 mL) from American Regent

• Vials of calcium gluconate and cupric sulfate were mixed up when infusions were prepared.

• Both vials are similar in size and have a similar pink color on the label, although one is from APP (calcium gluconate) and the other is from American Regent (cupric sulfate).

• Separate storage of these products in the pharmacy.

• If possible, purchase one of the products from a different manufacturer.

2

Melphalan (Mylan) diluent vial confused as actual drug vial

• Mylan’s lyophilized melphalan is packaged with a diluent that is not clearly labeled and has been confused with the actual drug.

• The vials of drug and diluent are the same size, both have white caps and similar label colors, and the diluent label has the drug name listed prominently.

• Add an auxiliary label to the diluent to properly identify it, or, until Mylan improves the labeling, use a different manufacturer for this product.

2

Mix-ups between ENGERIX-B (hepatitis B vaccine, Novartis) and methylergonovine maleate (American Regent)

• Novartis sent a letter to hospitals that highlighted the accidental administration of methylergonovine instead of the ordered hepatitis B vaccine to newborns.

• Two of the recent mix-ups involved Engerix-B and generic methylergonovine, which are packaged in vials that look very similar.

• Separate newborn medications from those used for mothers.

• If newborn and perinatal medications must be stored together in ADCs, use locked, lidded medication bins for pediatric products, and highlight whether medications are for the mother or newborn on selection screens.

• If possible, administer newborn medications in an area that is separate from where medications are administered to the mother.

2, 4, 5

Mix-ups between methadone and methylphenidate

• A community pharmacy dispensed methadone in a vial labeled with the prescribed drug, methylphenidate, to a child.

• The mix-up also has happened in hospitals.

• Both drugs have a 10-mg strength, and they may appear together on computer selection screens.

• Configure mnemonics in order-entry systems to prevent confusion between methadone and other drugs that start with “met” or “meth” and have similar strengths.

• Separate methadone and methylphenidate in storage areas.

• Implement bar-code scanning in the pharmacy to identify when the wrong product has been selected from the shelf.

1, 2, 5

ADC, automated dispensing cabinet; ISMP, Institute for Safe Medication Practices; NMBA, neuromuscular blocking agent; PBP, pharmacy bulk package; USP, United States Pharmacopeia

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Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature

(continued)

Technology

Title

Problem/Discussion Point

Recommendation

Name mix-ups with cloBAZam (ONFI) and clonazePAM (KLONOPIN)

• Name similarity between cloBAZam and clonazePAM has led to several reports about the potential for confusion.

• The drugs share some similar indications (eg, Lennox-Gastaut syndrome), but there is a 10-fold difference in the strength of available dosage forms.

• ISMP plans to add the pair of cloBAZam and clonazePAM to its List of Confused Drug Names and added cloBAZam to its List of Look-Alike Drug Names with Recommended Tall Man Letters.

• Ensure that your institution has appropriate safeguards to allow health care providers to differentiate these 2 medications.

Potassium chloride (KCl) injection concentrate in a syringe

• Due to a shortage of KCl injection concentrate in vials and PBPs, a technician purchased KCl 20 mEq syringes from an outsourcing company.

• An overwrap with a warning statement was removed and the syringes were left on a counter.

• A pharmacist thought these were cefazolin syringes, because they had a similar red cap, and placed them in the refrigerator with other cefazolin syringes.

• The company no longer provides KCl syringes, but other companies may do so.

• ISMP urges hospitals to only purchase KCl in vials, not syringes, and to never remove caps or overwraps with warning statements until just before use.

Potential mix-up of NOVOLOG (insulin aspart, Novo Nordisk) and NIMBEX (cisatracurium, Abbott Laboratories)

• In an emergency department, a pharmacist found a carton of NovoLOG insulin in a refrigerator bin where Nimbex cartons were stored.

• Both have very similar-looking packaging.

• A mix-up either way could be fatal.

• In pharmacy and clinical areas where NMBAs are needed, they should be stored separately in a sealed container, lidded bin, or intubation kit.

• Affix a ‘warning label to NMBAs stating: Warning: Paralyzing Agent—Causes Respiratory Arrest.’

• When an NMBA is no longer needed, place any leftover vials, bags, and syringes of the drug in a sequestered bin for immediate pharmacy removal.

2, 4

Similarities between INTRALIPID (IV fat emulsion) and VIPERSLIDE

• A mix-up is possible between Intralipid (IV fat emulsion) and a non-drug product called ViperSlide, a lubricant to reduce friction with devices used during atherectomy procedures.

• While conducting an inspection of an interventional vascular lab, a pharmacist found ViperSlide, which has a milky white appearance.

• It is packaged in a 100-mL bag that looks almost identical to the 100-mL Intralipid 20% bag.

• Understanding the steps involved in various procedures where ViperSlide might be used at your hospital, and checking to see if these 2 look-alike products are available, can help you identify risks and implement strategies.

• For example, store these products separately or in an ADC with separate lidded drawers to reduce the risk for a mix-up.

2, 4

USP Prescription Container Labeling standard

• USP has created a web page on outpatient prescription container labeling (General Chapter <17>) to guide organizations in the presentation of information in a patient-centered manner.

• Hospitals that provide outpatient prescription services to patients and/or staff should assess current labeling procedures to ensure they match the guidelines (www.ismp.org/sc?id=142).

ADC, automated dispensing cabinet; ISMP, Institute for Safe Medication Practices; NMBA, neuromuscular blocking agent; PBP, pharmacy bulk package; USP, United States Pharmacopeia

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1, 2, 4, 5

Table 2. Addressing Concerns Involving Infection Control Technology

Title

Problem/Discussion Point

Recommendation

Avoid multidose vials in the OR

• The use of multidose vials in the OR has resulted in infection outbreaks and errors.

• Cross-contamination is always a possibility when using multidose vials.

• Also, when medications are supplied in quantities that exceed the amount typically given, practitioners may misinterpret the amount in the vial as a single dose, leading to overdoses.

• The Association of PeriOperative Registered Nurses recently released a set of recommended practices (http://alturl.com/xapaa) that include a recommendation to collaborate with pharmacists to procure and store only single-dose vials in ORs and postanesthesia units.

• Multidose vials should be avoided.

• The document outlines other best practices to use in the OR when procuring, prescribing, dispensing, administering, and monitoring the effects of medications.

CMS citing reuse of insulin pens

• In May 2012, CMS announced that hospitals will be cited if surveyors identify the sharing of insulin pens (www.ismp.org/sc?id=77).

• Regurgitation of blood into the insulin cartridge after injection risks disease transmission if the pen is used for more than 1 patient, even if the needle is changed.

• Educate practitioners about the risks associated with sharing pens (CMS announcement suggested that some may not be aware of this risk).

• Dispense pens for individual patients, with a pharmacy label that includes the patient’s name.

Do not use an insulin pen for multiple patients

• Repeated events suggest there is a widespread misunderstanding that sterility can be maintained between patients by affixing a fresh needle on a pen device.

• Studies have shown that biological contamination occurs in up to half of all reused insulin pens.

• This concern led the CDC to issue a clinical reminder regarding increasing reports of improper use of insulin pens (www.cdc.gov/injectionsafety/clinicalreminders/insulin-pens.html).

• To reduce the risk for cross-contamination, insulin pens should be assigned to individual patients and labeled using a “flag” attached to the body of the pen without covering the drug name.

• If ongoing education and monitoring of proper use of pen devices cannot be accomplished, hazardous conditions may persist, and hospitals may need to consider whether patients would be safer with dispensing of vials or prefilled syringes of insulin.

Eye drop– related infections

• Sharing of eye drop containers between patients and between both eyes of 1 patient has led to serious eye infections from cross-contamination.

• Although most products include preservatives to prevent the growth of bacteria and fungi, organisms can still thrive on the tip of the bottle.

• Rates of contamination as high as 35% have been noted in some studies; although infections are rare, they can happen and even cause blindness in some cases.

• To reduce costs, ophthalmic specialty hospitals often have mandatory training, competency, and monitoring programs to teach and validate safe administration of eye drops.

• Hospitals without this level of training and monitoring should dispense separate containers of eye drops for each patient and each eye.

• Once they are discharged, patients can use a device (eg, Owen Mumford) that does not allow the bottle to touch the eye when they squeeze out the drops.

New tools on safe injection practices

• The CDC has had to investigate many outbreaks of life-threatening infections caused by injection errors.

• Lack of initial and continued infection-control training, denial of the problem, drug shortages, and lack of appreciation for the consequences of unsafe injection practices all have been at the root of these outbreaks.

• The CDC and the Safe Injection Practices Coalition released a suite of new materials to help health care providers learn about and follow safe injection practices (http://blogs.cdc. gov/safehealthcare/?p=2802).

• The tools include PowerPoint slides, videos, podcasts, posters, and a press release kit.

• Health care facilities are encouraged to use the new tools.

Proper use of single-dose vials

• Use of single-dose or single-use vials for multiple patients can lead to contamination and spread of life-threatening infections and is not recommended.

• The CDC has reiterated its position on improper use of single-dose vials in response to concerns that such a policy contributes to shortages (www.cdc.gov/injectionsafety/CDCpositionSingleUseVial.html).

• Drug shortages and drug waste concerns must be dealt with appropriately and single-dose or single-use vials must be used as intended.

• However, the CDC notes that shortages of some essential medications may warrant pharmacy repackaging to subdivide contents of unopened single-dose/single-use vials via implementation of meticulously applied practice and quality standards following USP Chapter <797>.

CDC, Centers for Disease Control and Prevention; CMS, Centers for Medicare & Medicaid Services; ISMP, Institute for Safe Medication Practices; OR, operating room

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Table 2. Addressing Concerns Involving Infection Control

(continued)

Title

Problem/Discussion Point

Recommendation

Sterile compounding tragedy should spur assessment and action in hospitals

• The recent outbreak of fungal meningitis cases caused by contaminated steroid injections from a compounding pharmacy has led to scrutiny in these facilities.

• The outbreak also should lead hospitals to assess their own internal sterile compounding practices.

• Only 13% of pharmacy school deans feel their students have been adequately trained in sterile compounding before graduation.

• Use commercially available, ready-to-use, FDA-approved products from pharmaceutical manufacturers when possible.

• For medically necessary products that are not commercially available, carefully select and use a compounding pharmacy (www.ismp.org/ sc?id=111) or internally compound the products.

• Tools are available to help assess and train staff in sterile compounding (www.ashp.org, www.criticalpoint.info/home), including ISMP’s Guidelines for Safe Preparation of Sterile Compounds (www.ismp.org/Tools/guidelines/ IVSummit/IVCGuidelines.pdf).

• Establish a surveillance team to regularly test compounded preparations and monitor for compliance with USP Chapter <797>.

Technology

CDC, Centers for Disease Control and Prevention; CMS, Centers for Medicare & Medicaid Services; ISMP, Institute for Safe Medication Practices; OR, operating room

Table 3. Medical Devices and Other Discussion Items Title

Problem/Discussion Point

Recommendation

Apothecary measurement system a factor in medication errors

• A nurse gave a patient 5 drams (18.45 mL, 1.845 g) of acetaminophen concentrate liquid (100 mg/mL) instead of 5 mL. • The dose was measured in a cup with scales labeled in drams, fluid ounces, cc, mL, tsp, and tbsp.

• Confusion has been reported frequently between drams, ounces, mL, tsp, and tbsp.

• ISMP supports complete adoption of the metric system for prescribing and measuring liquid doses.

• The hospital should use oral syringes or dose cups without apothecary gradations to measure and administer oral liquid medications.

Covidien ChemoPlus gown may not afford worker protection

• A technician accidentally sprayed iron dextran injection on her ChemoPlus Protective Gown sleeve and it seeped through onto her clothes.

• Although the ChemoPlus product description states that the fabric is “splash resistant,” the gowns do not meet OSHA, ASHP, or ONS recommendations for chemotherapy protection.

• Only the company’s ChemoPlus Poly-Coated and the ChemoBloc Poly-Coated Gowns meet the recommendations and are appropriate personal protective equipment for handling chemotherapy and other hazardous drugs.

• Don’t be misled into believing you are maximally protected during preparation and administration of chemotherapy and other hazardous drugs by the brand name “ChemoPlus.”

• If you are using ChemoPlus gowns, be sure they are poly-coated and meet OSHA, ASHP, and ONS recommendations.

Distractions and interruptions contribute to medication errors

• Clinical staff are interrupted as often as once every 2 to 5 minutes.

• Distractions and interruptions include anything that diverts attention away from the current task, forcing attention on a new task at least temporarily.

• Identify the sources of common interruptions and remedy any system issues such as frequently missing medications; untimely dispensing of medications; or frequent invalid, insignificant, or overly sensitive computer alerts and device alarms.

• Provide staff with a quiet area/no interruption zone with a dedicated medication room or a cordoned off area in which to select and prepare medications.

• Avoid placement of ADCs in hallways or busy nurses’ stations.

• Ask all staff to avoid interrupting other staff members during critical medication tasks.

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Technology

Table 3. Medical Devices and Other Discussion Items Technology

Title

Problem/Discussion Point

Recommendation

Harm associated with drug shortages

• According to our recent survey, drug shortages— particularly with DOXOrubicin, fentaNYL, morphine, electrolytes, antibiotics, phentolamine, and phytonadione—have extracted a significant toll on patient safety during the past year.

• The problems that have been cited most often involved suboptimal treatment from use of an alternative medication that was not the drug of choice, errors with alternative medications, and errors when a pharmacy attempted to compound a product or strength no longer available.

• When faced with a drug shortage, conduct a mini FMEA (sample format at http://www.ismp.org/ tools/FMEA.asp) to assess the potential hazard to patients and potential misuses of alternatives.

Determine how to best manage the risk for serious errors and adverse reactions to alternative drugs, and make any necessary procedural and technological changes to support safe use.

• When possible, have pharmacy prepare and dispense alternative drugs in the most ready-to-use form.

High-alert medications left behind by contracted services

• A 20,000 units/mL heparin vial was found in a hospital’s OR, despite a decision to not stock this unsafe concentration.

• It was determined that an organ harvesting team had left the unused vial behind.

• In another case, a hospital-contracted renal transplant service left sodium chloride 23.4% (used to reduce cramping during hemodialysis) on several nursing units.

• Staff unaccustomed to the atypical stock can mistake the products for less concentrated forms of the drugs.

• When outside groups contract to provide services, hospital leadership must work with the pharmacy to ensure that the medications and dosage forms that might be used are reviewed and agreed on by the pharmacy.

• At that time, alternative products may be discussed and/or arrangements made to securely store products normally not available at the hospital.

• Pharmacy staff should also conduct regular visits to patient care units to observe drug storage.

Is it insulin or heparin?

• Some health care practitioners are engaging in an at-risk behavior in which they intentionally draw heparin into an insulin syringe when they do not have a syringe with a 25-gauge needle to use for subcutaneous heparin injections.

• Even if the insulin syringe is clearly labeled as containing heparin, health care practitioners may associate the orange-capped syringe with insulin, not heparin.

• Provide commercially available prefilled syringes of heparin with 25-gauge needles.

• Be sure you have all the necessary medicationrelated supplies in all your patient care units, including parenteral and oral syringes (smallvolume oral syringes in neonatal/pediatric units), infusion pumps, infusion tubing, port caps, etc.

• Do not employ policies that force staff to engage in workarounds to provide care to their patients.

ON-Q PainBuster Post-Op Pain Relief System (I-Flow Corporation) has a Luer connector

• The ON-Q pump, intended to infuse anesthetic solution around surgical wound sites, incorporates tubing that attaches to infusion equipment with a Luer connector, which is common to IV lines.

• With bupivacaine and other local anesthetic solutions, patient harm is possible if the ON-Q pump is inadvertently attached to an IV line.

• Affix a label to the ON-Q solution container stating, Warning: Regional Block Only.

• Always trace the solution to the patient access point or vice versa to prevent inadvertent attachment of the ON-Q tubing to an IV access port.

ADC, automated dispensing cabinet; ASHP, American Society of Health-System Pharmacists; FMEA, failure mode and effects analysis; ISMP, Institute for Safe Medication Practices; MAR, medication administration record; ONS, Oncology Nursing Society; OR, operating room; OSHA, Occupational Safety and Health Administration

Table continues on next page

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• Learn from errors occurring in other organizations through the ISMP Medication Safety Alert! and other published accounts of medication errors, and proactively take measures to prevent similar errors.

Effective results depend on understanding the entire medication-use process through varied perspectives and disciplines.

ISMP is a nonprofit organization that works closely with health care practitioners and institutions, regulatory agencies, professional organizations, and the pharmaceutical industry to provide education about medication errors and their prevention. ISMP independently reviews medication errors that practitioners and patients have voluntarily submitted to the ISMP Medication Error Reporting Program. ISMP is an accessible

resource for any pharmacist or organization interested 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 identifies errors that have been reported by other organizations and offers recommendations to prevent those errors from occurring in the pharmacy.

The information in the tables of this review summarizes many of the significant error-prevention strategies 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.

Text continues on page 8

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Table 3. Medical Devices and Other Discussion Items

(continued)

Title

Problem/Discussion Point

Recommendation

Red flags that represent credible threats to patient safety

• Intimidation in the workplace has repeatedly surfaced as a significant barrier to safety.

• A natural deference to expertise can lead to unintended complacency and tolerance of risk that goes unchallenged.

• Raise the index of suspicion for errors, always anticipating and investigating the possibility when anyone, regardless of experience or position, voices a concern or when patients are not responding to treatment as anticipated.

• Staff need to trust in their own experiences to augment the expertise of others, and to be receptive to staff who ask questions.

• Visit www.ismp.org/sc?id=102 for a list of skills to encourage appropriate responses to concerns.

Smart pump custom concentrations without hard “low concentration” alerts

• ISMP has received reports of overdoses due to misprogramming of infusions with custom concentrations that do not employ a hard minimum concentration alert.

• Accidentally programming a lower concentration than the actual product concentration results in the delivery of a higher dose than prescribed because more volume will be infused.

• The resulting “low concentration” alert from smart pumps has been misinterpreted as a “low-dose” alert.

• Without a hard minimum concentration limit, errors due to the misprogramming of an infusion pump can lead to life-threatening events.

• Assess your facility’s vulnerability to this type of error.

• Clarify with staff any confusion regarding the inverse relationship between dose and concentration, and the differences between “low-concentration” and “low-dose” alerts.

• Limit the number of standard concentrations for drug infusions.

• If a custom concentration is needed, set a hard minimum concentration limit.

• Use distinctive labels to distinguish custom concentrations.

• Express the drug concentration on the label and MARs the same way it needs to be entered into the pump (eg, mg/mL, total drug/total volume).

Teaspoonful– mL mix-ups with midazolam (VERSED) syrup

• A nurse preparing a 2-mg dose of midazolam syrup mixed up mL and teaspoonful and measured out 1 teaspoonful instead of 1 mL. • The BD oral syringe she used had both teaspoonful and mL scales.

• Oral syringes with a mL-only scale are not available in 5 mL and larger sizes.

• ISMP has called for limiting the units of measure to the metric system for devices, computer screens, medication orders, and dosing instructions on labels.

• Evaluate the oral liquid dosing devices used in your facility, and alert staff to the risk for measuring errors if both scales are on the syringe barrel.

• ISMP has asked manufacturers of dosing cups and oral syringes to make mL-only devices available for hospital use.

Tubing misconnections self-assessment tool for health care facilities

• Tubing misconnections are frequent and preventable errors that pose a significant risk to patient safety and can result in devastating outcomes.

• Because of human factors, the clinical environment, and the interconnectivity of Luer connectors, health care professionals have mistakenly connected the wrong devices and delivered substances via the wrong route.

• Hospitals are encouraged to complete a new self-assessment tool that guides users to evaluate current delivery systems and mating devices (www.baxter.com/healthcare_professionals/clinical_center_of_excellence/connections_portfolio/ programs/tubing_misconnection_index.html).

• By completing the assessment, hospitals will identify potential tubing misconnection risks and develop an action plan to mitigate risks through processes, device selection, and education.

Technology

3

ADC, automated dispensing cabinet; ASHP, American Society of Health-System Pharmacists; FMEA, failure mode and effects analysis; ISMP, Institute for Safe Medication Practices; MAR, medication administration record; ONS, Oncology Nursing Society; OSHA, Occupational Safety and Health Administration

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The first column lists the medications, devices, or other problematic issues involved. The second column describes the specific error or problem involved.

The third column 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 appropriately within a well-designed medication-use system.

The key summarizes the technology addressed in

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the tables, along with specific criteria that ISMP feels should be included.

For Part 1 of this 2-part series, go to http://qrs.ly/mg3c5wl.

Suggested Reading Cohen 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.

PRINTER-FRIENDLY VERSION AVAILABLE AT PHARMACYPRACTICENEWS.COM

Closed-System Transfer Devices For Safe Handling of Injectable Hazardous Drugs LUCI A. POWER, MS, RPH Senior Pharmacy Consultant Power Enterprises San Francisco, California

W

orker exposure to chemotherapy and other hazardous drugs (HDs) during

preparation and administration has been a concern for more than 30 years.1 Both early and recent studies show workplace and worker contamination, biological marker changes in exposed workers, chromosomal damage in workers, and adverse reproductive events correlated with occupational exposure to chemotherapy, especially the alkylating agents.2-6

Guidelines for safer handling of HDs are available from the American Society of Health-System Pharmacists, the Oncology Nursing Society, the Occupational Safety and Health Administration, among others, with most groups advocating engineering controls, personal protective equipment, and safe work practices as the primary methods for reducing worker exposure.7-9 Closed-system transfer devices (CSTDs) play an increasing role in many health systems as part of an overall approach to reduce occupational exposure to HDs. Part 1 of this series describes the available CSTDs and reviews studies supporting the efficacy of these devices; part 2 will focus on the FDA’s product classifications for “closed” or “contained” systems and how they fit into a complete program for handling HDs.

Novel Intervention and Initial Studies A novel intervention developed in Sweden, an HD containment system, or CSTD, called PhaSeal (Carmel

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Pharma), received FDA clearance under 510(k) in 1997 as a Class II medical device. A manufacturer-sponsored study done in a Swedish oncology center and published in a US peer-reviewed journal in 1999 demonstrated that the PhaSeal system, which covers pathways of injectable drug transfer during preparation and administration, reduced contamination of workplace surfaces compared with results seen using standard aseptic practices in previously published studies.10 PhaSeal was used from May 1996 to June 1997, during which time 534 doses (446 g) of fluorouracil (FU) and 132 doses (135 g) of cyclophosphamide (CP) were prepared by 3 experienced nurses mixing on a table top.

Wipe samples were taken one time at 17 spots (15 single, snap-shot wipe samples and 2 blanks) in and around the drug preparation room at the end of the working day, before cleaning. Samples were analyzed for FU and CP. The authors stated that levels of cytostatic drug contamination after 1 year of use of the

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PhaSeal system were far lower than those detected following the use of traditional preparation techniques (as reported in other published work at different European locations), but no data on doses or amounts of CP and FU handled in the comparative studies were reported.10 Although the authors concluded that the results show no detectable levels of environmental contamination from CP or FU in an outpatient clinic following 1 year of use of the PhaSeal system for the preparation and administration of cytostatic drugs, CP was detected in a single-wipe sample taken from the floor in the corridor outside the preparation room. The authors do not address this. Additionally, no statistical evaluation was done of the results of the samples.

A large oncology medical center in the United States undertook an extensive study of PhaSeal that was supported in part by the manufacturer.11 In a preliminary presentation of this study, Connor et al demonstrated that the PhaSeal device used in conjunction with a biological safety cabinet (BSC) and conventional cleaning procedures, resulted in a 60-fold reduction in surface contamination with ifosfamide (IF) in the BSCs and a 3-fold reduction overall in the pharmacy area, where it was common to handle 19.5 g per day of IF.11 In a continuation of their study, Connor et al used the PhaSeal CSTD in a new IV compounding pharmacy, conducting one baseline wipe sampling of 18 areas for FU, CP, and IF.12 PhaSeal was used to compound the CP and IF, and traditional needleâ&#x20AC;&#x201C;syringe technique was used for FU. The wipe sampling was repeated once every 4 weeks for 24 weeks, resulting in 6 post-intervention sampling dates. Overall surface contamination was decreased. The authors concluded that a closed-system device, in conjunction with the use of BSCs in an IV admixture area, appeared to contain surface contamination resulting from the preparation of CP and IF. The results of this study led to the adoption of PhaSeal as the norm at the medical center where the study was conducted.

This extensive study demonstrated a number of issues in handling HDs. The remodeled pharmacy retained the same floor and walls, and floor contamination was detected at baseline and persisted throughout much of the study. Cleaning processes were ineffective and resulted in a failure to achieve a true baseline. At the beginning of the study there was low to moderate IF contamination on several locations on the floor; this declined to a very low level by the end of the study. On the final sampling day, a high level of IF was detected in 1 of the 2 BSCs. Although a spill was not documented, the high level may have been the result of improper use or failure of the PhaSeal System, unreported breakage, or contamination by some other means. It should be noted that this study was conducted before the investigation of surface contamination on the outside of drug vials. Subsequent studies show that CP and FU vials are routinely contaminated when received from manufacturers and distributors.13 In another manufacturer-supported study, Wick et

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al looked at wipe samples of preparation and administration areas and urine samples of 8 staff members (7 active, 1 control) in a newly constructed ambulatory care infusion center and pharmacy facility.14 Using CP and IF as their marker drugs, the investigators collected 17 wipe samples before implementation (BI) of the PhaSeal system in December 2001 and then collected 21 wipe samples 6 months after implementation (AI). BI, all 17 wipe samples had detectable levels of CP (5 with a CP value above the linear range of the assay) and 11 of the 17 had detectible levels of IF. AI, only 7 wipe samples had detectable levels of CP (none above the range of the assay), and 15 had detectable levels of IF (5 above the range of the assay).

BI, 52 individual urine samples were collected from the 7 subjects and 1 control. Participants provided 24-hour urine samples toward the end of the workweek, when, theoretically, employee exposure would be highest. Thirty milliliters of each urine sample was sent for analysis. Of the 52 samples, 10 had detectable levels of IF. One sample belonged to a technician who worked in the pharmacy but did not prepare chemotherapy drugs. The other 9 samples belonged to a pharmacist who was involved in order entry and checking. The last IF order was processed 3 weeks before these urine collections. Eighteen urine samples had detectable levels of CP. One nurse had a positive sample, a second nurse had 3 positive samples, 1 pharmacy technician had 8 positive samples, and each pharmacist had 3 positive samples.

AI, 54 urine samples were collected from the same 8 participants. All samples were below detectible limits of IF and CP. The authors said that the 5 employees who had detectable levels BI could have been exposed in numerous ways, including handling vials or touching previously contaminated surfaces. Additionally, although AI surface contamination decreased for CP but increased for IF, both agents were not detectable in the second set of urine samples. The authors offer no explanation as to the apparent discrepancy between handling activities of CP and IF and the uptake of drug in the workers. The authors conclude that the PhaSeal system appeared to reduce surface contamination with and exposure of health care personnel to CP and IF. In the discussion of their study, the authors noted that unlike a BSC, which represents a one-time capital expenditure that can be depreciated, PhaSeal creates an added annual expense. Depending on configuration and order volume, this system may add $6 to $15 to the cost of each chemotherapy drug infusion. During this study, the authors purchased the PhaSeal system at a price negotiated by their group purchasing organization. They estimated that the system would add approximately $300,000 in annual expenses if deployed fully across their entire hospital system. It is possible to add the cost of the system to the cost of the chemotherapy drug infusion, but reimbursement will vary according to payer mix. The authors also

stated, “Our most compelling reason for implementing the PhaSeal system was our ethical responsibility to safeguard our employees. Our study demonstrated a potential health risk, as well as identified a tool that appears to reduce that risk.”

These early studies suggested that CSTDs helped to contribute to reduction of surface contamination and employee exposure to HDs. It must be remembered that good compounding techniques and robust cleaning procedures also are important factors that mitigate outside sources of contamination.

NIOSH Alert and CSTDs In 2000, The National Institute for Occupational Safety and Health (NIOSH) assembled a team to review new studies and update recommendations for HD safe handling practices. This resulted in the 2004 Alert: Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings.15 After reviewing the intervention studies, NIOSH included a section on closed systems in the Alert.

In the 2004 Alert, NIOSH defines a “closed system” as a device that does not exchange unfiltered air or contaminants with the adjacent environment. It further defines a “closed-system drug-transfer device” for use in compounding and administering sterile doses of chemotherapy and other HDs, as a drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of HD or vapor concentrations outside the system. From this definition, the term and concept of CSTD were developed, although the acronym, CSTD, is not used in the Alert. Based on the studies published up to that time, the authors of the Alert noted that “Evidence documents a decrease in drug contaminants inside a Class II BSC when a closed-system transfer device is used” and concluded that facilities should “consider using devices such as closed-system transfer devices, glovebags, and needleless systems when transferring [HDs] from primary packaging (such as vials) to dosing equipment (such as infusion bags, bottles, or pumps).”15 The NIOSH definitions of the 2 terms (closed system and closed-system drug-transfer device) are descriptive but do not include a performance standard. To adequately assess a CSTD, there should be a performance standard that would establish the test methods and criteria for successfully meeting the standard.

Similar to the ASTM standard on chemotherapy gloves,16 specific drugs or surrogates, predetermined drug amounts and concentrations, exposure time, and acceptable containment limits are needed to determine if a CSTD system is effective. Although absolute containment is ideal, it is unlikely and, as in radiation safety, ALARA (As Low As Reasonably Achievable) should be acceptable.

In the absence of a performance standard, researchers have proposed a number of methods and surrogates to assess the effectiveness of various devices marketed

In traditional compounding with needles and syringes, leakage has been shown as both powder and liquid aerosols around the drug vial septum, the disengaged needles, and the point of injection into the IV bag. In traditional administration with open IV bag ports, IV set spikes, and Y-site connections, leakage has been shown during preparation for administration (spiking and priming the IV bag) and during disengagement of chemo IV sets from patients.

A CSTD should cover the following steps in the compounding and administration process during which the drug has been shown to be released into the environment during manipulation, ie, when: • Injecting the syringe/needle into vial through septum • Disengaging syringe/needle from vial septum • Injecting syringe/needle into IV bag • Spiking the IV bag by placing an IV set into a bag containing drug • Priming the IV set to remove air before attaching to patient access • Administering an IV push dose from a syringe into a Y-site of IV tubing • Disengaging secondary sets or push connections from primary set or from patient

Figure. How should a CSTD work?

as closed systems (Figure, Table 1).10,12,14,17-29 For example, a series of studies from Sweden have used radioactive technetium to evaluate different types of closed systems, finding both diaphragm and filtered systems to be fairly equivalent with respect to containment.17,18,29 In one of these studies, the authors noted, however, that “the tested system (filtered) in this paper cannot physically be regarded as a closed system according to the National Institute for Occupational Safety and Health definition of closed system (NIOSH, 2004), since air can pass in and out of the system during preparation.”18 The authors subsequently reversed their position after

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conferring with NIOSH.30 In a letter to the editors of the journal, the authors quote a NIOSH statement that: “the Alert’s glossary was not really intended to be a specification guide for equipment design criteria. Rather, we sought to identify the desired function that the defined piece of equipment should provide. In the case of the CSTD, the intended function was to preserve the sterility of the product while preventing the escape of a [HD], in whatever form it may exist, into the surrounding environment. In that regard, if a hypothetical CSTD was successful in meeting these performance criteria during the drug transfers for which it was intended, we (NIOSH) would probably consider it as meeting the definition. If however, the [HD] under manipulation included a vapor component or could change phase to vapor during the drug transfer process, leading to escape of drug from the system, then that system would fail to meet the intended function of our definition.”30 The FDA recently created a new Class II Device Product Code, ONB, with the description “Closed Antineoplastic and Hazardous Drug Reconstitution and Transfer System.”31 This product code has no performance standard or specification guide. It does, however, specify “antineoplastic and other hazardous drugs” in the definition, possibly limiting the surrogates that may be used to evaluate such devices.

There are a number of FDA-cleared Class II medical devices that are marketed as “CSTDs” or other “closed” or “contained” systems available from various manufacturers. They differ in how they attempt to meet the NIOSH definition of a closed-system drug-transfer device (Table 2).15 For the remainder of this article, CSTD will be used to describe a generic Class II medical device marketed for the purpose of safe handling of HDs. The following describes the available FDA-cleared Class II medical devices generically termed CSTDs. PhaSeal is a proprietary system of a vial device (Protector) that uses a locking cap with a small spike to secure access to a vial. The Protector uses a diaphragm to contain the air from the vial and any liquid, powder, or gaseous aerosol generated in reconstitution or transfer. An Injector attaches to a syringe and accesses the Protector with a unique locking system. Once locked, the Injector passes a cannula through the Protector spike into the vial through a double membrane. The diaphragm expands and contracts to handle the air from the syringe and vial. PhaSeal has an Infusion Adapter that allows a closed connection between the drug in a syringe and an IV bag and a dry connection to the spike of any IV set. PhaSeal also provides an adapter for the syringe into a Y-site for IV-push administration.

ChemoClave Genie and Spiros by ICU Medical uses a closed male luer (Spiros) that attaches to Clave connectors to allow needle-free access to HD vials and IV sets. The Genie is a vial-access device that uses an expandable balloon inside the vial to equalize vial pressure when liquid drug is withdrawn. The Genie is equipped with a needle-free Clave connector. ICU Medical has a selection of IV devices with Clave connectors

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that facilitate transfer of drug through syringes using the Spiros. These devices provide a system for access to the IV bag, IV sets, and Y-sites for various administration techniques. ICU Medical also provides several vented vial-access spikes with hydrophobic filters that fit various sizes of vials.

OnGuard by B. Braun uses Tevadaptor components to provide a “contained medication system.” The 2 primary components are the Tevadaptor Vial Adaptor and Tevadaptor Syringe Adaptor. The vial adaptor contains an activated charcoal drug-binding matrix and a hydrophobic 0.2-micron sterilizing-grade membrane to contain HD aerosols. All system components use elastomeric seals to prevent fluid escape and provide audible and tactile confirmation of secure connections.

OnGuard has devices that address compounding and administration via needle-safe connectors. OnGuard provides a bag-access device, IV push adapters, and IV sets that are compatible with its system components.

Texium by Care Fusion is a closed male luer designed to partner with the SmartSite needle-free valve to deliver a closed system for compounding and administration of HD doses. The SmartSite Vented Vial Access Device uses a 0.2-micron hydrophobic air-venting filter to equilibrate air pressure in HD vials during compounding. The SmartSite Add-On Bag Access Device allows the Texium to connect to an IV bag to add drug and provides a dry connection for spiking an administration set into the IV bag. The Texium male luer connects to any SmartSite valve for various administration techniques.

Equashield by Equashield Medical uses a proprietary syringe unit with 2 chambers—a liquid chamber and an air chamber—located at the end of the syringe piston.

A dual-needle air-to-liquid exchange system communicates between chambers displacing liquid from the vial with equivalent air from the air chamber. Equashield maintains constant equal pressure inside the vial to prevent the escape of vapors and aerosols. Equashield uses tight seal double-membrane connectors between its system components—the vial and syringe adapters and the bag and IV-push adapters. Equashield has fixed fully shielded needles to prevent accidental sticks.

Assessing a CSTD In the absence of a performance standard, some CSTDs have been evaluated in published studies, many in peer-reviewed publications. Some manufacturers have chosen to use contracted laboratories to assess the effectiveness of their devices in a limited setting with a selected protocol. Studies have been done in clinical environments and in controlled laboratories.

Some studies use surface wipe sampling of marker drugs to assess HD residue, whereas others have used surrogates including fluorescein, titanium tetrachloride, and radioactive technetium to assess the containment properties of CSTDs. Each method has had some success in providing insight into how and how well different CSTDs function, but no method has been adopted

as determining criteria for workplace or worker safety for the CSTDs (ie, a performance standard).

In reviewing the literature and available information on CSTDs, the preponderance of studies has been done with PhaSeal, the first of the new generation of protective devices to clear the FDA’s 510(k) process.

Carmel Pharma increased awareness of the issue of workplace contamination with HD residue by sponsoring wipe-sampling studies in clinical settings. Two major studies were described in the section on Novel Intervention and Initial Studies.12,14 Two more-recent publications chronicle sponsored wipe samplings before and after PhaSeal implementation, the first group describing evaluations from June 2000 to May 2005 at 22 US hospital pharmacies and the second describing evaluations from August 2004 to November 2010 at 30 US hospital pharmacies.19,20

Clinical Studies and Wipe Sampling CSTD studies often are referred to as “clinical” because they are done in a clinical setting with real drug doses that will be administered to patients.

These studies use wipe sampling of specific “marker” drugs to evaluate surface contamination. Some of these studies examine both the preparation and administration areas for levels of surface contamination before and after intervention. Although clinical studies offer a perspective on the overall degree of HD surface contamination found in actual working facilities, they have limitations in assessing interventions as specific as CSTDs.2,12,14 Most clinical studies do not control for outside sources of contamination, for example, the drug residue found on the outside of many drug vials. They rarely control or report cleaning activities and when cleaning is done in relation to sampling or if the cleaning procedures are effective in removing the marker HD.12,14 Clinical studies often are affected by spills that may not be related to the CSTD but affect the overall level of surface contamination.12 These studies also are affected by using a “snap-shot” technique, taking wipe samples at a single time (a “snap shot”) during a compounding and/or administration period that may extend for weeks. One of the most difficult variables to control in a clinical study is how much drug was actually handled before sampling.

Most clinical studies do not even attempt to identify specific drug quantities, generally providing an “average” amount of the marker drugs used in a given time period. In wipe-sampling studies, there are variations in the number of wipe samples taken, the range of sizes of the area to be sampled, the amount of solvent used to sample the desired space, the recovery of the drug from a given surface material using a specific solvent, the people who do the wipe sampling, and the period of time studied. The technique for wiping and the force exerted also affect the recovery of marker drug from surfaces. Many of the studies have a small number of samples and most have no statistical significance. Overall, clinical studies evaluating CSTDs

have not demonstrated a direct correlation of drugs handled to surface contamination measured.

PHASEAL STUDIES Harrison et al conducted a detailed and comprehensive study.21 Using an educational grant from Carmel Pharma, the authors designed a multisite, clinical, wipe-sampling study to compare surface contamination with FU and CP in a 3-phase study. Phase 1 was before the use of PhaSeal; phase 2 was during use of PhaSeal; and phase 3 was after PhaSeal was removed from all 3 sites. During the 36-week study, 18 time points and 342 samples ensured sufficient data for statistical analysis. All operators were well trained in the new system. Cleaning methods and times were controlled, as was spill reporting, and spill cleanup protocols were in place. CP and FU were reported as mean amount of drugs prepared per 2-week sampling period per site. All data were normalized per total grams of CP prepared during each 2-week sampling period.

Precleaning or wipe sampling of CP and FU vials was not reported. Post-test multiple comparisons showed surface contamination with CSTD use (phase 2) to be significantly less than without CSTD use (phase 1, P<0.001; phase 3, P<0.001). The median surface contamination showed statistically significant differences across the 3 phases for each site (site A: P=0.0164; site B: P=0.0458; site C, P<0.0001). Contamination in the CSTD phase was less than in the control phases, but the differences did not reach statistical significance (P>0.05, Dunn test) for sites A and B. The authors noted that the levels of contamination detected before CSTD use for 2 sites were much lower than they anticipated and generally less than reported in the literature to date. They concluded that the use of a CSTD in the BSC in conjunction with standard HD preparation techniques significantly reduced CP surface contamination compared with standard techniques alone.

In a 24-month cross-sectional study supported by Mayne and Carmel Pharma, Tans et al looked at surface and glove contamination of FU, CP, and IF in different periods with and without PhaSeal.22 They did not find the PhaSeal system effective in reducing surface contamination, but their results may have been influenced by a big spill due to an incorrect use of PhaSeal. There was an improvement in glove contamination with the use of the PhaSeal system.

In the 2 previously mentioned studies chronicling wipe samples and use of PhaSeal, the ratio of “spot wipes” to facilities is very low.19,20 In the study of 22 US hospital pharmacies, the authors reported 114 samples per 22 sites where the surface areas wiped ranged from 300 to 11,050 cm2. Statistical analysis is reported for the composite results.19 Although 68% of the wipe samples of the 4 surfaces tested positive for CP with the CSTD in use, compared with the standard preparation techniques, a significant reduction in levels of contamination was observed for all drugs (CP: P<0.0001; IF: Text continues on page 8

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Table 1. CSTD Intervention Studies With Marker Drugs Or Measurable Surrogates Citation

Study Type/ Methodology

Intervention Comparison Results

Sponsor

Comments

Sessink Hosp Pharm 199910

Clinical/not controlled; CP, FU; snapshot single wipe sample taken once over 1 y, 17 spots

PhaSeal

Published studies

Reduced HD surface contamination compared with published reports

Financial support

by Carmel Pharma

No PEC in use; no BI wipes

Connor AJHP 200212

Clinical/not controlled; CP, IF, FU; snap-shot wipe samples at baseline (18 spots), then every 4 wk for 24 wk (6 AI sampling dates)

PhaSeal for CP, IF

Needle syringe for FU

PhaSeal appeared to contain surface contamination resulting from preparation of CP and IF when used with a BSC in a high-volume IV admixture area

Partial support

by Carmel Pharma

Vial residue not considered; cleaning appears ineffective; â&#x20AC;&#x153;trueâ&#x20AC;? baseline not achieved with cleaning and sampling, although levels decreased over time

Nygren J Environ Monit 200217

Laboratory setting; simulated preparation and administration of radioactive 99mTc and platinum standard; surface contamination measured by radioactive leakage of 99m Tc and air sampling with platinum for emissions; 10 nurses simulated 6 preparations and administrations (6 mL of radioactive solution in 10-mL syringes)

PhaSeal

Traditional technique

Difference in airborne emission was small and NS, although no statistical analysis was done; all subjects had leakage in preparation and administration using open technique, but it varied; leakage was consistently less using the closed system, which showed 3-4 times lower volumes for all measurements

Support by the Swedish Council for Working Life and Social Research

Studies with radioactive tracers use small volumes of tracer manipulated with small syringes; this does not appear to be a good surrogate for HD doses that are generally large and require large syringes to prepare and administer; larger volumes are more difficult to manipulate

Wick AJHP 200314

Clinical/not controlled; CP, IF; snap-shot wipe and urine sampling; BI: wipe samples from 17 spots and 52 urine samples; AI: 21 samples as a single snap shot once and 54 urine samples

PhaSeal

BI and AI in same setting after 6 mo

Wipe samples BI: 17/17 detectable levels of CP; 11/17 detectable levels of IF AI: 7/21 detectable levels of CP; 15/21 detectable levels of IF, with 5/15 over range of assay Urine samples BI: 10/52 detectable levels of IF, 18/52 detectable levels of CP AI: All samples were below limits of detection for CP and IF

Support

by Carmel Pharma

Authors noted some deficiencies in the study and concluded that PhaSeal appeared to reduce employee exposure to and surface contamination with CP and IF; they elected to implement PhaSeal in all of their compounding and administration sites, despite a significant cost increase

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Table 1. CSTD Intervention Studies With Marker Drugs Or Measurable Surrogates Citation

Study Type/ Methodology

Intervention Comparison Results

Sponsor

Comments

Tans J Oncol Pharm Pract 200422

Clinical/not controlled; CP, FU, IF; surface and glove contamination over 24 mo in different segments with and without intervention; 104 spot samples taken BI and 4 times AI

PhaSeal

BI and AI in same setting

Authors note intervention did not show a clear difference in reduction in surface residue, possibly due to a big spill caused by an incorrect use of the system; improvement noted in glove contamination with PhaSeal

Support

by Mayne and Carmel Pharma

Only the results of glove tests were interesting to the authors due to higher levels of contamination, so changes were made to increase glove testing

Harrison AJHP 200621

Clinical/ controlled for cleaning and spills; CP, FU; wipe sampling cross-sectional study done in 3 phases (control/ CSTD/control) in 3 sites; 36-wk study, 18 snap-shot time points, and 342 samples

PhaSeal

BI and AI in each site compared with standard preparation techniques

324/342 wipes positive for CP; median surface contamination significantly different across 3 phases (P<0.00001), consistent across sites; CSTD in BSC with standard HD technique reduced CP residue compared with standard techniques alone; no conclusive result for CSTD for FU outside of BSC

Support by unrestricted educational grant from Carmel Pharma

FU prepared on countertop, not in PEC

Nygren Ann Occup Hyg 200818

Laboratory setting; simulated preparation of radioactive 99m Tc; 8 pharmacists made 75 test preparations in BSC; 6 mL of diluted 99mTc was manipulated to simulate preparation; bench covers and gloves were collected for radiation assessment as a measure of leakage

Tevadaptor (marketed in the United States as OnGuard with Tevadaptor components)

Leakage compared with results of previous studies

Leakage was <100 nL for all 75 preparations and <1 nL for 70 preparations; biggest spill during a single preparation was 53.8 nL; showed Tevadaptor drughandling system has performance similar to drughandling systems regarded as closed systems

Manufacturers of the device paid the hospital pharmacy at the University Hospital of Northern Sweden for the tests

Authors refer to a Swedish Pharmacy (Apoteket AB) Internal Quality Manual that prescribes a limit value of 100 nL total spill volume on bench cover and gloves for 1 preparation; this appears to be performance standard for Sweden; studies with radioactive tracers use small volumes of tracer manipulated with small syringes

Ledford HOPA 201023

Clinical/not controlled; CP, FU, MTX; wipe sampling; each system assessed along with routine decontamination using SurfaceSafe and standard techniques in the same clinical setting for 14 d

PhaSeal compared with ICU Medical CSTD (exact components not reported)

Surface contamination measured by wipe sampling for 14-d period with each intervention

Authors concluded that the products generally are equivalent and resulted in un-detectable levels of CP, FU, and MTX (P=0.08-0.14)

Funding not disclosed

In treatment areas, terminal PhaSeal Injector was not consistently used, but the complete ICU Medical system was used and contributed to 70% lower levels of exposure to the HDs analyzed

AI, after implementation; BI, before implementation; BSC, biological safety cabinet; CP, cyclophosphamide; FU, 5-fluorouracil; HD, hazardous drug; IF, ifosfamide; MTX, methotrexate; NS, not statistically significant; PEC, primary engineering control; SA, surface area; SD, standard deviation; 99mTc, technetium 99m Based on references 10, 12, 14, 17-29.

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Table 1. CSTD Intervention Studies With Marker Drugs Or Measurable Surrogates (continued) Study Type/ Methodology

Citation

Intervention Comparison Results

Sponsor

Comments

Zock J Oncol Pharm Pract 201124

Laboratory setting; controlled for amounts of drug, cleaning, specific manipulations; simulated preparation of CP doses; wipe samples of vials, surfaces of BSC, floor and preparerâ&#x20AC;&#x2122;s gloves; 22 wipe samples and 5 field blanks for both phases

PhaSeal and ChemoClave (Genie/ Spiros)

Wipe sampling of marker drug CP, with identical protocols for each intervention

After ChemoClave: no CP detected on BSC airfoil/grill or floor; CP was detected on BSC workbench and 1 pair of gloves After PhaSeal: CP detected on the BSC workbench, but not on BSC airfoil/grill, floor, or gloves

Support

by ICU Medical

Authors concluded that small number of samples precluded statistical analysis; of 20 g CP reconstituted, only 6 g were actually transferred using small increments and syringes

Sessink J Oncol Pharm Pract 201119

Clinical/not controlled; CP, IF, FU; snap-shot wipe sampling taken once BI and AI at each of 22 US hospital sites, 114 wipes/22 sites (about 2 samples per site BI and AI)

PhaSeal

BI and AI in same setting compared with the standard preparation techniques

AI: composite results show significant reduction in levels of contamination for all drugs (CP: P<0.0001; IF: P<0.001; FU: P<0.01)

Financial support provided

by Carmel Pharma

Individual site samples too small for statistical analysis; variables include range of SA wiped (300 to 11,050 cm2) and each site performed own wipe samples

LeGarlantezec Ann Pharm Fr 201127

Laboratory setting simulated preparation of 99mTc (modification of Nygren18,19); evaluation criteria included transfer performance of the radioactive solution from one vial to another, measuring leakage, contamination, dead space, residual volume, and efficiency

PhaSeal with expansion chamber; Tevadaptor with filter; ChemoClave with filter and Spiros; Smartsite with filter and Texium

Weighted ratings for transfer performance of solution from vial to vial; leakage of device; ease of use; operator preference considered

Teva and CareFusion devices seemed more efficient with ability to transfer solutions with low dead volume and low-level contamination around manipulation area; PhaSeal scored poorest in efficiency and user preference but high in containment

No sponsor disclosed

Training was not addressed and filtered systems are more intuitive to use; studies with radioactive tracers use small volumes of tracer manipulated with small syringes

Text continued from page 5

P<0.001; FU: P<0.01).

The study of 30 US hospital pharmacies yielded 143 samples or approximately 2 wipes per site before and after intervention.20 The statistical analysis again is based on the composite with a significant reduction in levels of contamination being observed for all surfaces after the CSTD compared with standard preparation techniques (P<0.0001). In this second study, 80% of the wipe samples of the 4 surfaces tested positive for CP contamination with use of the CSTD.

STUDIES

OF

OTHER CSTDS

A Florida medical center presented a wipe-sampling study sequentially comparing PhaSeal and the ICU Medical CSTD (exact components not reported) for contamination during preparation and administration

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of FU, CP, methotrexate (MTX), and platinum agents.23 Each system was assessed along with routine decontamination using Surface Safe and standard techniques in the same clinical setting for 14 days. In the pharmacy, both CSTDs provided equivalent control of surface contamination when used in combination with daily cleaning treatment. In the treatment areas, the terminal PhaSeal Injector was not consistently used, but the complete ICU Medical system was used and contributed to 70% lower levels of exposure to the HDs analyzed in the study. The authors concluded that the products are generally equivalent and resulted in nondetectable levels of FU, CP, and MTX (P=0.08-0.14). As in most clinical wipe-sampling studies, the amounts of drug handled were not reported. The assumption is that during each 2-week period, the drugs handled in the clinical setting would be similar for each CSTD. Sponsorship of the

Table 1. CSTD Intervention Studies With Marker Drugs Or Measurable Surrogates Citation

Study Type/ Methodology

Intervention Comparison Results

Sponsor

Comments

Clark J Oncol Pharm Pract 201326

Clinical/not controlled; CP, FU; wipe sampling of 12 locations as 3 snap shots: with existing methods and no cleaning, after thorough cleaning and 2 mo AI, and 12 mo AI (Equashield); areas peripheral to compounding BSC were wiped

Chemo Dispensing Pin and Equashield

Existing technique of Chemo Pin compared with CSTD (Equashield) intervention

The results of first 2 sets of wipe samples showed contamination with CP on about half of the positions in all departments during both collection periods, but levels of contamination were very low (most just above the detection limit); results from final collection period showed no contamination with CP or FU in the pharmacy, infusion suite or offices of the cancer center

No specific grant from any funding agency in the public, commercial, or notfor-profit sectors

The authors concluded that use of CSTDs for preparing and administering chemotherapy eliminated surface contamination with cytotoxic agents at ambulatory chemotherapy infusion center; this appears overstated because many factors affect surface contamination in a year-long period that could not be determined by a single snap shot of 12 wipe samples

De Ausen AJHP 201328

99m

Tc in form of sodium pertechnetate; 15 wipe samples performed by each of 9 participants for sample size of 135 per system; syringe and vial adapters were connected and 6 mL of the test solution were drawn into syringe; then vials and syringe adapters were disconnected and wipe sampling was done on the syringe adapters and their paired spiked vial adapters at usual point of entry

ChemoClave with Genie and Spiros; OnGuard Contained Medication System with Tevadaptor components; and PhaSeal

Leakage measured by radioactivity detected on swabs was compared among all systems

Significant difference in control radioactivity detected, with ChemoClave having a higher mean than both PhaSeal and OnGuard; differences seen in leakage among devices, with PhaSeal having lowest geometric mean leakage, followed by OnGuard and ChemoClave; mean leak volume varied significantly among participants

Funded by the Department of Pharmacy, Tripler Army Medical Center

Study limited to leak volumes on CSTD connection between the syringe and vial; wiping methodology requires touching the membrane connections; PhaSeal has most recessed membrane of the vial access devices, so it is the most difficult to reach, possibly affecting the results; common comment from participants was that it was more difficult to learn how to use PhaSeal than the other devices

Sessink Hosp Pharm 201320

Clinical/not controlled; CP; snap-shot wipe sampling taken once BI and AI at each of 30 US hospital sites, 143 samples/30 sites

PhaSeal

BI and AI in same setting compared with the standard preparation techniques; results compared with previous study22

AI: analysis of composite results showed significant reduction in levels of contamination (P<0.0001); 80% of the wipe samples of the 4 surfaces were positive for CP contamination with CSTD, but levels of CP recovered were lower

Financial support provided

by Carmel Pharma

Individual site samples too small for statistical analysis; results of this and 2010 study are identical

AI, after implementation; BI, before implementation; BSC, biological safety cabinet; CP, cyclophosphamide; FU, 5-fluorouracil; HD, hazardous drug; IF, ifosfamide; MTX, methotrexate; NS, not statistically significant; PEC, primary engineering control; SA, surface area; SD, standard deviation; 99mTc, technetium 99m Based on references 10, 12, 14, 17-29.

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Table 1. CSTD Intervention Studies With Marker Drugs Or Measurable Surrogates (continued) Citation Sewell EAHP 2013

Study Type/ Methodology Laboratory wipesampling study of 5 marker drugs (cisplatin, oxaliplatin, and carboplatin— all assayed as platinum—and epirubicin and FU); surface wipe samples, used gloves and preparation pads were collected for analysis; surfaces of filled syringes and infusion bags also sampled

Intervention Comparison Results

Sponsor

Comments

Tevadaptor (marketed in US as OnGuard with Tevadaptor components)

Support

by Teva

Researcher concluded that Tevadaptor reduced both the frequency and amount of surface contamination by the marker drugs when used in similar quantities BI

Compared with standard needle and syringe technique (BI)

BI: all sampled surfaces (including surfaces of filled syringes and infusion bags) contaminated with marker drugs AI: isolator surfaces were below limits of detection of assays; and contamination on gloves, preparation mats, and surface of infusion containers was markedly lower than at baseline

AI, after implementation; BI, before implementation; BSC, biological safety cabinet; CP, cyclophosphamide; FU, 5-fluorouracil; HD, hazardous drug; IF, ifosfamide; MTX, methotrexate; NS, not statistically significant; PEC, primary engineering control; SA, surface area; SD, standard deviation; 99mTc, technetium 99m Based on references 10, 12, 14, 17, 22-29.

study was not disclosed.

In a simulation study supported by ICU Medical, Zock et al used wipe sampling of CP in a controlled environment with a specific handling protocol to compare PhaSeal and the ICU Medical ChemoCLAVE closed system using the Genie and Spiros.24 They used an experimental laboratory setting with a Class 100 clean room and a Class II BSC vented to the outdoors for all procedures. One technician with 7 years of experience with PhaSeal and more than 1 year using the ICU Medical devices performed the dilutions and transfers to syringes and IV bags. Attempts were made to control, minimize, and evaluate other known sources of environmental contamination including precleaning workarea surfaces that would be wipe-sampled as well as wipe-sampling CP 1-g vials before mixing. All wipe sampling was done using Cyto Wipe Kits (Exposure Control B.V.) and samples were stored and shipped to Exposure Control and assayed using previously validated recovery and analytical methods.

Two separate trials simulating HD compounding of CP in a specific protocol were performed with the 2 different closed-system products. After cleaning and before compounding CP, 3 wipe samples of specific work surfaces were done before each intervention, and all samples were below the limit of detection. Composite wipe sampling was done of the 40 CP 1-g vials used for the study. Two wipe samples of vials used in the ChemoCLAVE trial were above the level of detection. The remaining vial wipes were below detection.

Low levels of CP were detected on the BSC workbench surface following both trials. The authors noted that

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based on the limited number of samples obtained during this preliminary study (12) and the determination of the presence of the CP on the drug vials, no statistical evaluation was performed to compare the relative effectiveness of the 2 systems tested and that further study and statistical analyses are needed. In this protocol, only 6 g of the 20 g of CP were actively transferred for each phase of the study, so more than two-thirds of the drug was discarded. In actual practice, the volumes of transfer would be greater and the time involved probably much smaller.

Sewell presented a wipe-sampling study of 5 marker drugs prepared in a negative-pressure pharmaceutical isolator in the UK’s University of Plymouth Aseptic Laboratory.25 The initial preparation of epirubicin, FU, cisplatin, oxaliplatin, and carboplatin (the latter three assayed only as platinum) was done with conventional syringe and needle technique. This was then compared with the surface contamination obtained over a second period of preparation using a Tevadaptor device (similar to the US CSTD OnGuard with Tevadaptor components). Wipe samples were taken for 1 week (baseline period) from predefined areas in the isolator and from the surfaces of IV infusion bags and prefilled syringes.

Gloves and preparation mats used during this period also were collected and analyzed. Following a 1-week training period, the Tevadaptor was introduced and wipe sampling of the same surfaces and collection of consumables was continued for a further week (intervention period). All samples were analyzed using validated high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detector, HPLC with fluorescence

Table 2. Available CSTDs Device(s)

Company

Components

Website (s)

CareFusion Closed-system solution: Texium closed male luer and SmartSite needle-free valve products

CareFusion

Filtered drug vial adapter—SmartSite needle-free valve and vented vial-access device; Needle-free syringe adapter-Texium closed male luer; SmartSite add-on bagaccess device; needle-free primary and secondary sets help achieve a closed system during administration of HDs when partnered with the Texium closed male luer.

http://www.carefusion.com/ medical-products/infusion/ivsets-accessories/texium.aspx http://www.carefusion.com/ medical-products/infusion/ iv-sets-accessories/SmartSite. aspx www.carefusion.com/pdf/infusion/closed_system_solution_ brochure.pdf

BD PhaSeal CSTD

Carmel Pharma, BD Medical

Drug vial adapter with expanding diaphragm for containment (Protector); Needle-Safe syringe adapter (injector) that advances and retracts metal needles when it is locked into connection device; Infusion adapter add-on bag-access device; IV push adapter (connector) attaches to the patient’s IV line to connect to the injector; long design may be used with needle-free ports. Selection of IV infusion sets with PhaSeal connectors.

www.carmelpharma.com http://www.bd.com/ pharmacysolutions/phaseal/

ChemoClave Needle-free CSTD featuring Genie and Spiros

ICU Medical, Inc.

Genie vial adapter has a Clave needle-free valve connector and an internal balloon that expands inside the vial to equate pressures; Needle-Free syringe adapter (Spiros) closed male luer; CH-74 protected filter vial-access device for vials not accommodated by Genie; Clave CSTD bag spike and bag spike CSTD with Clave additive port and dry spike; large selection of administration devices.

http://www.icumed.com/products/oncology/hazardousdrug-closed-systems-andcstds/chemoclave-cstd.asp

ONGUARD Contained Medication System with Tevadaptor components

B. Braun Medical, Inc.

Dual-filtered vial-access device for 20-mm closures; converter ring included for vials with 13-mm closures, Needle-Safe syringe adapter clicks onto vial adapter with no twisting; IV bag adaptor with secondary set or/spike port adaptor; Needle-safe IV push adaptor.

http://www.bbraunusa. com/products.html?acs= 1&prid=PRID00006969& id=00020743040000000370

EQUASHIELD – HD CSTD

Equashield Medical, Ltd.

A proprietary syringe unit with 2 chambers, a liquid chamber and an air chamber, located at the end of the syringe piston is the containment device; a vial adapter attaches to the drug vial and the unique syringe clicks onto the vial adapter; shielded needles provide needle-safe protection; doublemembrane connectors are used between the syringe unit and other components: IV bag spike adaptor, luer lock adaptor; luer lock connectors (male and female luer lock connections to luer lock ports).

http://www.equashield.com/

CSTD, closed system transfer device; HD, hazardous drug

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detector, and inductively coupled plasma mass spectrometry techniques as appropriate.

Baseline results showed all of the surfaces sampled were contaminated with the marker drugs, including the surfaces of filled syringes and infusion bags.

During the intervention phase, isolator surfaces were below limits of detection of the assays and the contamination measured on gloves, preparation mats, and the surface of infusion containers was markedly lower than during the baseline period. Sewell concluded that the use of the Tevadaptor device reduced both the frequency and amount of surface contamination by cytotoxic drugs when the marker drugs were used in similar quantities as during the baseline period.25 The study also validated researcher concerns that the isolator is difficult to clean and any contamination left on the isolator surface may be transferred to the final product. Reducing the contamination on isolator surfaces reduced the contamination measured on gloves, preparation mats, and the final doses. The manufacturer sponsored the study.

Clark et al looked at contamination beyond the actual compounding BSC and the area immediately surrounding it, focusing on 5 areas adjacent to the pharmacy compounding area, including the dispensing counter, the half door and door handle, and areas in the infusion suite and offices areas.26 Twelve samples were taken during each of the 3 snap-shot periods: baseline, 60 days after implementation of the CSTD (EquaShield, Equashield Medical) and cleaning, and 1 year later. The results from the first 2 sets show low levels of contamination with CP in about half of the positions in the 3 departments during both collection periods. The results from the final collection period show no contamination above the limits of detection with CP or FU in the pharmacy, infusion suite, or offices of the cancer center. The authors concluded that this independent study showed that “implementation of the [CSTDs] for preparing and administering chemotherapy eliminated surface contamination with cytotoxic agents at the ambulatory cancer chemotherapy infusion center.” However, many factors would impact surface contamination in a yearlong period that could not be determined by a single snap shot of 12 wipe samples. For example, the amount of marker drugs (CP and FU) handled during the time preceding each sampling is not reported, nor is cleaning detailed during the year before the final sampling or in the period immediately preceding the final sampling. These factors would significantly affect the amount of surface contamination.

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Visual Assessments A strong visual assessment of the contamination generated using the traditional system compared with that generated with PhaSeal was published in 2003.32 In a Carmel Pharma–sponsored study done by a member of the Scientific Advisory Board of Carmel Pharma, fluorescein was prepared both as a dry powder and as a 0.05% solution in saline in 100-mL vials for use as a surrogate agent. A series of manipulations were performed, with the products scanned with UV light and photographed using a digital camera with the room lights turned off to enhance the visualization of the fluorescence. Multiple manipulations were performed with 60-mL syringes. The traditional preparation of needles, syringes, and unprotected IV ports resulted in leakage demonstrated by visual fluorescence, whereas the PhaSeal system resulted in no visual leakage.

Although no attempt was made to quantify the leakage, and visual fluorescence is not a sensitive method of assessment, this study presents a relatively easy and inexpensive evaluation of any device purporting to be a “closed system.”

Equashield contracted a fluorescein study with an outside analytical laboratory in 2009 to evaluate dry connections in the EquaShield, PhaSeal, and Tevadaptor/Onguard CSTDs.33 This study used small vials of 0.05% fluorescein solution with multiple transfers of 2-, 5-, and 7-mL done with 20-mL syringes. Ten to 15 transfers were done with visual leakage assessed using UV light and photography. Administration simulation was done as 10 manipulations. This product-sponsored study resulted in only Equashield being residue-free during all manipulations. Both Tevadaptor/OnGuard, and PhaSeal showed leakage. Of PhaSeal systems, 40% showed leakage after a considerable number of manipulations (between 8 and 15 manipulations). As PhaSeal restricts the use of its system to 10 manipulations, most of these leaks would be outside the parameters of appropriate use. As with other visual assessments, no attempts are made to quantify the “leakage.”

An alternative visual method of assessing the integrity of devices marketed as closed systems was developed at a major university medical center by another member of the Scientific Advisory Board of Carmel Pharma.34 A literal litmus test for examining leakage between 2 components of selected CSTD systems, the vial caps and the syringe adapters, was done by filling syringes with an unidentified low pH liquid and injecting the fluid into vials attached to selected transfer devices.

After aspirating back and disconnecting, the connections of each device were pressed against litmus paper

to detect the presence of any fluid. Every component of each device was tested for 10 manipulations. In this test, visible leakage occurred outside of the components on the ICU Medical System Spiros and Clave connections; the B.Braun OnGuard System; and the Cardinal Health/ Alaris System during all manipulations. No leakage was observed in any of the manipulations with the PhaSeal System. It should be noted that PhaSeal has the most recessed membranes of any of the available CSTDs, making the vial cap adaptor and the syringe adapter the most difficult to swab during aseptic processes. The recessed membranes also are difficult to access with the litmus paper, possibly reducing the wicking of liquid from the membranes.

This test presents another simple and inexpensive method for an initial assessment of CSTDs. It should be noted, however, that this system, as the fluorescein, provides no quantitative data to determine if any of these systems would meet a performance standard.

Visual Assessment for Vapor: To Filter or Not To Filter Several HDs are believed to vaporize at normal atmospheric conditions, thus by the terms of the CSTD definitions, closed systems must contain vapor. A unique system for creating a vapor was formulated at a major university medical center and the visual demonstration published by 2 members of Carmel Pharmaâ&#x20AC;&#x2122;s Pharmacy Advisory Board.35 Developed by the University of Utah in 2007, titanium tetrachloride (TiCl4) provides a strong visual measure of containment. This protocol showed that all systems available at the time, with the exception of PhaSeal, failed a vapor challenge.

However, the appropriateness of TiCl4 as a surrogate has been questioned. It has no properties similar to any of the available HDs and it is not a quantifiable chemical. It is difficult to use and has its own hazards. The demonstration itself shows a single attempt at containment by each of the devices. The authors noted that an independent laboratory reproduced the test, but they did not report the number of replications and conditions of the testing.

In direct rebuttal to the University of Utah study, B. Braun and Teva conducted 2 studies.36,37 The Teva laboratory repeated the TiCl4 smoke tests with Tevadaptor, and saw no smoke escaping from the system.36 After a repeated injection of smoke, the venting channels of the system appeared to get blocked by a white substance (TiO2) and no more smoke could be injected. When very high pressure was applied to try to force more smoke in the vial, in most cases, the blocked

venting channels prevented further use of the system.

On one occasion, smoke was seen to escape from the system. On visual inspection of this test sample, the Tevadaptor membrane appeared to be damaged by the hydrochloric acid that is formed in the reaction of TiCl4 with moist air in combination with the pressure forcefully applied to the system. B.Braun compared physical and chemical characteristics of actual HDs to those of TiCl4 in a contracted report and demonstrated the effectiveness of the Tevadaptor filters with etoposide, carboplatin, doxorubicin, and CP in tests conducted by an independent laboratory.37 Equashield tested its device against PhaSeal and the ICU Genie/Clave with TiCl4 in a paid laboratory protocol.38 ICUâ&#x20AC;&#x2122;s product did not contain the vapor. The Equashield system appeared as effective as PhaSeal in visually containing the vapor.

Surrogate Interventions: Technetium Several quantitative studies have been done with radioactive technetium. Many of the CSTD systems contain this surrogate because it is a true particle not a vapor. Radiation, however, has its own safety and exposure limits, and manipulating large volumes of up to 50 mL in 60-mL syringes using multiple transfers may exceed these limits. Technetium also has a short half-life, so activities and measurements must be taken immediately. Systems requiring more time would show smaller volumes transferred. These issues present an argument against using radioactive technetium as a useful surrogate.

A study by Nygren et al investigated the difference in airborne emission and surface leakage with the traditional open technique and the PhaSeal system.17 Platinum was used for the airborne emission tracer, with air samples taken in the preparation and administration areas. The radioisotope technetium 99m was used to measure spills and leakage on surfaces by measuring radiation on gloves and benchtops. Ten nurses were the test participants and each nurse prepared and administered 6 doses in the open system and the closed system via IV push. There was a large variation in leakage among the nurses using the traditional system for preparation and administration. The closed system resulted in a decrease in measured radiation of 3 to 4 orders of magnitude. Airborne emission was difficult to measure but was less than surface leakage when the PhaSeal system was put into use. However, the difference in airborne emission between the techniques was small and not statistically significant.

The authors concluded that when using the traditional

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technique, even skilled nurses encounter large spills and have difficulty avoiding leakage. In contrast, inexperienced nurses could, after a short introduction, use the PhaSeal system with only minor spills.

The small number of participants and the fact that doses of only 6-mL volumes in small syringes were used weaken this study. It is surprising that there was significant leakage with such small syringes and volumes. Many HD doses are much larger and require larger volumes (60-mL syringes), creating significantly more risks for leakage and spills, so this simulation is limited in its scope.

In another study, Nygren et al tested the Tevadaptor for spill and leakage during drug preparation using a radioactive technetium surrogate as in previous studies.18,29 In the test procedure, 6 mL was withdrawn from a 10-mL vial of technetium surrogate, using a disposable syringe and the Tevadaptor. The syringe was then disconnected from the vial and connected to an infusion bag using a connection device for the Tevadaptor and the content was injected into the IV bag. After the injection, the syringe was disconnected from the infusion bag. Bench covers were used to capture any radioactive surrogate leaked during the process. The bench cover and the gloves were collected after each preparation and measured for radioactivity, which would indicate leakage.

The test results showed the spill was less than 100 nL for all 75 preparations and was less than 1 nL for 70 of the preparations. This is comparable with the previous study of PhaSeal.17 The test shows that the Tevadaptor drughandling system has similar performance as drug-handling systems regarded as closed systems.

French researchers used a radioactive solution of sodium pertechnetate per the Nygren study29 to evaluate multiple CSTDs using several criteria.27 Four devices available in the United States and France were compared: PhaSeal with expansion chamber; Tevadaptor with filter; Clave with filter and Spiros; and Smartsite with filter and Texium. Evaluation criteria included transfer performance of the radioactive solution from one vial to another measuring leakage, contamination, dead space, residual volume, and efficiency. No details of training on use of the systems was included, but PhaSeal is noted not to be intuitive to use and several of the areas where PhaSeal scored low may be due to the fact that the operator was not familiar with the need to accommodate air/fluid transfers by drawing air into the syringe before transfer. Because the other CSTDs compared are filter systems, they are used more easily with no training. As with all test systems using radioactive

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solutions, the volumes transferred in this study were quite small (only 2-mL syringes were used), but small syringes and volumes are not true tests of HD transfers.

Additionally, the half-life of this agent is quite short, so the time required performing a task negatively affects the perceived efficiency. Although PhaSeal scored high in containment, the weighted rating for that function was less than for efficiency, where it scored badly. Efficiency and operator ease-of-use scores made PhaSeal the least acceptable in this study.

A US group also used a liquid radioactive technetium isotope as a surrogate to evaluate several systems: ChemoClave with Genie and Spiros; OnGuard with Tevadaptor components; and PhaSeal.28 Using a variation of the test method proposed by Nygren,29 investigators used wipes to sample for surrogate leakage on the CSTD connections. Nine manufacturer-trained oncology pharmacists and pharmacy technicians each manipulated one system set of 15 preparations.

Syringe and vial adapters were connected, and 6 mL of the test solution was drawn into the syringe; then the vials and syringe adapters were disconnected, and a 70% isopropyl alcohol prep pad was wiped on the usual entry points of the syringe and paired spiked vial adapters. Because the OnGuard syringe and PhaSeal vial adapters have an outer rim that projects from and surrounds the points of vial entry, the prep pads were inserted into these enclosed spaces and turned 720 degrees twice. As in the Nygren study,29 the researchers controlled for the time lapse from collection to performance of measurements to correct for degradation of the surrogate. Comparisons among participants and devices were conducted via analysis of variance (ANOVA) on 135 wipe samples per system (15 wipe samples per each of 9 participants).

ANOVA results indicated significant differences among devices in leakage of the test solution, with the PhaSeal device having the lowest geometric mean leakage (0.1 nL; 95% confidence interval [CI], 0-0.2 nL), followed by the OnGuard (1.5 nL; 95% CI, 1.1-1.9 nL) and ChemoClave (35.6 nL; 95% CI, 29.1-43.6 nL) devices.

Overall, the reported leak volumes were small. The authors noted that the clinical implications of the leakage levels detected are unknown and that there are no standard amounts or limits above which clinically significant complications, such as secondary malignancies, are known to arise.

Other Factors A Canadian medical center compared 3 CSTD systemsâ&#x20AC;&#x201D;PhaSeal, OnGuard, and ChemoClave

(components not reported)—to identify any negative, user-related issues.39 Using a prospective, within-subject study design, in which each participant completed a task using each system in counterbalanced order. Mixing and administration were done with a visual fluorescein marker. Quantitative data was collected about error and success rates using a checklist, along with qualitative data about participant’s experiences using a questionnaire, photos, and video. Twelve nurses and 12 pharmacy assistants participated in the study.

PhaSeal required the most amount of time to complete the tasks overall. PhaSeal and OnGuard showed comparable effectiveness based on the amount of fluorescein detected on critical sites. PhaSeal generally scored lower on user preference and user comments about ease of training. ChemoClave required the least amount of time to complete the tasks for both pharmacy assistants and nurses; however, it appeared to be the least effective based on the amount of fluorescein detected on critical sites. The author concludes that no CSTD system is perfect; all systems showed varying degrees of usability challenges. Each system requires proper staff training, and reliance on user intuitiveness is not enough.

Conclusion There are a number of FDA-cleared Class II medical devices that are marketed as “CSTDs” or other “closed” or “contained” systems, and they differ in how they attempt to meet the NIOSH definition of a CSTD. A variety of surrogates and test systems have been used to evaluate these devices for their effectiveness in reducing surface contamination generated in the handling of HDs, thereby reducing occupational exposure to these harmful agents. Results from the reviewed intervention studies indicate that closed systems provide better protection from HD exposure than traditional techniques. This is especially true with administration tasks. In clinical settings, studies done predominantly with PhaSeal, provided varying results.

Whereas in some studies, environmental monitoring showed little or no contamination, others showed that contamination did occur, although at lower levels.

Use of a closed system is shown to reduce leakage of HDs during normal drug preparation and administration activities, compared with the use of needles and syringes, but these devices do not completely eliminate exposure. Some of the factors that influence exposure may include user technique, BSC function, and unpredictable occurrences such as breakage or spills. Because leakage did occur in several studies,

the products cannot be considered completely “closed systems.” Thus, closed systems should be considered adjuncts to, and not substitutes for, other safe handling precautions.

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