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The Pharmacist’s News Source

pharmacypracticenews.com

Volum me 40 • Number 8 • August 2013

Printer-friendly versions available online

in this issue UP FRONT

4

MRI detects spinal infections from contaminated NECC steroids

POLICY

10 12

FAQs on outsourcing versus insourcing of sterile products 340B: Get ready for audits and possible legislative changes

CLINICAL

MEETING HIGHLIGHTS

44

Making treatment decisions for patients with antibiotic hypersensitivity

55

IVIG FAQ: dosing considerations in obese patients.

Pharmacists Feeling Pain Over AMA Resolution

T

Physician group blasts profession’s ‘intrusion into medicall practice’

he American College of Physicians (ACP) has advised clinicians not to use intensive insulin therapy (IIT) to manage hyperglycemia in surgical and medical intensive care unit (SICU and MICU) patients with or without diabetes.

The ACP concluded that targeting blood glucose levels between 80 and 100 mg/dL does not lower the risk for ICU-related mortality and increases the risk for hypoglycemia by more than five times.

Amir Qaseem, MD, PhD, MHA, the director of the ACP’s Department of Clinical Policy and lead author of the ACP report ((Am J Med Qual 2013 May 23. [Epub ahead of print]), said he is “very confident” in the recommendation that clinicians use blood glucose targets of 140 to 200 mg/dL in these ICU populations. “Although many hospitals and health care systems developed protocols to implement IIT routinely in critically ill patients,

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OPERATIONS & MGMT

58

Tight Control Of ICU Glucose Takes a Big Hit

In this month’s Leadership in Action column, Ernest Anderson Jr., asks, ‘Are you really in charge?’

EDUCATIONAL REVIEW

The Future of Antibiotics: Preserving A Precious Commodity See page 38.

see ICU GLUCOSE, page 52

Casting a Wider Safety Net For Elderly Patients Minneapolis—The Pharmacological Intervention in Late Life (PILL) Service, an innovative elderly care outreach program developed by the Veterans Administration Boston Healthcare System (VABHS), has reduced 60-day hospital readmissions and improved a host of other clinical outcomes.

The PILL Service has shown its economic worth as well: In 2012, the

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see PILL SERVICE, page 48

A

bluntly worded American Medical M Association (AMA) resolutio on that was intended to curb a barragge of retail pharmacy phone calls to p physicians requesting additional infformation about pain medication prrescriptions has triggered a backlaash from pharmacists, some of who om objected to the resolution’s shaarp tone as a departure from the mo ostly collegial relationships that exist between the two professions.

“It’s a step backward,” said David D Craig, PharmD, BCPS, a clinicaal pharmacy specialist at the H. Leee Moffitt Cancer Center and Research h Institute, in Tampa, Fla. “I work collabo oratively witth many physicians who do not agrree with this reso lution at all. In fact, they welccome any pharrmaacccis ist’ ts input, advice and recommendattions.”

The policy passed by the AM MA House of Delegates in June was written in reesponse to what th the he

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see AMA RESOLUTION, page 116 6

Big Ideas for Boosting Drug Safety Minneapolis—The 2013 Summer Meeting of the American Society of Health-System Pharmacists, a smaller version of the mammoth Midyear Meeting held each fall, included some big ideas nevertheless. Here, we cover several noteworthy posters dealing with diverse aspects of medication safety.

Insulin Is Unrecognized Source of Errors Only after it installed an automated adverse drug event (ADE) surveillance system did BJC Healthcare—a 13-hospital system in the St. Louis region—realize that 75% of all ADEs occurring throughout its network resulted from insulin-related severe hypoglycemia.

FDA Watch

“Severe hypoglycemia wasn’t on anybody’s radar,” said Paul Milligan, PharmD, the senior clinical lead at BJC Learning Institute’s Center for Clinical Excellence.

The new system also was used to document the underlying causes of harm and generated monthly hospital-specific reports. And it pinpointed, by hospital (even down to the unit level), where the harm occurred. Previous ADE surveillance relied on self-reporting or random sampling, as many health systems still do. That process, Dr. Milligan noted, was arduous, time-consuming and could be misleading because information about the underlying

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see BIG IDEAS, page 46

The Book Page

Telavancin receives nosocomial pneumonia indication.

Handbook on Injectable Drugs: 17th Edition

See page 54.

See page 57.

Lawrence A. Trissel, FASHP

ge

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For the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

Start with TREANDA® (bendamustine HCI) for Injection for established front-line CLL therapy Single-agent TREANDA tripled median PFS Progression-free survival (PFS)* Survival distribution function

1.0 TREANDA (n=153)

0.9

Chlorambucil (n=148)

18 Months

0.8

median PFS

0.7 0.6 0.5 0.4

6 Months

0.3

median PFS

0.2 P<.0001 HR=0.27 (95% CI: 0.17, 0.43)

0.1 0 0

5

10

15

20

25

30

Months

*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6).

HR=hazard ratio.

CI=confidence interval.

TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I–IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles.

The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia.

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL).

Efficacy relative to first-line therapies other than chlorambucil has not been established.

• TREANDA is administered with a convenient dosing schedule – The recommended CLL dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol.

Women should be advised to avoid becoming pregnant while using TREANDA Please see accompanying brief summary of full Prescribing Information.

Learn more at TREANDAHCP.com ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2576c January 2013

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established.

CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely.

In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration].] Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections.

Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death.

Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema.

Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert).

Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies.

There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions]] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial.

The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.

Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions]] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. •Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.

DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

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Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates.

TRE-2511e (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

November 2012

4 Up Front

Pharmacy Practice News • August 2013

Capsules

surf

MRI Detects Spinal Infections From Contaminated Steroids

AUGUST 2013

watch

M

The five most-viewed articles last month on pharmacypracticenews.com: 1. Oral Oncology Drugs Rife With Challenges 2. Operating Room Noise May Pose Risks to Clinicians 3. Acid-Suppressing Drugs Overprescribed in Infants 4. Discharge Plan Reduces COPD 5. Solving Difficult Drugs and Devices Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘If 340B were to go away, hospitals would be forced to

close pharmacies, suffer reductions in work force, and reduce or eliminate patient access to medications as well as other comprehensive services.’

—Lisa Scholz, PharmD

See article, page 12

agnetic resonance imaging is able to identify patients with fungal spinal or paraspinal infection, even if the patients have no new or worsening symptoms, according to a new study.

“We found infections in patients with little to no symptoms,” said lead author Anurag N. Malani, MD, the medical director of the Infection Prevention & Antimicrobial Stewardship Programs at Saint Joseph Mercy Health System, in Ann Arbor, Mich. “And signs and symptoms can be subtle, difficult to distinguish from chronic pain,”Dr. Malani told Pharmacy Practice News.

Evaluating patients from a single site in Michigan, who were at risk for infection because they had received methylprednisolone injections from a contaminated lot prepared at New England Compounding Center, the source of last fall’s multistate outbreak of meningitis, Dr. Malani and colleagues identified 172 patients who had received contaminated methylprednisolone and had not sought related medical care (JAMA 2013;309:2465-2472). Of these patients, 108 (63%) had a normal magnetic resonance imaging (MRI) scan, 30 (17%) had an equivocal result and 34 (20%) had an abnormal MRI scan. The abnormalities included phlegmon; abscess; osteomyelitis or diskitis; and arachnoiditis. Twenty-five of the patients with equivocal findings were rescreened, and two were found to have abnormal scans, for a total of 36 patients (21%) with abnormal MRI results.

Of those, 35 met the Centers for Disease Control and Prevention’s case definition for probable fungal spinal or paraspinal infection. Thirteen of the patients with an abnormal MRI result were asymptomatic: They had no change in back or neck pain, no evidence of radiculopathy and no lower-extremity weakness. The 35 patients with probable infection received antifungal therapy: voriconazole with or without liposomal amphotericin B. Twenty-four patients underwent surgery, and 17 of those became confirmed cases when laboratory evidence of fungal infection was found.

Study limitations, according to the authors, include the small numbers of patients and uncertainty as to whether early treatment due to MRI findings will improve outcomes. It also is not known, they wrote, whether the results can be generalized to all patients who received tainted methylprednisolone, especially those exposed to less heavily contaminated lots.

Patients in the study were exposed to the highly contaminated lot 06, which “had a higher risk of developing infections than lots 05 and 08,” said Dr. Malani.

Thomas F. Patterson, MD, FACP, FIDSA, a co-author of an editorial accompanying the study (JAMA 2013;309:2493-2495) told Pharmacy Practice News that “the MRI results are subtle and often difficult to interpret, leading to perhaps overtreatment of some patients.”

MRI scans “are costly tests with potential side effects of their own—making the risk–benefit ratio uncertain, especially this late after the contaminated injections occurred, noted Dr. Patterson, the chief of the Division of Infectious Diseases, a professor of medicine and the director of the San Antonio Center for Medical Mycology at The University of Texas Health Science Center at San Antonio. “These findings suggest that careful follow-up by patients’ individual physicians is needed. If symptoms persist or worsen, then additional testing, including MRI of the spine, may be needed.”

—George Ochoa Dr. Malani reported being on the speakers’ bureau for Cubist and a shareholder of Pfizer.

Dr. Patterson reported serving on data review committees and scientific advisory boards for Astellas, Merck, Pfizer, Toyoma and Viamet, receiving grants from Astellas and Merck and receiving payment for lectures from Merck and Pfizer. Dr. Thompson reported no relevant financial conflicts of interest.

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Volume 40 • Number 8 • August 2013 • pharmacypracticenews.com

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Individual issues are $7.00 (U.S.) or $10.00 (outside U.S.).

McMahon Publishing is a 41-year-old, first-generation, family-owned publishing company dedicated to providing medical professionals with essential, up-to-date news. As

the second largest publisher of medical newspapers, McMahon produces Anesthesiology News, Clinical Oncology News, Gastroenterology & Endoscopy News, General Surgery News, Infectious Disease Special Edition, Pain Medicine News, Pharmacy Practice News.

Rheumatology Practice News and Specialty Pharmacy Continuum.

INFECTIOUS DISEASES

REIMBURSEMENT

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH Peggy McKinnon, PharmD, Lexington, M MA

Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

A family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers and several annual or semiannual Special Editions.

Matt Spoto, Senior Account Manager mspoto@mcmahonmed.com

new release 2013

introducing

NOW AVAILABLE as an Interactive Searchable Database for Drug Selection, Interpretation, and Quality Control Procedures!

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

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This online implementation of CLSI’s most widely recognized antimicrobial susceptibility testing document provides information for drug selection, interpretation, and quality control as well as the latest recommendations for detecting resistance mechanisms, all arranged in an easy-to-use, interactive, and searchable format.

Sort information by tables, organisms, and agents.

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customer service at 610.688.0100 or customerservice@clsi.org.

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6 Policy

Pharmacy Practice News • August 2013

Reimbursement Matters

“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health.

Please email the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Your New Reimbursement BFF? CMS.gov!

E

nsuring accurate reimbursement for medications and procedures is a daunting task if you haven’t yet grasped the fundamentals of proper coding and billing, hence my May 2013 column on the basics of how to ensure accurate payments (“Time To Take Leadership With Billing and Data Transmission,” page 12). To keep the learning momentum going, here’s a few additional concepts and strategies you’ll need to embrace in

order to keep the funds flowing from the Centers for Medicare & Medicaid Services (CMS) and other payors.

First, however, a quick review: As I noted in my previous column, all payors use the same basic code sets that are set by either CMS or the American Medical Association. I also emphasized that no matter how eloquent you are in your description of what medications or services you provide for the patient, the

method for transmitting this information to the payor is through an assigned code.

This also applies to the collection and analysis of aggregate data and the subsequent decisions that are based on that data and that then drive reimbursement at the national level.

Getting in the Info Loop Now that we have those basics down pat, let’s consider a few key reimburse-

ment strategies to get you going in the right direction. One of the best steps for you to take is to ensure that you have a strong flow of information regarding changes to reimbursement policies and procedures. To that end, I’m a big fan of creating an e-library to have at your fingertips and keeping its contents current.

Or you can rely on the information that is sent to your facility, eventually filtering its way in a timely fashion (hopefully) down to the pharmacy department and the individuals who need to implement changes and updates. Here are some key documents and links to get started:

1

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responsive way of doing business delivers unsurpassed customer service, consistent quality, convenience and a steady pipeline of essential products to your organization.

At Amneal, we understand that you are committed to providing each and every patient with the best care, in the right form, accurately and in a timely manner.

Amneal has proven itself as a vital partner in that equation. * In prescriptions of unbranded generics per IMS, March 2013

Our newest product:

Zoledronic Acid Injection Available in Single Use Vials

a m n ea l.com Copyright © 2013 Amneal Pharmaceuticals, All Rights Reserved - AI-ZOL-0613-PPN

Bonnie Kirschenbaum, MS, FASHP

Healthcare Common Procedure Coding System (HCPCS) Codes.

These are the codes that describe medications and products that may be reimbursed. The HCPCS Quarterly Update is available for download. Find this at http://www.cms.gov/Medicare/Coding/HCPCSReleaseCodeSets/HCPCS_ Quarterly_Update.html. The file can be viewed in a number of ways, including alphanumeric or a table of drugs, and is sortable by year. Find those views at http://www.cms.gov/Medicare/Coding/HCPCSReleaseCodeSets/AlphaNumeric-HCPCS.html and further sort as needed. The accompanying screenshot provides a glimpse into the wealth of information available.

Updates from your Medicare administrative contractor (MAC).

CMS has divided the country into geographic regions and assigned a MAC to serve as an intermediary between your facility and CMS. All financial transactions are submitted to the MAC, who is responsible for processing them for payment. There are subtle differences between how each MAC chooses to operate, the documentation the MAC requires and how a variety of other issues are handled. It’s imperative that you know who the MAC is for your region and that you get onto its e-distribution mailing list for updates. The following link will

2

Policy 7

Pharmacy Practice News • August 2013

Reimbursement Matters take you to an interactive map. Click on the state you’re interested in and the site will provide contact information http:// www.cms.gov/Research-Statistics-Dataand-Systems/Monitoring-Programs/ provider-compliance-interactive-map/ index.html. Of course, you’ll be getting all information—not just that pertinent to pharmacy—but it’s easy to scan and discard these quickly. Save the pertinent ones or their links in your e-library. Be careful when you call a colleague in a different region and ask for help. The answer you get may not be what your MAC is looking for. Rather than succumb to myths, find the facts that apply to you!

MedLearnNetwork (MLN) Matters Newsletters. Having the MLN newsletters in your e-library is vital to understanding the actions that you need to take to ensure reimbursement when it’s available. If you don’t ask for it correctly, you definitely won’t be getting the correct amount of updates! Put yourself on the mailing list to keep current and search back issues to establish a baseline; older or original announcements still prevail if nothing has changed. Search through the entire document, and remember that several payment issues may be covered in one publication. Use these links: · CMS Medicare Learning Network at http://www.cms.hhs.gov/MLNProducts/downloads. · Archive of MLN Matters articles notices as of June 2007 at https://list.nih. gov/cgi-in/wa.exe?A0=MLNMATTERSL. To make sure you’re accessing the most helpful recent updates, start by putting MLN Matters Number MM8338, released June 7, 2013 and effective July 1, 2013, at the top of your list. The MLN Matters section on Billing for Drugs, Biologicals, and Radiopharmaceuticals contains a wealth of information on medications that have payments based on average sales price, effective July 1, 2013.

It also lists drugs that have payments based on Outpatient Prospective Payment System (OPPS) pass-through status that took effect July 1, 2013, such as Flublok (influenza virus vaccine) and Fluarix quadrivalent (influenza virus vaccine).

Doxil, 10 mg) was replaced with HCPCS code Q2050 effective July 1, 2013. The status indicator for HCPCS code J9002 was changed to E, “Not Payable by Medicare,” effective July 1, 2013. · HCPCS code J3487 (Injection, Zoledronic Acid [Zometa], 1 mg) and HCPCS code J3488 (Injection, Zoledronic Acid [Reclast], 1 mg) were replaced with HCPCS code Q2051 effective July 1, 2013. The status indicators for HCPCS codes J3487 and J3488 were changed to E, “Not Payable by Medicare,” effective July 1, 2013.

I would strongly suggest you use these two very important code changes as a test case—review the billing steps at your facility and if the changes aren’t yet in the system, fix what’s not working! Here are some key questions to ask during that self-evaluation: Q: How did your pharmacy department receive this information?

Q: Who is responsible for making these changes in your pharmacy computer system pharmacy drug master (PDM) or drug library?

Q: How did the CDM get changed

so that it matches the PDM or drug list?

Q: How are you going to identify patients who require rebilling if this slipped through the cracks and wasn’t implemented by July 1?

Like so many quality improvement initiatives, if you’re not asking the right questions, you won’t get the right answers when it comes to improving your reimbursement policies and procedures. Good luck in entering this process honestly and thoroughly. The rewards you reap will be well worth the effort!

■

3

Code Changes for Doxorubicin And Zoledonic Acid Here are two specific examples of important code changes that you might have missed without a system in place for obtaining important payment updates: · HCPCS code J9002 (Injection, Doxorubicin Hydrochloride, Liposomal,

340 B Alert: Is Program in Danger?

Legislative initiatives to limit the scope of the 340B drug pricing program are brewing, and hospitals are nervous about the future of the deep discounts. An update on these developments, along with tips for surviving a 340B audit, start on page 12.

N NOW APP APPROVED Kcentra

DURING WARFARINRELATED BLEEDS…

bin othrom eversal r P r o t R ac irst 4-F ent Warfarin F e h t Urg a™— Kcentr CC) for g P n F i c 4 ( u e Introd centrat n o C x e Compl Important Safety Information Kcentra is indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA—eg, warfarin) therapy in adult patients with acute major bleeding. Kcentra is not indicated for urgent reversal of VKA anticoagulation in patients without acute major bleeding. Kcentra is for intravenous use only.

Warning: Patients being treated with Vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events.

Potential benefits of reversing VKA should be weighed against the risk of thromboembolic events, especially in patients with history of such events.

Resumption of anticoagulation therapy should be carefully considered once the risk of thromboembolic events outweighs the risk of acute bleeding. Both fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance. Monitor patients receiving Kcentra, and inform them of signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation (DIC), cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra might not be suitable for patients with thromboembolic events in the prior 3 months.

Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any of its components (including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin). Kcentra is also contraindicated in patients with DIC. Because Kcentra contains heparin, it is contraindicated in patients with heparin-induced thrombocytopenia (HIT).

Hypersensitivity reactions to Kcentra may occur. If patient experiences severe allergic or anaphylactic type reactions, discontinue administration and institute appropriate treatment.

In clinical trials, the most frequent (≥2.8%) adverse reactions observed in subjects receiving Kcentra were headache, nausea/vomiting, arthralgia, and hypotension.

The most serious adverse reactions were thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis.

Kcentra is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.

The safety and efficacy of Kcentra in pediatric use have not been studied, and Kcentra should be used in women who are pregnant or nursing only if clearly needed.

Please see brief summary of full prescribing information on reverse.

Approved by the FDA for the urgent reversal of Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute major bleeding Non-activated 4F-PCC containing Vitamin K– dependent coagulation Factors II, VII, IX, and X, and antithrombotic Proteins C and S

Kcentra has over 15 years of clinical experience as Beriplex® in 25 countries.

For more information, please visit www.Kcentra.com or call the toll-free Kcentra Hotline: 1-855-4KCENTRA (1-855-452-3687)

Urgent Warfarin Reversal Kcentra is manufactured by CSL Behring GmbH and is distributed by CSL Behring LLC. Kcentra is a trademark of CSL Behring and Beriplex is a registered trademark of CSL Behring GmbH. ©2013 CSL Behring LLC 1020 First Avenue, PO Box 61501, King of Prussia, PA 19406-0901 USA www.CSLBehring-us.com www.Kcentra.com KCT11-12-0003 7/2013

8 Policy

Pharmacy Practice News • August 2013

Medication Safety

Older Heparin Labels Still on Shelves During transition to new vial label, extra precautions urged

I

t’s been several months since the U.S. Pharmacopeial Convention (USP) updated labeling standards for Heparin Sodium Injection, USP, and Heparin Lock Flush Solution, USP, in an effort to reduce the risk for medication errrors. But according to a recent alert from the National Alert Network (NAN), some older, problematic ver-

‘Although the [NAN] alert says you could use up [supplies of heparin] with the older label, it’s probably safer to remove and replace it with the new labeled product.’

—Bona E. Benjamin, BS Pharm

sions of the heparin label remain in pharmacy stocks. Thus, precautions

KCENTRA™ (Prothrombin Complex Concentrate [Human]) For Intravenous Use, Lyophilized Powder for Reconstitution Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use KCENTRA safely and effectively. See full prescribing information for KCENTRA. WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the potential risks of thromboembolic events, especially in patients with the history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding.

BBoth fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events.

BKcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months.

---------------------------------INDICATIONS AND USAGE-----------------------------------Kcentra, Prothrombin Complex Concentrate (Human), is indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute major bleeding.

Kcentra is not indicated for urgent reversal of VKA anticoagulation in patients without acute major bleeding.

-----------------------------DOSAGE AND ADMINISTRATION--------------------------------For intravenous use only I Kcentra dosing should be individualized based on the patient’s baseline International Normalized Ratio (INR) value, and body weight.

I Administer Vitamin K concurrently to patients receiving Kcentra to maintain factor levels once the effects of Kcentra have diminished.

B Repeat dosing with Kcentra is not supported by clinical data and is not recommended.

I Administer reconstituted Kcentra at a rate of 0.12 mL/kg/min (~3 units/kg/min) up to a maximum rate of 8.4 mL/min (~210 units/min.).

Pre-treatment INR

need to be taken to reduce the risk for more heparin mishaps.

2–<4

4–6

>6

Dose* of Kcentra (units† of Factor IX) / kg body weight

25

35

50

Maximum dose‡ (units of Factor IX)

Not to exceed 2500

Not to exceed 3500

Not to exceed 5000

* Base dosing on actual potency, which is stated on the carton and will vary from 20-31 Factor IX units/mL. Nominal potency is 500 units per vial, approximately 25 units per mL after reconstitution. † Units refer to International Units. ‡ Dose is based on body weight up to but not exceeding 100 kg. Do not exceed stated maximum dose for patients weighing more than 100 kg.

--------------------------------DOSAGE FORMS AND STRENGTHS-------------------------I Kcentra is available as a single-use vial containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S as a lyophilized concentrate.

-------------------------------------CONTRAINDICATIONS ------------------------------------Kcentra is contraindicated in patients with: I Known anaphylactic or severe systemic reactions to Kcentra or any components in Kcentra including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and Human albumin.

I Disseminated intravascular coagulation.

I Known heparin-induced thrombocytopenia. Kcentra contains heparin.

--------------------------------WARNINGS AND PRECAUTIONS-----------------------------IHypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment.

I Arterial and venous thromboembolic complications have been reported in patients receiving Kcentra. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thrombotic or thromboembolic (TE) event within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months.

I Kcentra is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

------------------------------------ADVERSE REACTIONS--------------------------------------IThe most common adverse reactions (ARs) (frequency *2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, arthralgia, and hypotension.

IThe most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis.

To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-9156958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

-----------------------------USE IN SPECIFIC POPULATIONS---------------------------------Pregnancy: No human or animal data. Use only if clearly needed.

Based on April 2013 version.

The revisions, which took effect May 1, stipulate that the label of new heparin products present clearly the strength of the entire container of medication, followed by how much medication is in each milliliter (mL), according to the USP website and the NAN alert. In the past, the label emphasized the per mL amount, with the container volume appearing elsewhere. This led to errors in which practitioners misunderstood the per mL amount as the total amount in the vial, and on that basis administered dangerous heparin overdoses.

The NAN alert cites a recently reported example, in which a nurse and medical resident intended to administer a dose of 3,000 units of heparin to a patient. Both practitioners mistakenly thought that each 10-mL vial of heparin held a total of 1,000 units, when each vial actually contained 10,000 units (1,000 units/mL). As a result, they administered 30,000 units to the patient instead of 3,000. The error was fatal, with the patient dying after developing an intracranial hemorrhage and brainstem herniation.

‘Don’t expect or hope that people will see the new [heparin] label; that’s not a good strategy to prevent errors. Be proactive in informing them.’

—Matthew Grissinger, RPh, FASCP A Long-Awaited Change For Safer Labeling “We’ve been waiting for a change in the heparin label for quite a while,” Bona E. Benjamin, BS Pharm, the director of Medication-Use Quality Improvement for the American Society of HealthSystem Pharmacists, in Bethesda, Md., told Pharmacy Practice News. “The total drug content of a container as well as the concentration is important information for pharmacists.” Ms. Benjamin noted that she works with Michael R. Cohen, RPh, MS, ScD, FASHP, the president of the Institute for Safe Medication Practices (ISMP), to author and distribute the NAN alerts, through members of the National Coordinating Council for Medication Error Reporting and Prevention.

There will be a transition period during which vials with both the old label and the new will be available, according to the NAN alert. “Although the alert says you could use up the product with

•

see HEPARIN, page 14

Policy 9

Pharmacy Practice News • August 2013

Medication Safety

FDA Takes Action Against Illegal Online Pharmacies the websites included: • Avandaryl (glimepiridee and rosiglitazone): Used to treat type 2 diabetes and to minimize potential associated risks, including edema caused byy fluid retention or heart failure, Avandaryl must be prescribed by a certified health care provider and dispensed by a certified pharmacy

with a medication guide explainw in ng the potential risks.

• “Generic Celebrex”: FDAapproved, brand-name Celebrex (celecoxib) is used to treat the signs and symptoms of osteoarthritis and

rheumatoid arthritis and to manage acute pain in adults. There is no FDA-approved generic version of this product. To minimize the potential associated risks, including gastroin-

•

see ONLINE PHARMACIES, page 13

ANTI-INFECTIVES

MEROPENEM.

uring the last two weeks of June, the FDA took action against more than 9,600 websites that illegally sell potentially dangerous, unapproved prescription medicines to consumers.

Working with international regulatory and law enforcement agencies, the FDA seized offending websites and more than $41 million worth of illegal medicines worldwide.

“Illegal online pharmacies put American consumers’ health at risk by selling potentially dangerous products,” said John Roth, the director of the FDA’s Office of Criminal Investigations, in a statement. “This is an ongoing battle in the United States and abroad, and the FDA will continue its criminal law enforcement and regulatory efforts.”

The FDA’s action occurred as part of the sixth annual International Internet Week of Action, a global cooperative effort to combat the online sale and distribution of potentially counterfeit and illegal medical products. The international operation, called Operation Pangea, took place from June 18 to June 25. During this year’s effort, Operation Pangea VI, the FDA’s Office of Criminal Investigations worked in coordination with the U.S. Attorney’s Office for the District of Colorado to seize and shut down 1,677 illegal pharmacy websites.

According to the FDA, many of the websites they encountered appeared to be operating as a part of an organized criminal network. The sites falsely purported to be “Canadian pharmacies,” and displayed fake licenses and certifications to convince U.S. consumers to purchase drugs that they advertised as “brand name” and “FDA-approved.”

These websites also used the names of major U.S. pharmacy retailers to trick consumers into believing that an affiliation existed with these retailers.

Some examples of the phony websites, which now have been seized and display a message from the FDA’s Office of Criminal Investigations Cybercrime Investigations Unit, include: • www.canadianhealthandcaremall.com • www.walgreens-store.com • www.c-v-s-pharmacy.com As part of its investigation, the FDA targeted websites that were selling unapproved and potentially dangerous prescription medicines that could pose significant risks to public health. The drugs seized by the agency were not from Canada, and were neither brand name nor FDA-approved. Prescription products purchased from the websites also bypassed existing safety controls required by the FDA, including the requirement of a valid prescription from a licensed health care provider.

Some of the medicines sold illegally by

IMIPENEM.

D

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COME AND GET ‘EM.

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Medical Information 800-551-7176 Customer Service 888-386-1300 www.APPpharma.com

Reference: 1. As of January 2013.

10 Policy

Pharmacy Practice News • August 2013

Compounding FAQ Compounded sterile products:

To Insource or Outsource? That Is the Question!

Jerry Siegel, PharmD, FASHP Clinical Associate Professor The Ohio State University Columbus, Ohio Managing Partner Safe Medication Management Associates, Inc.

Howard Cohen, MS, RPh, FASHP President Safe Medication Management Associates, Inc.

Julie Kennerly, PharmD PGY2 and MS Candidate The Wexner Medical Center The Ohio State University Columbus, Ohio

Compounded sterile products (CSP) can be prepared within the health-system pharmacy (insourced) or prepared by an external compounding pharmacy for the health system (outsourced). Since the events of this past fall related to tainted compounded products given to patients, many health care systems are considering bringing the preparation of CSPs inhouse. We answer some questions about what that process entails, offering tips to help facilities determine whether a switch to insourcing makes sense.

Q: Why outsource?

A: Health systems have been using compounding pharmacies to provide routinely compounded products, make better use of the labor force, and decrease the need to expand facilities.

Drug shortages also have been a major driver for outsourcing certain products. Lack of available capital dollars to purchase and maintain equipment for complicated products such as total parenteral nutrition (TPN) may be another reason that pharmacy directors looked to outsource (Table 1).

Q: What is beyond-use dating (BUD) and how does it differ in a compounding pharmacy?

A: United States Pharmacopeia (USP) Chapter <797> regulations define the time after a CSP is prepared via the combination of 2 or more single-use sterile products during which it can still be used.1 A single-dose vial may be opened inside an ISO 5 environment and used for up to 6 hours. If it is opened outside an ISO 5 environment, it must be used within 1 hour. Unless scientific data exists to extend the dating of a CSP, it is considered to be safe from a sterility standpoint for up to 24 hours. Outsourced compounding pharmacies have their own “in-house” data to extend this standard that is considered BUD. The rigor and validity of this testing should be verified by an FDA-registered laboratory. It is presumed that the site of com-

Table 1. Pros and Cons of Insourcing And Outsourcing CSPs Insourcing Pros

Cons

May improve wholesale discount by increasing volume purchased • Allows facility to maintain control of performance of pharmacy personnel and assure competency • Reduces waste due to improved inventory management and use • May lower overall cost of preparation • Allows direct oversight of pharmacy processes and responsibility for actions

• May not be able to obtain some drugs due to shortages • May not be able to get best prices for products such as TPN • Requires additional responsibility for recruitment, training, and testing of all personnel • Requires facility to establish or outsource BUD validation • Requires that facility is compliant and has certified and trained personnel • Requires appropriate management expertise to oversee pharmacy CSP production processes

Outsourcing Pros

Cons

• Allows facilities to obtain drugs with critical shortages • Reduces need for manpower at health system • Shifts responsibility for staffing to outsource pharmacy • Decreases waste with extended BUD • Increases perceived safety with USP <797> compliance • Outsource pharmacy provides oversight and responsibility for all aspects of production, including sterility, stability testing, delivery, and integrity of products

• Pharmacy has to buy drugs and may be off-contract and cannot track pedigree source • Labor charge is incorporated in service fee • Need to ensure the BUD is supported by scientific data • Need to inspect for compliance to USP Chapter <797> and conduct regular audits, including unannounced visits • Health facility still has to assume responsibility for pharmacy process without on-site management

BUD, beyond-use dating; CSPs, compounded sterile products; TPN, total parenteral nutrition; USP <797>, United States Pharmacopeia (USP) Chapter <797> regulations

Table 2. Differences Between Traditional Compounders and Compounding Manufacturers Traditional Compounders

Compounding Manufacturers

Regulatory body

State board of pharmacy

FDA

Standard

USP Chapter <797>

Good Manufacturing Practices

Prescription requirement

Patient-specific (before or after compounding)

None

Reporting requirement

None

List of drugs compounded during the previous 6-month period to FDA

Registration fees

None

pounding is fully compliant with USP <797> to label the drug with the BUD. BUD has the potential to minimize drug waste by allowing a more efficient distribution system. However, BUD also

$15,000 if >25 employees, plus cost of inspection

can lead to much greater waste if the distribution of product exceeds use.

Additionally, the risk factors for sterility increase over time because microorganisms such as fungi may take in excess of

5 days to reproduce in a clinically significant infectious burden. Thus, use within 24 hours may reduce the risk for causing nosocomial infections via the infusion of potentially contaminated products.

Eric S. Kastango, MBA, RPh, FASHP, the president and CEO of Clinical IQ, LLC, and his colleagues have studied compliance with USP Chapter <797> standards in health-system pharmacies and found average compliance to be approximately 75%.2 Although some areas of noncompliance were specific to certain facilities, the lack of appropriate sterility testing, action plans, and employee testing were among the most frequent issues they found.

The primary distinction between manufacturers and compounders is who regulates them. Manufacturers are under the purview of the FDA, whereas individual state boards of pharmacy regulate compounding pharmacies (Table 2). The latter makes it more difficult to assure product integrity when crossing state lines, and board inspections are not nearly as rigorous as the FDA’s Good Manufacturing Practice standards.

New legislation to amend the Federal Food, Drug, and Cosmetic Act with respect to compounding drugs has recently been proposed to more clearly define these differences.3 The draft legislation defines compounding manufacturerr as an entity that (1) makes sterile drug products without receiving or in advance of a prescription and introduces those drugs in interstate commerce; or (2) “repackage[s] a drug using sterile preservative-free single-dose vials or by pooling sterile drugs.”

There is an exception for pharmacies located within a “health system” that compound and ship drugs for dispensing within that health system (which may include interstate shipment); this is considered a traditional compounder, subject to specified conditions, if the entity otherwise meets the definition of a traditional compounder. Under these proposed guidelines, a health system could compound sterile products from a centrally located site and distribute and use them throughout its own system.

Weighing Benefits of Insourcing A pharmacy director can go through the process outlined in the Figure (page 14) to assess whether it would derive sufficient return on investment (ROI) by insourcing its CSPs. In many cases, after including the cost of labor, supplies, and facility upgrades, the ROI will be positive and realized within 1 year. For a health system with the capacity to operate 5 days per week and produce 800 doses of

•

see CSPs, page 14

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12 Policy

Pharmacy Practice News • August 2013

Reimbursement

Gearing Up To Save 340B Drug Discount Program Be ready for audits as well as to defend the program Minneapolis—Although the specifics are unknown, legislation to limit the 340B Drug Pricing Program is likely to be introduced in the relatively near future, according to a legislative affairs specialist speaking at the American Society of Health-System Pharmacists (ASHP) 2013 Summer Meeting. As lawmakers continue to scrutinize the discount drug program, pharmacists in participating health systems need to prepare for the increased likelihood of an audit by the Health Resources and Services Administration (HRSA) or a drug manufacturer.

They also must work collaboratively to craft a cohesive message that will defend the program against legislative attacks, said Joseph M. Hill, ASHP’s director of federal legislative affairs.

The finding of a 2011 investigation by the Government Accountability Office (GAO) that “HRSA’s oversight of the 340B program is inadequate to provide reasonable assurance that covered entities and drug manufacturers are in compliance with program requirements” has fueled concerns by critics that some safety net providers may not be using the program as intended (http://www.gao.gov/products/GAO-11-836). For example, in a 2013 letter to HRSA, Sen. Charles A. Grassley (R-Iowa) stated, “Because hospitals who participate in the 340B program have broad discretion as to whom to sell their deeply discounted 340B drugs, hospitals can elect to sell all of their 340B drugs to only fully insured patients while not passing any of the deeply discounted prices to the most vulnerable, the uninsured” (http://www.grassley.senate. gov/about/upload/2013-03-27-CEG-toHRSA-340B-Oversight-3.pdf ).

According to Mr. Hill, this recent scrutiny of the 340B program by Mr. Grassley, the ranking member of the Senate Judiciary Committee, has created a climate in which hospitals put themselves at risk for a Congressional inquiry if they defend the program.

Attempts to link the 340B program with the current drug shortage served as “the springboard for Congress to get on board and attack the program,” noted Mr. Hill. “One of the negative arguments is that hospitals are getting these discounts, and, rather than pumping [the savings] back into patient care, they’re building lavish facilities and using the savings on things other than care for the indigent.

Although my understanding is that hospitals were never directed to use the funds in a certain way, it’s [the opponents’] way of saying this program is bad,” he said.

The current problems stem, in part, from different views about the 340B program’s purpose, according to Lisa Scholz,

PharmD, the chief operating officer and chief pharmacy officer of the Washington, D.C.-based Safety Net Hospitals for Pharmaceutical Access (SNHPA). “This program was started to assist the covered entities in stretching their scarce resources so that they can take care of more patients,” she said in an interview.

“The drug industry wants to point fingers at the covered entities and say they aren’t utilizing the program as intended, but the drug industry is wrong to say that only uninsured and indigent patients should be receiving 340B-purchased drugs.

“Congress intended the program to

support hospitals in serving more eligible patients, not uninsured patients only,” Dr. Scholz added. [See H.R. Rep No. 102-384(II) at 12 (1992).] “The 340B savings were intended to help the entities increase patient access and provide more comprehensive services, including specialty services such as oncology and rheumatology, ancillary services such as radiology and laboratory, and medication therapy management. If 340B were to go away, hospitals would be forced to close pharmacies, suffer reductions in work force, and reduce or eliminate patient access to medications as well as

other comprehensive services.”

The current climate around the 340B program is more than merely negative, Dr. Scholz stressed. “We’re under siege,” she said. But she added, “don’t be fearful” and avoid taking action. ”Keep in mind why this program was started and who it was for. … This is about patients and community benefit.”

The challenge facing covered entities is to counter the negativity individually and collectively by demonstrating the 340B program’s positive effect, said Mr. Hill.

“We’ve got some folks who are asking some questions, and they’re people in

Auditing Tips From the Trenches Representatives from two 340B participating hospitals that have undergone HRSA audits described some of their experiences during an educational session at the ASHP 2013 Summer Meeting. Here, they share some advice for 340B-covered entities preparing for an audit.

Froedtert Hospital, Milwaukee Review your policies and procedures, audit internally on a regular basis to test your compliance and network with other audited entities to prepare for a 340B audit, advised Todd Karpinski, PharmD, the executive director of pharmacy at Froedtert Hospital, in Milwaukee. The 550-bed academic medical center and disproportionate share provider, which is affiliated with the Medical College of Wisconsin, completed a HRSA audit of its 340B program in 2012, with no adverse findings.

“We entered a pharmacy contract agreement in April, and in a couple of months, heard about the audit,” said Dr. Karpinski. “That was the trigger for us, as [was] our significant growth in outpatient purchases in oncology infusion and non-oncology infusion drugs.”

The hospital formed a multidisciplinary 340B team with leaders and staff from finance, pharmacy, legal and compliance. The team met weekly and reached out for advice to other audited organizations. It used Apexus’ self-assessment gap analysis tool and a stoplight report to address areas of risk in advance. Major projects included a review of 340B policies and procedures. “We had 15 policies for 340B activities that may or may not have been updated based on new technology that had been implemented, so we created a new policy where everything we had around 340B was in one site,” Dr. Karpinski said.

The hospital’s focus on responding quickly and efficiently to HRSA’s data requests helped the audit go more smoothly, he noted. Some institutions with whom Froedtert had networked said they regretted not paying enough attention to this aspect of the review.

The audit itself took two days, with day 1 devoted to a review of 30 retail/contract pharmacy orders and day 2 devoted to a review of 35 hospital outpatient department orders, policies and procedures, contract pharmacy issues, Medicaid billing, central pharmacy operations and the hospital’s contract with the Medical College of Wisconsin.

Dr. Karpinski advised updating the provider list frequently to make sure it stays current, contacting the state to learn how it handles Medicaid billing because this differs from state to state and having someone on hand during the audit with strong knowledge of the electronic medical records (EMRs) system.

Stressing that this is “a rapidly evolving area,” he said, the audits are becoming more sophisticated as the auditors gain experience.

Shands Jacksonville Medical Center, Florida Shands Jacksonville Medical Center, a safety net hospital in Duval County, Florida, was among the first covered entities to be audited by HRSA. The medical center took the review, which was completed with no adverse findings, “very seriously,” said Patrick Barnes, RPh, a team leader for drug control. A team from compliance and the ambulatory pharmacy prepared a presentation on the 695-bed hospital and its 340B program, a “carve-in” program that purchases and dispenses 340B drugs for Medicaid patients.

The audit focused primarily on looking for diversion and duplicate discounts, comparing invoices to acquisition costs and wholesaler invoices to Medicaid billing; verifying physician eligibility; and a review of EMRs, split-billing, the hospital’s indigent care contract with the city of Jacksonville and its Medicare cost report.

During the review, the hospital showed HRSA the 340B random self-auditing process it had developed. These selfaudits can help organizations identify and eliminate system errors earlier, and pave the way for a successful external review, Mr. Barnes said. The HRSA experience itself shed light on ways to fine-tune those self-audits. Mr. Barnes learned, for example, that he had been auditing inventory pharmacy but not split-billing.

He recommended “up-front controls” to eliminate errors as well. At Shands Jacksonville, one of those up-front controls is a Shands Card for 340B-eligible patients.

Mr. Barnes also advised pharmacists to “make sure you’re accurately represented on the Medicaid-exclusion file. It’s important to contact the Medicaid office to determine what it’s doing and how it’s collecting rebates, and then have them send you the documentation.”

—Susan Birk For more advice on how to prepare for a 340B audit, see related story, next page.

Policy 13

Pharmacy Practice News • August 2013

Inpatient drugs

positions of power. Not only that—they’re able to put a lid on, for now, people who are speaking up in support of the program, at least from an individual hospital perspective,” he said. “From a professional society or trade association perspective, it is incumbent on us as stakeholders to develop a clear message on how 340B benefits the community. I hope my comments will be taken as a wake-up call. It’s time for us to get together to talk about how we develop a consistent message … and then work collaboratively to ensure we can fend off future attacks. “The good news is we have nothing specific that we’ve seen now,” he said, although a report on 340B by Sen. Grassley could be forthcoming later this year.

In preparation, ASHP is “trying to work

Vaccines Drugs not directly reimbursed FDA doesn’t require NDC

Biologics with a prescription

Based on Social Security Administration. Compilation of the Social Security laws. Payment for covered outpatient drugs. Sec. 1927. http://www.ssa.gov/OP_Home/ssact/title19/1927.htm. Accessed July 18, 2013.

through all the potential areas where Congress may attack the program,” Mr. Hill said. Among these are eligibility and the program’s rapid expansion. The num-

ple,” he said. Rallying key leaders around the 340B program creates political support and a valuable sounding board for working through compliance issues and exploring areas, such as contract pharmacies, that can expand the program’s reach to eligible patients, he said.

“It’s really critical that [340B] not be left to the pharmacy director to have sole responsibility” for an audit, echoed Maureen Testoni, the general counsel for Safety Net Hospitals for Pharmaceutical Access (SNHPA), in Washington, D.C. The participation of people from finance and billing, for example, can help ensure that the organization is meeting requirements for under HRSA’s “definition of patients,” Ms. Testoni said.

Similarly, IT staff can support efforts to identify instances of diversion—the provision of a drug to an individual who is not a patient of the entity according to 340B requirements—by providing data related to drug administrations for eligible patients, added Kim Doud, 340B audit and compliance manager for Kirkland, Wash.-based Talyst, which sponsored the webinar. “Working together with that integrated team is an incredibly important way to make sure transactions you consider 340B-eligible are

ONLINE PHARMACIES

ucts and claim to contain dapoxetine, the safety or efficacy of which has not been determined by the FDA. People with certain heart conditions should not take medicines containing vardenafil or sildenafil, and these medications also have potentially dangerous drug–drug interactions and serious adverse effects.

• Clozapine: This agent is FDAapproved to treat severe schizophrenia and is associated with potentially fatal agranulocytosis, a severely low

testinal bleeding, heart attack and stroke, Celebrex must be dispensed with a medication guide explaining potential risks.

• “Levitra Super Force” and “Viagra Super Force”: Levitra (vardenafil) and Viagra (sildenafil) are FDA-approved to treat erectile dysfunction. Levitra Super Force and Viagra Super Force are not FDA-approved prod-

Clinic-administered drugs

NDC, National Drug Code; OTC, over-the-counter

ollowing a 2011 Government Accountability Office (GAO) report highlighting the need for more oversight of the 340B Drug Pricing Program, the Health Resources and Services Administration (HRSA) audited 51 program participants in 2012 and is expected to audit 400 more by the end of this year.

Drug manufacturers have begun auditing 340B participants as well. A recent webinar explored best practices to help covered entities become “audit ready.”

Chief among these practices is the creation of an interdisciplinary 340B team or steering committee including pharmacy, legal, compliance, finance and information technology (IT) leaders, said Gary Johnson, PharmD, the chief pharmacy officer at the University of Kentucky, in Lexington. Covered entities will need to review their 340B policies and procedures to prepare for an audit, but the formation of that steering committee should come first, he said.

“The pharmacy department often is in a situation of trying to manage 340B complexities without much broader organizational understanding around 340B, so when you bring some of these nuanced issues forward, such as contract pharmacy … it’s difficult to educate peo-

continued from page 9

OTC drugs with a prescription

Figure. What does 340B cover?

Preparing for a 340B Audit

F

Outpatient prescription drugs

ber of hospitals participating in the 340B program grew from 591 in 2005 to 1,673 in 2011, according to the GAO. Mr. Hill predicted that the next wave of criticism

administered to valid patients,” she said.

The panelists strongly recommended conducting trial audits to test compliance in areas such as enrollment, diversion, duplicate discounts, the GPO exclusion (the rule prohibiting certain covered entities from purchasing outpatient 340B drugs through their group purchasing organization) and, if applicable, contract pharmacy. “Be diligent with those [monthly or quarterly] selfaudits to give yourself a sense of assurance that things are working as intended,” said Ms. Doud.

OPA a Useful Resource...

Check the Office of Pharmacy Affairs (OPA) website (http://opanet.hrsa. gov/opa/) to make sure the appropriate clinics are registered, Ms. Testoni advised. Then, to make sure your systems are working properly, “take a sample of claims and trace those all the way through so you can be sure the drug dispensed to the 340B patient met the “definition of patient,” that the patient was seen in the area of the hospital that qualifies for 340B, and that the person was an outpatient,” she said.

Exceptions to requirements aren’t always clear-cut, and pharmacists may look to other experts within the organization to assist in diving into a patient’s history through the electronic medical

(and dangerous) white blood cell count that can predispose patients to serious, life-threatening infections. To minimize potential risks, consumers who are prescribed clozapine must be enrolled in a registry that ensures regular blood count monitoring.

In addition to potential health risks, these online pharmacies pose non– health-related risks to consumers such as credit card fraud, identity theft and computer viruses.

The FDA encourages consumers to

Reimbursement would target relationships between covered entities and contract pharmacies.

The one area where everyone seems to agree is that covered entities need updated guidance from HRSA that is relevant to the current health care system, Dr. Scholz said. That guidance has begun with audits of covered entities. Last year, HRSA audited 51 covered entities and has published the results of 34 audits (http://www.hrsa.gov/opa/programintegrity/auditresults/). Many more audits are being conducted this year.

Additional guidance comes from the 340B Coalition of national organizations representing 340B providers. The coalition is helping stakeholders navigate the operational and compliance

•

see 340B, page 14

records system, said Ms. Doud. Communication and collaboration with experts in other areas is extremely useful in these instances. If an administration appears to be noncompliant, conversations with people in compliance, for example, can help determine whether the administration is truly an exception.

Then, “it’s up to your steering committee to understand … how it should be reported,” Ms. Doud said.

...As Well as Apexus and SNHPA Ms. Doud encouraged pharmacists to read and keep links to 340B regulations and HRSA releases, resources and tools from Apexus, the prime vendor for 340B, and advocacy groups, including SNHPA. A trial audit also can help prepare for the HRSA data requests that are a major part of every review, she added. The agency typically asks for six months of data on eligible 340B administrations, as well as various elements within that request. “Hospitals don’t always have immediate access to those data elements, so performing that mock audit and bringing those elements to the table offers the basis for a conversation that may not have existed before,” she said. Thus, the trial audit can help an organization spot problems and nip them in the bud.

—Susan Birk

report suspected criminal activity to the Office of Criminal Investigations at www.fda.gov/OCI. The FDA also sponsors “FDA BeSafeRx—Know Your Online Pharmacy,” a national campaign to educate consumers about the dangers of buying medicine from fake online pharmacies and to help people safely buy medicine online. Information is available online at www.fda.gov/ BeSafeRx. —Based on a press release from the FDA

14 Policy

Pharmacy Practice News • August 2013

Compounding FAQ

CSPs

be more stringent and not give credit for standards that are only partially met. Although a professional third party must certify all equipment such as laminar flow hoods and biological safety cabinets, the equipment in the rest of the cleanroom, such as room airflow exchange and pressure monitoring, does require external certification.

A false sense of compliance exists when a “hood certifier” places a label on a hood, although the device is not inside any sort of clean room environment.

As many directors of pharmacy evaluate the possibility of transitioning back to insourcing CSPs, they must be sure that they are, in fact, providing a safer product for their patients. There are certain things that, as a director of pharmacy and responsible pharmacist, you cannot outsource. Honesty, integrity, and responsibility are among them.

continued from page 10

standard CSPs per day, for example, the cost of building a new clean room could be in excess of $1 million and labor costs could be approximately $500,000 per year including benefits. This cost is an estimate to hire 2.4 full-time equivalent pharmacists and 4.8 technicians to work 8 hours a day on weekdays. It may take longer to realize the ROI for parenteral nutrition products because the cost to invest in compounders and tubing may offset the margin to produce the product.

Each analysis should include options that provide for ROI for total outsourcing as well as outsourcing without products such as TPN, cardioplegia solutions, and elastomeric pain pumps.

When outsourcing, the director of pharmacy and the health system have the responsibility to inspect any outsourcing pharmacy, including via unannounced visits. Although a cursory tour of the facility may be impressive with respect to a clean room’s appearance, the outcomes and follow-up of employee and facility sterility testing and methodology are more important.

The responsibility for full compliance with USP Chapter <797> is the same whether you outsource CSPs or insource the products. Although selfassessment may be beneficial to test compliance with USP Chapter <797> standards, it has been our experience that an unbiased expert third party will

References 1. United States Pharmacopeial Convention.

General chapter <797> pharmaceutical compounding–sterile preparations. In: United States Pharmacopeia National Formulary.

Rockville, MD: United States Pharmacopeial Convention; 2008.

Figure. Process for determining the ROI for consideration of insourcing CSPs.a BUD, beyond use dating; CSPs, compounded sterile products; ROI, return on investment a

ROI = (outsource cost of drug + markup + delivery) – (insource cost of drug + cost of labor, equipment, and quality program)/time

340B

HEPARIN

continued from page 13

continued from page 8

complexities of such issues as the new HRSA guidelines for the use of GPOs. Apexus, HRSA’s awarded prime vendor for the 340B program, has developed an educational program called 340B University, which is led by faculty from HRSA, Apexus, and the drug and pharmacy wholesale industries.

The vendor also has developed online resources for covered entities, including a self-assessment tool for audits and draft policies and procedures that can be customized to their practice sites. “We are teaching HRSA’s perspective and interpretation of the rules, so it’s clear to all stakeholders how you should run a compliant 340B program,” said Christopher Hatwig, RPh, FASHP, the president of Apexus, in an interview. “The purpose of the audits is not to be punitive or to attack customers; it’s actually to drive compliance,” said Mr. Hatwig, adding, “Every customer in the country can run a compliant program.”

the older label,” Ms. Benjamin said, “it’s probably safer to remove and replace it with the new labeled product.” If the decision is made to use up the old product, the alert recommends storing it separately from the new, and using up all of the old product before dispensing the newer versions.

“It’s important to walk around the organization and look at what is in stock,” Matthew Grissinger, RPh, FASCP, the director of error reporting programs at ISMP, said in an interview. “Don’t think that heparin is only in the pharmacy. The pharmacist should take into account all the locations where heparin is used, in and out of the pharmacy. The emergency room, the ICU, etc, have it.”

Mr. Grissinger added, “Don’t expect or hope that people will see the new label; that’s not a good strategy to prevent errors. Be proactive in informing them.” He also stressed the importance of making changes to databases.

“With computerized prescription order entry and barcoding systems, make sure it matches what’s on hand.”

The NAN alert also advises keeping vial sizes of all high-alert drugs, including heparin, as small as possible to reduce the chance of overdoses. “Heparin is a highalert drug,” Ms. Benjamin said. “Special precautions are

—Susan Birk

2. Douglass K, Kastango ES, Cantor P. The 2012 USP <797> compliance survey: measuring progress. Pharm Purch Prod. 2012;9(10):4.

3. Pharmaceutical Compounding Quality and Accountability Act. S.959. /113th Congress. http://thomas.loc. gov/cgi-bin/bdquery/D?d113:3:./ temp/~bd9KB3:@@@L&summ2=m&|/home/ LegislativeData.php?n=BSS;c=113. Accessed July 16, 2013.

Old (left) and new versions of heparin injection label. Both vials hold the same exact amount of medication.

Source: NAN Alert, June 10, 2013.

still needed for the new product—for example, an independent check, having someone else verify the correct dose. If possible, heparin doses should be prepared in the pharmacy.”

—George Ochoa

Ms. Benjamin and Mr. Grissinger reported no relevant financial conflicts of interest.

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16 Policy

Pharmacy Practice News • August 2013

Scope of Practice

A Pain Physician’s Perspective

AMA RESOLUTION continued from page 1

resolution described as “pharmacy intrusion into medical practice.” It stated that the AMA “deem[s] inappropriate inquiries from pharmacies to verify the medical rationale behind prescriptions, diagnoses and treatment plans to be an interference with the practice of medicine and unwarranted.” It also threatened that if the issue were not resolved, the AMA would “advocate for legislative and regulatory solutions to prohibit pharmacies and pharmacists from denying medically necessary and legitimate therapeutic treatments to patients.”

Scott Strassels, PharmD, PhD, a pain management specialist who spent more than seven years as an assistant professor and a researcher at the University of Texas at Austin College of Pharmacy, told Pharmacy Practice News that such a policy represented a “dangerous precedent to shut off important phone calls or important contact with prescribers. Nobody wants to spend time on the phone that they don’t really need to, but there are times when a pharmacist and prescriber need to be on the same page with regard to safety issues, and that includes the potential for drug interactions as well as the effect of a given drug for a particular person.”

B. Joseph Guglielmo, PharmD, the dean and chair of clinical pharmacy at the University of California, San Francisco School of Pharmacy, added that the future of patient care “has to be one in which medical information about patients is made available to all relevant health care providers, so that ... the safest and most effective medication use will take place.”

He noted that what has “limited pharmacists from maximizing their input in the community pharmacy setting has been the lack of such information.”

Prescription Drug Abuse At the heart of the issue is the federal government’s stepped-up efforts to block diversion of controlled medications and contain the growing nationwide prescription drug abuse epidemic.

In response to tightened Drug Enforcement Administration (DEA) scrutiny, many drugstore chains have beefed up their controls over narcotic drug dispensing by their pharmacies. The result has been more pharmacy phone calls and faxes to prescribers requesting the validation of information to ensure that the pain-killing drugs were not being abused or falling into the wrong hands.

Richard Pieters, MD, a radiation oncologist at the University of Massachusetts Medical Center and the president-elect of the Massachusetts Medical Society, who wrote the original draft for the AMA resolution, told Pharmacy Practice News that a major reason for the AMA’s action was the Walgreens Company’s policy of

‘There are times when a pharmacist and prescriber need to be on the same page with regard to safety issues.’

—Scott Strassels, PharmD, PhD requiring its pharmacists to “demand” information before filling narcotic prescriptions, including diagnoses, International Classification of Diseases Ninth Revision codes, patient treatment plans and previously tried medications.

“This is beyond the scope of practice for the pharmacist,” Dr. Pieters said. “It’s not appropriate to be asking that kind of question. It’s an intrusion into the practice of medicine.” He said “pharmacy phone calls for allergies, drug interactions, strengths are totally appropriate. And we understand that there is a [prescription drug abuse] scourge and that drug overdoses are a major problem. But this is not how you fix it. This is the drugstore chains trying to look like good citizens on the backs of the medical community.”

Walgreens did not reply to a request for comment, but a spokesman for the National Association of Chain Drug Stores told American Medical News that pharmacies have had to respond to new levels of DEA scrutiny over the purported overdispensing of controlled substances.

In June, Walgreens agreed to pay $80 million to settle DEA and Department of Justice charges that it failed to exercise sufficient controls over the dispensing of narcotic medications at some of its pharmacies ((Walgreens news release). As part of the settlement, the company also agreed to surrender its DEA registrations at six Florida pharmacies until May 2014 and at its Jupiter distribution center until September 2014. Walgreens also instituted an education program for its pharmacy team members to provide them “with the tools, training and support they need to ensure the appropriate dispensing of controlled substances and to improve collaboration across the industry.”

Kermit Crawford, the president of the Pharmacy, Health and Wellness division of Walgreens, said in a statement, “We are fully committed to doing our part to prevent drug abuse. We also will continue to advocate for solutions that involve all parties—including leaders in the community, physicians, pharmacies, distributors and regulators—to play a role in finding practical solutions that combat the abuse of controlled substances and ensure patient access to critical medications.”

As part of its controversial resolution, the AMA also stated that it was willing to work with stakeholders to develop “appropriate policy for pharmacists to work with physicians in order to reduce

W

illiam Hopkins, MD, an anesthesiologist/pain specialist in Campbell, Calif., has experienced first-hand the frustrations of dealing with pharmacists who have recently accelerated their demands for detailed clinical information for chronic pain patients—an experience that he says has led him to support the AMA resolution.

Most commonly, he noted, it is the “big-box” chain pharmacies that will send a fax or call him requesting diagnostic details on these patients, especially when opioids are involved. “They’ll also ask whether I have plans for transitioning the patient off opioids and onto alternative agents,” he said. “There simply is not enough time in my day to give them a detailed response on the responsible steps I have taken to ensure these patients’ regimens are appropriate, whether it’s counseling and education, consultations with their primary care physicians or other involved specialists.”

The “arrogance of ignorance” that underpins these requests by some pharmacists “is frankly astounding,” Dr. Hopkins said. “They presume that I didn’t already take these appropriate actions—that somehow I am prescribing controlled substances indiscriminately. They make assumptions without assessing the patient and without knowing my level of evaluation and decision-making.”

By seeking to block his prescribing decisions, “these big-box pharmacists are rendering medical determinations without a good-faith assessment of the patient,” Dr. Hopkins said. “If I were to do that, I would be censured by the medical board. Franz Kafka couldn’t have envisioned a more absurd scenario.”

This is not to say, he stressed, that there aren’t physicians who misprescribe or patients who abuse medications. “This is a huge problem,” he said. “But questioning the clinical decisions of responsible physicians ... isn’t the solution.”

Dr. Hopkins added, “I am not anti-pharmacy. I hold community and hospital pharmacists in high regard. They provide a superb service by providing alerts on potential drug interactions, incorrectly written prescriptions, suspicious prescription-filling, etc. I wantt calls and faxes about those issues. What I don’t need are demands for detailed clinical information from a pharmacist who, far removed from the clinic, is making a medical decision at variance to my own, and in so doing, causing patient distress and wasting my time. This promotes friction and distrust. This latest trend seems driven by fear of current media and pressure, not by clinical competence or compassion.”

—David Bronstein

the incidence of drug diversion and inappropriate dispensing.”

Pharmacy Groups Chime In Pharmacy groups had various reactions to the AMA policy declaration. The National Community Pharmacists Association (NCPA) opposed it, calling it “shortsighted” and “simplistic” in its approach to the prescription drug abuse epidemic.

“We support a collective approach to controlling abuse and diversion that involves everyone: patient, pharmacist, pharmacy benefit manager, wholesaler, manufacturer and prescriber,” NCPA said. It also noted that “additional education of prescribers” was needed to combat prescription drug abuse, an apparent reference to the AMA’s failure to mention the role that inappropriate prescribing has played in such abuse.

At the American Pharmacists Association, Thomas E. Menighan, BSPharm, MBA, the executive vice president and CEO, said that although pharmacists were “disappointed in the passage of a resolution that discourages a team-based approach to health care, the policy provides an opening to find solutions for controlled substance verification.” He said it was “not pharmacy’s intent to delay patients from receiving these needed medications or to unnecessarily interrupt prescribers,” and added that the situation underscored “the need for pharmacy, medicine and regulators to collaborate on solutions that address the root cause of ... abuse problems in this country.”

Kasey Thompson, PharmD, the vice president of Policy, Planning and Communications for the American Society of Health-System Pharmacists (ASHP), said, “The bottom line is that there is a major prescription drug abuse epidemic in this country and we need to find more ways to work together as a health care community to solve it.”

He also said that “ASHP and our other pharmacy organizations have a really good working relationship with the AMA, and I’m quite confident that we’ll find productive ways to collaborate in an interdisciplinary fashion on this issue.

That’s what we’re focused on.”

As for the resolution itself, Dr. Thompson said he thought it did not “really reflect the state of collaboration that exists today. If you talk with a vast majority of ASHP’s 42,000 members, you’ll hear story after story about how they work in an interdisciplinary team in the care of patients. It’s the health care delivery system of the 21st century; there’s more collaboration, not less, going on.”

And indeed, Dr. Pieters said that, outside of the experiences that led to the AMA resolution, his own working relationships with pharmacists were “excellent. Pharmacists are very valuable members of the team. In addition to being a radiation oncologist, I’m board-certified in hospice and palliative medicine, and pharmacists are fantastic resources in terms of suggesting alternative drugs.”

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18 Technology

Pharmacy Practice News • August 2013

Practice Pearl

CDS Software Helps Facilitate VTE Prophylaxis Benjamin Anderson, PharmD, MPH Configuration Analyst-Informatics HealthEast Care System St. Paul, Minnesota

A

s HealthEast Care System transitioned from paper order sets to a computerized prescriber order entry (CPOE) and began attesting to stage 1 of the Centers for Medicare & Medicaid Services’ meaningful use requirements, informatics team members identified several order sets and processes that could benefit from clinical decision support (CDS). One of the key areas was related to ordering and documenting venous thromboembolism (VTE) prophylaxis.

A specific order set for VTE prophylaxis for medical patients existed at HealthEast, but several medical admission and postoperative order sets also had separate sections containing VTE prophylaxis orders. These sections often did not have key components for compliance, such as exclusion criteria for mechanical/pharmacologic prophylaxis, risk stratification guidance, and listings of appropriate medications with consistent dosing parameters.

The health system addressed this with a few workflow changes between March 2010 and February 2012. First, most of the individual VTE prophylaxis sections were removed from other order sets and were replaced with a link to the VTE prophylaxis order set (Figure 1). For a few postoperative order sets (orthopedic, cardiovascular, and bariatric procedures, as well as stroke admissions), the VTE sections were left within the order set but additional CDS was applied to guide ordering. Second, the VTE prophylaxis order set was standardized to cover medical and postoperative patients. Finally, several CDS tools were introduced into the VTE order set. The process resulted in 3 phases or iterations of the order set to allow full incorporation of provider feedback and address any issues that arose.

Phase 1 went live in March 2010, with changes focusing primarily on the introduction of CDS into the existing VTE prophylaxis order set and the addition of an expandable section for risk stratification (Table). This visually enhanced the order set and showed the provider only the recommended options that correlated with the stratification that was selected, thus removing the possibility of selecting prophylaxis options from the incorrect risk stratification. A required free-text field for “No pharmacological prophylaxis” was added. Under the new order set, enoxa-

Table. VTE Risk Stratification ❏ No

❏ Low Risk

❏ Moderate to High Risk

❏ Very High Risk

• Pharmacologic prophylaxis ordered at this time

• No VTE risk factors

• Age >60 y • CVA, including PICC • History of COPD, CHF, IBD, respiratory failure • Family history of thrombosis • Medical patient with additional risk factor (MI, sepsis, COPD, CHF, respiratory failure, or history of malignancy) • Major surgery planned with additional risk factor (MI, sepsis, COPD, CHF, respiratory failure, or history of malignancy) • Morbid obesity (BMI ≥40) • Anesthesia time >60 min

• Active cancer • Hip, pelvis, or leg fracture (<1 mo) • Stroke (<1 mo) • Acute spinal cord injury or major trauma (<1 mo) • Admit to ICU • Personal history of DVT, PE, or clotting disorder • Extended immobility (≥4 d)

BMI, body mass index; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA, central venous access; DVT, deep vein thrombosis; IBD, inflammatory bowel disease; MI, myocardial infarction; PE, pulmonary embolism; PICC, peripherally inserted central catheter © 2013 HealthEast Care System

Figure 1. VTE electronic order set link. © 2013 HealthEast Care System

parin doses were automatically adjusted based on the patient’s renal function and current health-system policy and orders were automatically placed for laboratory tests based on the medication selected for prophylaxis. Providers were receptive to these enhancements, which helped prepare them for subsequent changes.

Phase 2 went live in June 2011 and focused on increasing use of the VTE prophylaxis order set and enhancements of the order set to ensure appropriate documentation and improve Clinical Quality Measures (CQM) metrics for VTE prophylaxis. The order set linking to an integrated link was changed, which automatically directed the provider to the VTE prophylaxis order set from medical admission order sets and prevented providers from bypassing the VTE order set. The free-text field with an expandable list of approved reasons for “No pharmacological prophylaxis” and “No mechanical prophylaxis” also was replaced. Based on the risk stratification selected for the patient, required field logic was introduced to ensure

the correct therapies were ordered for the patient or appropriate documentation for “No prophylaxis” was recorded before the order set was submitted. These workflow changes were not reviewed with provider groups first and education about the new requirements was not provided, so subsequently there was some pushback from providers.

This led to the temporary removal of the integrated linking functionality, but links to the VTE order set still remained.

The primary goal of phase 3, which went live in February 2012, was to increase use of the standardized VTE order set for both medical and surgical patients admitted to the health system. The major changes included the introduction of a surgical patient option and a method to denote that VTE prophylaxis was already addressed for the patient (Figure 2). By including workflow for “VTE already addressed,” providers were open to the reintroduction of the integrated linking that automatically took them to the VTE order set from admission order sets. The addition of the surgical patient options allowed

Figure 2. VTE patient selection and VTE addressed acknowledgment. © 2013 HealthEast Care System

surgical admission patients to benefit from all the enhancements made to the order set. Additionally, per Surgical Care Improvement Project (SCIP) guidelines, instructions to the pharmacist to verify surgery end times before verifying pharmacologic prophylaxis orders were included. Order start times were offset by the appropriate number of hours from the time the order set was placed in the patient’s electronic medical record.

A final enhancement was the introduction of CQM VTE tracking orders. These unique orders for “not ordering pharmacological or mechanical prophylaxis” recorded the selected reason for not ordering a medication or therapy option to address VTE during the patient’s hospitalization; they also provided a convenient method to extract exclusion criteria and a mechanism through which pharmacists could follow up with providers who required additional education regarding use of the order set.

Based on prior feedback from providers, during phase 3 interactive demonstrations were conducted of the updated functionality for key provider groups to obtain provider buy-in. The changes that would allow for increased compliance with SCIP and CQM measures related to VTE prophylaxis were emphasized. Provider educators were asked to construct a brief 1-page document for providers, explaining the required fields in the form, how to address these fields, and how to bypass the order set if the patient’s VTE status was previously addressed during the hospital encounter.

In March 2012, the order set became available with all the phase 3 functionality, except for integrated linking from admission order sets. At that time, the electronic order set was used for 85% of all new admissions. This high rate of use during go-live was attributable

•

see ORDER SET, page 24

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Indications and Usage NEXTERONE (amiodarone HCl) Premixed Injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy.

Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

Important Risk Information NEXTERONE (amiodarone HCl) Premixed Injection is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE, including iodine • Cardiogenic shock • Marked sinus bradycardia • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available • NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits fi of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.

• Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported in 16% (288/1836) of patients treated with intravenous amiodarone. Clinically significant fi hypotension during infusions was seen most often in the first several hours of treatment and appeared to be related to the rate of infusion. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In some cases, hypotension may be refractory and result in a fatal outcome. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including: vasopressors, positive inotropic agents and volume expansion.

• In 4.9% (90/1836) of patients in clinical trials, drug-related bradycardia that was not dose-related occurred while patients were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available.

• Elevations of blood hepatic enzyme values ALT, AST, GGT are commonly seen in patients with immediately life-threatening VT/VF. / In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE. • Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent.

• There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings included pulmonary infi filtrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. Two percent (2%) of patients were reported to have acute respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary toxicity including pulmonary fifibrosis is a well-recognized complication of long-term amiodarone use.

• Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal.

• The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%).

• Drug Interactions • Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone.

• Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required.

• Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in effi ficacy. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.

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Baxter, Galaxy, Nexterone and the Sphere Graphic are trademarks of Baxter International Inc.

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NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use Brief Summary of Prescribing Information. See PI for Full Prescribing Information.

1 INDICATIONS AND USAGE NEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information].

Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage (bleeding), fever, arthralgias (joint pains), eosinophilia (abnormal blood counts), urticaria (hives), thrombotic thrombocytopenic purpura, or severe periarteritis (inflammation around blood vessels).

• Cardiogenic shock.

• Marked sinus bradycardia.

• Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available.

5 WARNINGS AND PRECAUTIONS NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.

5.1 Hypotension Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients.

Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information].

In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information].

5.2 Bradycardia and Atrio-ventricular Block In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available.

5.3 Liver Enzyme Elevations Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment.

Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information].

In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE. 5.4 Proarrhythmia Like all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP , in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7) in full prescribing information].

Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias.

5.5 Pulmonary Disorders Early-onset Pulmonary Toxicity There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings have included pulmonary infiltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death.

ARDS Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy.

Pulmonary Fibrosis Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone).

5.6 Loss of Vision Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE. 5.7 Long-Term Use There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone.

5.8 Thyroid Abnormalities Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal.

There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in full prescribing information].

Hyperthyroidism and Thyrotoxicosis Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear.

Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3.

Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone.

Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism.

The institution of antithyroid drugs, Ƶ-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland.

Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism.

When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning.

Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE. Hypothyroidism Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients.

5.9 Surgery Perform close perioperative monitoring in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics.

Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri

5.10 Corneal Refractive Laser Surgery Advise patients that most manufacturers of corneal refractive laser surgery devices contraindicate corneal refractive laser surgery in patients taking amiodarone.

Respiratory: y bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and /or mass, pleuritis

5.11 Electrolyte Disturbances Correct hypokalemia or hypomagnesemia whenever possible before initiating treatment with NEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.

Thyroid: d thyroid nodules/thyroid cancer

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days.

The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%).

Table 4 lists the most common (incidence *2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related.

Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN CONTROLLED AND OPEN-LABEL STUDIES (> 2% INCIDENCE) Study Event

Body as a whole Fever Cardiovascular System Bradycardia Congestive heart failure Heart arrest Hypotension Ventricular tachycardia Digestive System Liver function tests normal Nausea

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

24 (2.9%) Cardiovascular 49 (6.0%) 18 (2.2%) 29 (3.5%) 165 (20.2%) 15 (1.8%) Digestive System 35 (4.2%) 29 (3.5%)

Cardiovascular 41 (4.0%) 21 (2.0%) 26 (2.5%) 123 (12.0%) 30 (2.9%) Digestive System 29 (2.8%) 43 (4.2%)

Cardiovascular 90 (4.9%) 39 (2.1%) 55 (2.9%) 288 (15.6%) 45 (2.4%) Digestive System 64 (3.4%) 72 (3.9%)

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting.

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of amiodarone. 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.

Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever

Pancreatic: pancreatitis Renal:l renal impairment, renal insufficiency, acute renal failure

Vascular: r vasculitis 7 DRUG INTERACTIONS Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone.

Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein.

HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis.

Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required.

Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D Reproductive and teratology studies performed in rabbits and rats at doses of up to 100 mg/kg per day (about 1.4 times the maximum recommended human dose on a body surface area basis) revealed no evidence of embryotoxicity at 5 mg/kg and no teratogenicity was observed at any dosage in rabbits.

Maternal toxicity and embryotoxicity were observed in rats in the 100 mg/kg group.

Use NEXTERONE during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.

8.2 Labor and Delivery It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects.

8.3 Nursing Mothers Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug.

8.4 Pediatric Use The safety and effectiveness of amiodarone in pediatric patients have not been established; therefore, the use of amiodarone in pediatric patients is not recommended.

8.5 Geriatric Use Clinical studies of amiodarone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Carefully consider dose selection in an elderly patient.

10 OVERDOSAGE There have been cases, some fatal, of amiodarone overdose. Effects of an inadvertent overdose of intravenous amiodarone include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity.

Treat hypotension and cardiogenic shock by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Monitor hepatic enzyme concentrations closely. Amiodarone is not dialyzable.

Baxter Healthcare Corporation Deerfield, IL 60015 Baxter, Galaxy, Nexterone and the Sphere Graphic are trademarks of Baxter International Inc.

Cardiovascular: r hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema

Sourced from: 07-19-68-241 Rev. January 2012

Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal:l myopathy, muscle weakness, rhabdomyolysis

111923 04/13

24 Technology

Pharmacy Practice News • August 2013

Practice Pearl 90

ORDER SET

80

continued from page 18

Conclusion Integrated linking, standardization of VTE prophylaxis ordering, and CDS have helped improve CQM and SCIP compliance throughout the HealthEast Care System. During the implementation of these changes, the health system learned about the importance of stakeholder buy-in for electronic workflows and education about new

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to an increased visibility and volume of support staff available to help encourage use of the system. Once support returned to normal levels, usage of the form dramatically decreased. The availability of the order set with the absence of integrated linking reduced use of the order set. Then, once provider buy-in was achieved and the integrated linking was added back to the facility’s admission order sets in December 2012, VTE prophylaxis order set use returned to rates that were consistent with the overall CPOE usage for the facility. Overall, integrated linking proved to be a valuable tool for increasing the use of the standardized VTE order set (Figure 3).

SCIP VTE measures also showed improvement after the reintroduction of the integrated linking and automatic offsetting of start times for ordered medications.

Figure 3. Percentage of new admissions using CPOE VTE order set.

CPOE, computerized prescriber order entry; VTE, venous thromboembolism

or enhanced functionality in the CPOE environment. Despite health-system leadership requesting enhancements to improve CQM and SCIP VTE measures, the initial attempt did not suc-

ceed due to lack of end user buyin and education. A revised release, which involved the engagement of the stakeholders and used more integrated discussion, focused education, and a

rollout plan allowed for a successful deployment of integrated linking and use of required fields for documentation of VTE prophylaxis in patients at HealthEast Care System.

Telemonitoring study adds to literature supporting role of profession

Long-Term BP Control Gained via Pharmacist Help

A

lthough previous studies have shown the benefits of blood pressure management by clinical pharmacists, a new trial published in July in The Journal of the American Medical Association (2013;310:46-56) stands out because of its rigor and promise of long-term gains against persistent hypertension.

The study, involving the use of home telemonitoring technology, was carried out at 16 HealthPartners clinics in Minneapolis. It found that patients with uncontrolled hypertension whose cases were managed by specially trained pharmacists were significantly more likely to reach their blood pressure (BP) goals than others who received usual care. Moreover, the large gap in success rates between the study and control groups continued for at least six months after pharmacist-managed patients were returned to usual care by their primary physicians following the initial 12-month phase.

The 18-month cluster randomized trial ended late last year, but Karen Margolis, MD, MPH, the director of clinical research at HealthPartners Institute

for Education and Research, who led the investigation, told Pharmacy Practice News that preliminary data from patients’ electronic medical records hinted that improvements achieved by patients in the pharmacist case management group might be sustainable. To determine if that is true, their progress versus that of the control group will be tracked over four years, she said.

The study also was notable, Dr. Margolis said, because few limits were placed on recruitment. Previous investigations involving BP management by pharmacists or nurses, she said, often drew the line at enrolling patients with serious comorbidities. In contrast, the HealthPartners study included individuals with diabetes and kidney disease. Patients with those conditions were given a more exacting BP goal (systolic BP <130 mm Hg and diastolic BP <80 mm Hg). BP targets for others in the intervention group were less than 140/90 mm Hg. Patients were excluded from the study if they were pregnant or had the following severe comorbid conditions (stage 4 and 5 kidney disease or ratio of albumin to

creatinine of ≥700 mg/g, acute coronary syndrome, coronary revascularization, stroke within past three months, known secondary causes of hypertension, heart failure or left ventricular ejection fraction <30%).

Sixteen of HealthPartners’ 21 clinics with medication therapy management (MTM) pharmacists on board took part.

The 450 enrolled patients were randomly assigned to pharmacist case management at eight of the clinics (n=228) or to usual care at the other eight (n=222).

Patients in the intervention group received initial one-hour educational sessions with pharmacists. They were equipped with A&D Medical 767 PC automated oscillometric BP monitoring devices capable of storing and transmitting BP data via telephone, to be read by pharmacists logging in to a website set up to convey the results. Patients were advised to transmit six separate BP readings weekly—ideally three recorded in the morning and three in the evening.

Pharmacists followed the initial face-toface visits with regular telephone calls to patients at home, more often in the

first six months and then diminishing in frequency during the second phase depending on how well the patients were responding to treatment. Under a clinical practice agreement, pharmacists who received eight hours of formal training on the study protocol could prescribe or adjust medication therapy based on the BP results.

The differences in outcomes between the two groups were remarkable: 57.2% in the intervention group achieved their goals at six and 12 months compared with 27.2% of those receiving usual care (P ( =0.001). The doubledigit percentage gap also was clearly apparent at both six months (71.8% vs.

45.2%; P<0.001) and 12 months (71.2% vs. 52.8%; P=0.005), and remained at 18 months (71.8% vs. 57.1%; P=0.003).

Dr. Margolis said she was hopeful of receiving research support for a longer-term cost–benefit study that might show a reduction in serious cardiovascular events and set the stage for wider adoption of BP management by pharmacists or nurses.

•

see BP GOALS, page 54

Special Advertising Section

American Health Packaging AmerisourceBergen Technology Group Amneal lnstitutional APP Clinical and Laboratory Standards Institute CSL Behring CutisPharma, Inc. Grifols ICU Medical, Inc. Medi-Dose/EPS Pacira Pharmaceuticals, Inc.

The profiles in this section were submitted by the advertisers.

American Health Packaging Prepackaged Unit Dose Provides Many Benefits for Health Systems

AT A GLANCE Address American Health Packaging 2550-A John Glenn Ave Columbus, OH 43217 Phone: (800) 707-4621 Fax: (614) 492-0448 Website: www. americanhealthpackaging.com

Patient safety is a critical issue for health systems. As a result, many health systems seek bar-coded medications to dispense to patients. Bar-coded product, used in conjunction with bar code medication administration systems, automate the “five rights.” American Health Packaging is dedicated to supporting this health care initiative with its growing line of prepackaged unit-dose products.

Products Bar-coded unit-dose generics, unit-of-use bottles, complianceprompting packaging

Vice President/ General Manager Rick Knight

Vice President, Sales & Marketing Brian McMillan

There are many benefits to American Health Packaging prepackaged unit-dose products: Safety. Companies that specialize in pharmaceutical packaging are highly regulated and inspected by the FDA. Current Good Manufacturing Practices (cGMP) compliance ensures that products are packaged in a regulated and safe environment. Packaging professionals are adept at ensuring that the product’s lot number, National Drug Code and expiration date are recorded correctly and legibly.

Pharmacy Efficiency. Pharmacies are concerned with timely processing of orders that supply the proper medication to the patient at the appropriate time. Adding a multitude of steps to packaging and checking commercially available products in-house not only slows down this process, it also takes clinicians away from their core competency, patient care.

Liability Management. Packaging products within health-system pharmacies can involve various distractions in terms of quality systems and process controls. Errors that ensue can place the liability on the hospital as well as the caregiver. Purchasing medications from a highly regulated, cGMP-compliant company such as American Health Packaging can help to mitigate risk by shifting some burden of responsibility from the health system.

Cost Savings. In addition to shifting the potential cost of errors, health systems that choose on-site packaging must consider other direct costs, such as establishing the packaging infrastructure as

Find us at the intersection of patient safety and pharmacy efficiency.

26

Corporate Profile 2013

well as paying the highly trained professional staff to perform, manage and support non-core work.

Safety in Every Dose.

Bar coded to the dose level, American Health Packaging’s unit-dose line has grown substantially in recent years. The line now contains close to 400 SKUs and nearly one-third of those are industry-exclusive items.

The unit-dose products are bar coded to the dose level, many already converted to Global Trade Item Number and feature an extended shelf life. Additionally, color-coded labels with “tall man” lettering provide an extra safety feature to more easily differentiate similar cartons on the pharmacy shelf.

Our bar-coded unit dose supports health system patient safety efforts.

About American Health Packaging American Health Packaging is a subsidiary of AmerisourceBergen.

Its manufacturing facility is registered with the FDA and fully adheres to cGMP. Industry veterans with nearly 100 years of collective experience lead the quality and manufacturing departments. American Health Packaging is licensed by the Drug Enforcement Administration to package Schedule II to V controlled substances.

New unit dose launches include tretinoin capsules, misoprostol tablets, modafinil tablets, nifedipine capsules, zafirlukast tablets, oxandrolone tablets, montelukast chew tablets

Special Advertising Section Pharmacy Practice News

RxWorks™ From AmerisourceBergen Technology Group (ABTG) AT A GLANCE A platform designed to provide true integration of inventory, workflow, bar coding, packaging and carousel solutions, RxWorks is optimal for facilities that want greater inventory control, reduced medication errors and advanced unit-dose packaging, while best using limited space.

RxWorks is a scalable platform, designed to expand as you expand.

Company Background AmerisourceBergen Technology Group (ABTG) is a business of AmerisourceBergen Drug Corporation and has been a leader in the pharmacy automation industry for nearly 20 years. From small community pharmacies dispensing a few dozen prescriptions per shift to multifacility health systems supporting thousands of lives, ABTG has technology solutions that will help improve patient safety, streamline medication management processes and control costs. The ultimate goal is to provide its business partners with safer and smarter ways to care for their patients, customers and communities.

Product Overview RxWorks™ from AmerisourceBergen Technology Group (ABTG) is the platform on which many of ABTG’s inpatient pharmacy solutions are integrated. Features include: • A single database to manage and connect all of these components.

• Modularity that enables reporting consistency.

• A single point of entry for medications and users.

Beyond integration, RxWorks is an open system, which means that ABTG designed the platform to have interfacing capabilities with virtually any vendor or device.

340B offers a compreAddress hensive approach to track, report and replenAmerisourceBergen Technology ish 340B inventory, while Group improving the overall 1400 Busch Parkway Buffalo Grove, IL efficiency of the pharToll-free Phone: (877) 781-ABTG macy’s supply chain.

(2284) Implementing this soluWebsite: www.abtg.com tion provides the pharmacy with the assurance Vice President/ that its 340B savings will General Manager be maximized, and time spent ordering medicaTony Guarino tions will be minimized.

FastFind ® UniverEmployees sal. The carousel allows 250+ technicians to retrieve medications from a single location, and its ergonomic design minimizes technicians’ bending and reaching by picking from the waist height. Driven by the RxWorks platform, the FastFind Universal employs complete inventory management for all items stored in the carousel. That includes the ability to generate purchase orders directly from the carousel when inventory is running low.

FastPak® EXP. ABTG’s premier packaging solution, the FastPak EXP consists of packaging subunits that can be easily switched between standard or narrow widths: standard for traditional unit-dose and multidose solutions, narrow for automated dispensing cabinets or 30-day boxes. Innovative Smart Canisters are optional and can be interchanged quickly, enabling the automation of limitless oral solids.

Barcoding Station. The Barcoding Station allows bar codes to be added to products that are either not bar coded by the manufacturer or inadequately coded/unreadable by a barcode medication administration scanner. Through extensive market research and customer feedback, ABTG updates and launches new technology solutions routinely. Look for more cutting-edge introductions from ABTG coming soon!

Features and Options RxWorks Inventory. This powerful inventory management software module integrates pharmacy, automation, materials, finance, nursing and purchasing systems. With the ability to provide a perpetual inventory system for any number of locations, RxWorks Inventory helps facilities save time and money through better management of drugs and materials processes.

RxWorks Workflow. This integrated software solution is developed to address pharmacy needs for safer, more efficient workflow management. RxWorks Workflow easily integrates into the pharmacy environment and interfaces with the pharmacy information management system. Easy to learn and use, RxWorks Workflow is a comprehensive software solution that improves safety and workflow by efficiently guiding staff to the appropriate pick locations (automated and manual), and more importantly, ensuring the right drug is picked, in the right dose, for the right patient.

RxWorks 340B. Also integrated on the RxWorks platforms, RxWorks

Special Advertising Section Pharmacy Practice News

Corporate Profile 2013

27

Amneal Institutional™ AT A GLANCE Address Amneal Institutional 118 Beaver Trail Glasgow, KY 42141 Phone: (866) 525-7270 Email: Sales@amnealinstitutional.com

Specialized Products and Packaging Unit-Dose Packaged Oral Solids • Both existing and future Amneal products • Customer-defined, automationready packs Injectables (syringes, vials, bags) • Partner-developed and produced • Internal development with vertically integrated and finished product capabilities Distribution • Orders ship within 36 hours • Single, central Amneal distribution center in Glasgow, Ky.

In less than six years, Amneal Pharmaceuticals has become the seventh largest generic pharmaceutical manufacturer in the United States. The company has been recognized with awards, seen more than 118 million of its prescription drugs dispensed per year, built its infrastructure to a 35 billionunit annual capacity and has nearly 240 Abbreviated New Drug Applications filed or in development. Despite its phenomenal growth, this award-winning company remains passionate about continued expansion across its current business segments as well as into new products, dosage forms and markets, all while maintaining its total commitment to quality and superior customer value and relationships.

Amneal recently extended its philosophy further into the institutional market with the creation of Amneal Institutional (AI)—a business unit dedicated to generic products and packaging designed to meet the specific needs of health systems, clinics and physician offices.

With an average of more than 25 years in the The Amneal Institutional pharmaceutical industry, AI’s account manageValue ment team has extensive experience serving the Proactive, fully immersed into institutional market, widely defined as hospitals segment and other acute care facilities, outpatient surgi• Dedicated and committed cal and radiology services, oncology centers, experienced team and superb home infusion service providers, long-term care customer support centers, correctional facilities, specialty pharmaProven performance cies and group purchasing organizations.

• Superior supply, quality and With a distinct product selection that includes integrity specialty injectables (prefilled syringes, singleOrganizational relationships dose vials, pharmacy bulk packaging and premix • Transparent, collaborative and bags) and unit-dose packaging, Amneal is now customer-focused well positioned to fill the unique needs of these markets. Some of the near-term launches—products from a partnership with Agila Specialties— are on the FDA Drug Shortage List and should help address current market supply issues. Several other product launches are planned through year-end as well as a robust pipeline for 2014 and beyond. The new dosage forms join the same proven bulk oral solids, topicals and large-quantity oral liquid medications on which Amneal’s reputation was built, offering institutional pharmacies a broader selection of superb-quality generics.

A Move Into Biologics and Biosimilars Understanding the strategic direction of the industry, Amneal began moving into biologics in 2009 and expanded into biosimilars with the early 2012 acquisition of Therapeutic Proteins International (TPI), a biosimilars development firm in Chicago. TPI’s management team offers extensive, industry-wide experience in this rapidly evolving area of pharmaceuticals, in both the domestic and inter-

28

national markets. The company’s revolutionary patented disposable bioreactor-based manufacturing technology radically alters biologic production paradigms, enabling accelerated time to market.

With 40-plus tests—five of which are patented—per product, TPI delivers the same superior quality and extraordinary consistency for which Amneal goods are known. Amneal anticipates the first FDA approval of its TPI biosimilar product in 2014.

Beyond stellar products, Amneal offers a unique collaborative business style to the institutional area. A dedicated and committed account management team boasts extensive experience from a variety of injectable manufacturers. This highly focused sales leadership group—together with Amneal’s transparent and responsive way of doing business—promises to deliver industry-recognized customer focus bolstered by unrelenting quality, development of non-price value and a consistent supply of essential products to meet the institutional pharmacy’s needs and help improve the health of its patients.

Special Advertising Section Pharmacy Practice News

The APP Brand of Specialty Injectable Products From AT A GLANCE Fresenius Kabi USA Address

Fresenius Kabi is a leading global health care company that focuses on medicines and medical devices for critically and chronically ill patients inside and outside the hospital. Its APP brand of specialty injectable products is well known to hospitals and other health care providers in the United States. Fresenius Kabi provides a full line of critical care, anesthesia/analgesia, oncology and antiinfective products under the APP brand.

Table. APP Injectable Drug Products

Today, providing reliable access to quality specialty injectable products is more important than ever before. As part of a global company, Fresenius Kabi USA is positioned to provide high-quality products to its customers based on the following capabilities: • Access to multiple U.S.-based and global manufacturing locations • Redundant production lines that can be used when needed • Well-established relationships with suppliers • A secure global distribution network

Number of Product Families

Number of Products

Analgesia and anesthesia

16

124

Antiinfectives

28

79

Critical care

54

139

Oncology

27

63

Therapeutic Area

APP products are produced at multiple FDA-registered facilities located throughout the United States, Europe and Asia. To help further ensure that the company can reliably meet the needs of its customers, the global manufacturing capabilities of Fresenius Kabi have been utilized in times of great customer need.

What this ultimately means to health care providers and the patients they serve is that Fresenius Kabi USA has the commitment and resources to provide specialty injectable products that meet the highest quality standards.

Well Prepared To Serve Customer and Patient Needs

Fresenius Kabi USA Three Corporate Drive Lake Zurich, IL 60047 Phone: (847) 550-2300 Toll-Free: (888) 391-6300 www.fresenius-kabi.us

Customer Service (Ordering) Toll-Free: (888) 386-1300 FAX: (800) 743-7082

Medical Affairs Toll-Free: (800) 551-7176 FAX: (847) 413-8571

Products

Together, these capabilities define what customers and patients expect and rely on from a leader focused on supporting the care of critically and chronically ill patients inside and outside the hospital.

A leading supplier of multisource and branded injectable pharmaceutical products, primarily focused on the anesthesia/analgesia, anti-infective, critical care and oncology markets.

A Growing Portfolio of Quality Products In 2012, Fresenius Kabi USA was the second largest supplier of multisource products based on the number of units sold in the United States and Canada.1 The company ranks first in terms of the number of injectable drugs offered across four key therapeutic areas (Table).

There is a commitment to continually expand its already broad portfolio. Recently, Fresenius Kabi added Meropenem for Injection, USP (IV) and Imipenem and Cilastatin Injection, USP (IV) to its antiinfective portfolio; Acetylcysteine Injection, Tranexamic Acid Injection, Benztropine Mesylate Injection and Levetiracetam Injection to its critical care product line; and Oxaliplatin Injection, USP to its oncology portfolio.

Commitment in Action Fresenius Kabi USA has the resources to maintain its commitment to providing quality essential medicines. The company’s processes, production capabilities and people demonstrate its commitment in action on a daily basis.

Reference 1.

Special Advertising Section Pharmacy Practice News

IMS Health, September 2012.

Corporate Profile 2013

29

Clinical and Laboratory Standards Institute AT A GLANCE Address Clinical and Laboratory Standards Institute 950 W. Valley Road, Suite 2500 Wayne, PA 19087 Phone: (610) 688-0100 Fax: (610) 688-0700 Email: customerservice@clsi.org Website: www.clsi.org

Products Standards, companion products, webinars, workshops, certificate programs, document competency quizzes, symposia, training

Chief Executive Officer Glen Fine, MS, MBS, CAE

Senior Vice President, Operations Luann Ochs, MS

The Clinical and Laboratory Standards Institute (CLSI) is setting the standard for quality in clinical laboratory testing around the world. A not-forprofit membership organization, CLSI brings together the global laboratory community for advancement of a common cause: fostering excellence in laboratory medicine.

For over 40 years, our members, volunteers and customers have made CLSI a respected, transformative leader in the development and implementation of clinical laboratory testing standards.

Through our unified efforts, we will continue to set and uphold the standards that drive quality test results, enhance patient care delivery and improve health care around the world. CLSI distributes more than 75,000 standards worldwide each year.

Vision: Quality practices for better health.

Mission: Develop clinical and laboratory practices and promote their use worldwide.

Why Use CLSI Consensus Standards?

We have an array of standards that span nine main subject areas. By using CLSI standards, you save time and costs while improving process quality, speeding the development of standard operating procedures and implementing safer practices with greater ease and efficiency. CLSI Companion Products related to the standards are available to improve the ease of use of standards.

CLSI has a hierarchy of committees that oversee the development of our consensus standards. What’s unique about CLSI is that all of our committees have a balanced consensus body, which means that each of the three constituencies— government, industry and professional representatives—has an equal say when approving documents for publication.

Pharmacists—eM100 comes in a version just for you!

eM100™ is an easy-to-use interactive, searchable database for drug selection, interpretation and quality control procedures.

Why Volunteer With CLSI? Take part in developing standards that apply to the work you do each day. By donating your time and talents to improve the standards that affect your own work, you will play an active role in improving health care across the globe. Gain recognition from CLSI, your organization, your colleagues and your community by enriching your career and resumé through your contributions.

Clear Guidance on How To Improve Laboratory Practices Through CLSI’s educational resources, one can learn directly from the experts who developed the standards to implement those technical documents in his or her laboratory and improve quality. Enhance comprehension and use of CLSI standards and earn P.A.C.E.® continuing education credits along the way. Educational opportunities include webinars, document competency quizzes and certificate programs. Participate in webinars related to AST standards, quality management and upcoming CLSI standards. All our educational offerings can be found on our website at www.clsi.org/education-programs.

Why Join CLSI?

eM100 is an interactive, searchable database for drug selection, interpretation and quality control procedures. It is based on CLSI’s widely recognized AST standard M100-S23—Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement. The database can help you work more efficiently by providing the latest recommendations for detecting emerging resistance in an easy-to-use format.

You’ll find only the information you need to make informed patient recommendations. Membership discounts apply. If you already own M100-S23, you will receive an additional 50% off your member price for your 2013 eM100 subscription!

CLSI members have access to a network of more than 2,000 influential organizations across the global laboratory community. Members can receive up to 70% off the cost of CLSI documents, educational programs and companion products. Along with our revised membership levels and categories, this year we have introduced individual memberships! If you are interested in learning more about CLSI membership, email us at membership@clsi.org.

Raise your standards for excellence with the help of CLSI.

CLSI’s widely recognized standard M100-S23— Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement.

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Corporate Profile 2013

Special Advertising Section Pharmacy Practice News

CSL Behring Biotherapies for Life CSL Behring is a global leader in the plasma protein therapeutics industry. Committed to saving and improving the lives of people with rare and serious medical disorders, we research, develop, manufacture and market plasma-derived and recombinant biotherapies.

Our products are used around the world to treat coagulation disorders such as hemophilia and von Willebrand disease (VWD), primary immune deficiencies, hereditary angioedema and inherited respiratory disease, as well as neurological disorders in certain markets. We also manufacture products that are used in cardiac surgery, organ transplantation, burn treatment and to treat acquired bleeding and prevent hemolytic disease of the newborn.

CSL Behring maintains state-of-the-art manufacturing facilities that we have been expanding to keep pace with the growing demand for immunoglobulin and albumin.

Customer Focus At CSL Behring we are committed to the people who rely on our products. We never forget that our therapies are essential to the life and well-being of every patient. Each of us brings that sense of purpose to work every day. Our Core Values—customer focus,

innovation, integrity, collaboration and superior performance—underscore our purpose and our commitment to provide the best possible therapies and services.

AT A GLANCE Address

Innovation We continually leverage our medical and scientific expertise to develop new therapies, create new applications and innovative enhancements for our products, and identify underserved markets. We invest in emerging technologies to develop new products and improve existing therapies.

We continue to increase our investment, growing the R&D project portfolio and enhancing and expanding global capabilities where they can add the most value. CSL Behring has more than 1,000 R&D employees who serve on various global project teams to maximize individual expertise while leveraging core capabilities at each site.

We strive to ensure our manufacturing processes and facilities are state-of-the-art and can meet a growing demand for immunoglobulin and albumin. Our facilities combine advanced industrial-scale filtration technology, highly efficient separation processes and advanced formulation to generate our innovative plasma therapies.

CSL Behring 1020 First Avenue King of Prussia, PA 19406 Corporate Inquiries: Chris Florentz - (610) 878-4316 Product Inquiries: Sheila Burke – (610) 878-4209 Fax: (610) 878-4009 Website: www.cslbehring-us.com

Products CSL Behring is a global leader in the plasma-protein biotherapeutics industry, providing life-saving treatments that include recombinant biotherapies for a range of rare and serious medical disorders. CSL Behring also operates one of the world’s largest plasma collection networks, CSL Plasma.

CSL Behring is a subsidiary of CSL Limited, a biopharmaceutical company with headquarters in Melbourne, Australia.

Access to Care

Employees

Even the most innovative therapies are meaningless if people are not able to obtain them.

CSL Behring offers a broad range of programs and services to assist patients and physicians with reimbursement support and ways to ensure access to their therapies. We also partner with patient associations to advocate for legislation that protects patient and physician choice of therapy, appropriate standards of care, appropriate reimbursement and other topics that impact the rare disease communities we serve.

10,500+ employees in 30 countries

Recognition

Manufacturing Facilities Marburg, Germany Bern, Switzerland Kankakee, Illinois, United States Broadmeadows, Australia

CSL Plasma Headquartered in Boca Raton, Florida, United States Testing laboratories in Knoxville, Tennessee, United States; and Göttingen, Germany 75+ collection centers in the United States and eight in Germany

CSL Behring has been recognized by patient groups and the industry for its innovative lifesaving therapies. The European Organization for Rare Disorders presented its EURORDIS Award to CSL Behring for “pioneering work in developing and manufacturing therapies used to treat rare and serious medical conditions.”

The National Organization for Rare Disorders recognized CSL Behring for developing and marketing the first treatment in the United States for acute bleeding episodes in patients with congenital fibrinogen deficiency. Forbes has included CSL Behring in its Top 50 List of the world’s most innovative companies.

CSL Behring global headquarters in King of Prussia, Pennsylvania

Special Advertising Section Pharmacy Practice News

Corporate Profile 2013

31

CutisPharma, Inc. AT A GLANCE Address CutisPharma, Inc. 68 Cummings Park Woburn, MA 01801 Contact: Jim Nagle, Vice President–Business Development Phone: (781) 935-8141 ext. 120 Email: JNagle@cutispharma.com Website: www.cutispharma.com

CutisPharma, Inc., brings innovation and value to the prescription-compounding sector of hospital and health-system pharmacies. Patient-specific – Compounding Kits simplify the entire process by quickening preparation and helping facilitate reimbursements. What typically takes compounders up to 15 minutes to do now takes just minutes.

FIRST® – Omeprazole and FIRST® – Lansoprazole Suspension Unitof-Use Compounding Kits in 3, 5 and 10 oz sizes.

more easily through nasogastric (NG) tubes, with minimal clogging compared to current practice. Also, our three different sizes of packaging, 3 oz., 5 oz. and 10 oz., provide considerable prescribing flexibility.”

Compounding Kits for Often-Filled ‘Magic Mouthwashes’

CutisPharma, Inc., offers convenient kits that make dispensing some Greater efficiencies in the compounding process of the most commonly prescribed suspensions a simple, easy process. bring multiple financial and clinical gains to hospiCommonly known as ‘Magic Mouthwashes,’ the products include: Patient-Specific Prescription tal and health-system pharmacies. By using pre• FIRST® – Mouthwash BLM (Benadryl®, lidocaine and Maalox®) in Compounding Kits measured, pre-weighed unit-of-use prescription three sizes ® compounding kits, pharmacies and nurses save • FIRST® – Mouthwash BXN (diphenhydramine, lidocaine and FIRST – Omeprazole Suspension: significant staff time in preparation, help lower the nystatin) 3, 5, 10 oz. total costs of compounding, and refine their just• FIRST® – Duke’s Mouthwash (diphenhydramine, hydrocortisone and FIRST® – Lansoprazole Suspension: 3, 5, 10 oz. in-time inventories to ensure ingredients are on nystatin) FIRST® – Mouthwash BLM: 4, 6, 8 oz. hand when needed and ready to use over longer • FIRST® – Mary’s Mouthwash (diphenhydramine, hydrocortisone, FIRST® – BXN Mouthwash periods of shelf life. All dispensing containers are nystatin and tetracycline) FIRST® – Duke’s Mouthwash bar-coded for convenient bedside scanning.

Each FIRST® Kit has everything needed to compound one prescripFIRST® – Mary’s Mouthwash Clinically, the packaged reagents help deliver tion from one prescriber for one patient. They include pre-weighed FIRST® – 10% Hydrocortisone in consistent accuracy of the compound admixtures powders and a pre-measured suspension. The pharmacist needs only Ultrasound Gel and speed medication delivery to patients, if to add the powders to the liquid suspension, shake and dispense.

FIRST® – Progesterone Vaginal compounded according to instructions, because “The company now has a wide range of FIRST® ‘Magic Mouthwash’ Suppository USP: 25, 50, 100, they’re easier and quicker to use than the typical formulations to choose from, particularly for the most commonly pre200, 400 mg laborious processes.

These benefits, in turn, may scribed and used,” Dr. Muni said.

FIRST® – Testosterone MC: lead to better patient health outcomes. The kits FIRST® products save dispensing time and can be compounded by 2% Testosterone in White also help facilitate compliance with USP <795>. the pharmacist while the patient waits, thus increasing customer satMoisturizing Cream Base “Industry-wide savings can be vast. [The] FDA isfaction. Using FIRST® Mouthwash kits, the pharmacist can compound FIRST® – Testosterone: 2% estimates 30 million a prescription faster than those prepared in the Testosterone in White Petrolatum hospital-outpatient conventional way. and retail compound– 10% Hydrocortisone ing prescriptions are In Ultrasound Gel Compounding Kit filled per year. Inpatient figures are also significant, yet harder Primarily prescribed for physical therapy to pinpoint because they lack a single NDC patients, the FIRST® – 10% Hydrocortisone in number,” said Jim Nagle, Vice President– Ultrasound Gel Compounding Kit contains 6 Business Development at CutisPharma. g of micronized hydrocortisone USP in a 24-g The NDC number imprinted on each suspension with propylene glycol USP and end-use container in every CutisPharma simethicone USP. It also includes 36 g of ultraFIRST® – Kit facilitates third-party reimsound gel for topical use. The kit has a twobursement for health systems. The single year shelf life prior to compounding.

NDC number for the entire kit may also There are approximately 350,000 10% Hydroimprove patient safety, because of minicortisone in Ultrasound Gel prescriptions writmized dispensing errors, suiting the growten annually. A CutisPharma cost comparison The FIRST® – Magic Mouthwash line contains FIRST® – ing number of inpatient and outpatient Mouthwash BLM (4, 6 and 8 oz sizes), BXN, Duke’s and shows that FIRST® – 10% Hydrocortisone Kit Mary’s versions. pharmacies that bar-code prescriptions can yield a profit of over $9 for a compounding from point of dispensing to point of care. pharmacy versus a loss of over $16 when the admixture is compounded conventionally. Also, preparation time is cut Compounding Kits for Widely Used PPIs to two minutes from well over 15 minutes.

CutisPharma, Inc., also offers FIRST® – Omeprazole and FIRST® – LanGrowing Portfolio Serves Compounding Needs soprazole Patient Specific Oral Suspension Compounding Kits. These kits will help pharmacists quickly dispense these compounded preThe CutisPharma Kit portfolio is growing to meet pharmacy’s increasscriptions containing widely used proton pump inhibitors (PPIs). Tradiing reliance on compounding. To meet the need for efficiencies, safety tionally, compounded omeprazole and lansoprazole oral suspensions and convenience, all FIRST® Patient-Specific Compounding Kits follow can take up to several hours to prepare and have an unpleasant taste. the simple rule of “one prescription from one prescriber for one patient.”

With FIRST® – Omeprazole and FIRST® – Lansoprazole, pharmacists CutisPharma, Inc., now has 20 proprietary prescription compoundneed only add the liquid suspension to the powder, shake, and then ing kits on the market: five progesterone suppository compounding within minutes can dispense to the patient with improved flavoring. kits, two testosterone kits, one hydrocortisone kit, six Magic Mouth“We invested a lot of time to develop these new suspension kits. wash kits, three omeprazole suspension kits and three lansoprazole The results are a pleasant-tasting strawberry-flavored medication with suspension kits. Several more compounding kits, including a grapeadequate stability once compounded,” said Dr. Indu Muni, founder, flavored Vancomycin Suspension, are in the planning stages. chairman and CEO of CutisPharma, Inc. “These products offer another advantage for hospital use: Since the suspensions are made using powders and not pellets, our new compounded suspensions should flow

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Corporate Profile 2013

Special Advertising Section Pharmacy Practice News

Grifols Grifols is a global health care company headquartered in Barcelona, Spain. The company produces and markets plasma-derived medicines as well as hospital pharmacy products, compounded IV solutions, and in vitro diagnostic products for clinical laboratories.

Grifols employs more than 8,000 people in the United States and 11,200 people worldwide, and its products are sold in more than 90 countries.

AT A GLANCE Address Grifols 2410 Lillyvale Ave. Los Angeles, CA 90032 Phone: (888) GRIFOLS (474-3657) Website: www.grifols.com

A Legacy of Innovation At Grifols, a history of innovation defines our modern-day approach to medicine. More than 70 years ago, a Spanish hematologist named Dr. Jose Antonio Grifols Roig pursued a line of research that would set the stage for contemporary use of human plasma to treat disease.

Together with his sons, he founded Laboratorios Grifols in 1940.

Among their pioneering achievements, they obtained a patent in Spain for the process of plasma lyophilization, or freeze-drying of human plasma, along with the devices needed to inject plasma into patients who required its therapeutic properties. Shortly thereafter, in 1951, Dr. Jose Antonio Grifols Lucas published the first large-scale clinical data describing the plasmapheresis technique of extracting plasma from donors while returning their red blood cells. Combined with the work of Edwin Cohn, Grifols paved the way for the birth of the plasma fractionation industry as we know it today.

Expanding To Meet the Demand From these auspicious beginnings, Grifols has evolved into an industry leader in the collection, manufacture and marketing of plasma-derived therapies. Through recent acquisitions, Grifols is now the third largest global producer of plasma-derived medicines.

Grifols operates the world’s largest plasma collection platform, with 150 source plasma donation centers across the United States.

Grifols currently has the world’s highest plasma protein fractionation capacity of more than 8 million liters of plasma per year. To accommodate the growing global demand for plasma-derived medicines, Grifols is significantly expanding its three manufacturing sites in Clayton, N.C., Los Angeles, Calif., and Barcelona, Spain— the company’s global headquarters. The expansions include a

Divisions Edwin J. Cohn & Jose Antonio Grifols at the 4th International Congress of Blood Transfusion, Lisbon 1951.

new, 185,000-square-foot fractionation facility in Clayton and a new facility in Los Angeles dedicated to the production of immune globulin therapies. The new manufacturing facilities will increase the company’s capacity to fractionate plasma to 12 million liters by 2015.

In addition, this year, Grifols opened a new, state-of-the-art plasma testing laboratory in San Marcos, Texas, where every plasma donation undergoes rigorous scientific analysis prior to being approved for use in manufacturing.

The 72,000-square-foot facility houses the latest technology for conducting sophisticated viral testing, including transcription-mediated amplification to rapidly detect minute levels of viral material in plasma samples. The San Marcos laboratory, together with an existing plasma testing laboratory in Austin, will analyze millions of plasma samples annually.

Grifols is firmly committed to giving patients and health care providers broad access to our products. As Grifols grows, it continues to pursue its mission of improving the health and well-being of people around the world.

Bioscience: Specializes in the research, development, production and commercialization of high-quality plasma therapies.

Hospital: Specializes in operational solutions for compounding areas in pharmacy.

Diagnostic: Specializes in diagnostic instrumentation, reagents, software and related products for the clinical laboratory.

Products Albumin (Human), marketed as Albutein® 5%, Albutein® 25% and Plasbumin® _ 5 and Plasbumin® _ 25 Alpha1-Proteinase Inhibitor (Human), marketed as Prolastin®-C Antihemophilic Factor/von Willebrand Factor Complex (Human), marketed as Alphanate® Antithrombin III (Human), marketed as Thrombate III® Coagulation Factor IX (Human), marketed as AlphaNine® SD Factor IX Complex, marketed as Profilnine® SD Hyperimmune Globulin Therapy Products: • Rabies Immune Globulin (Human) • Tetanus Immune Globulin (Human) • Rho (D) Immune Globulin (Human) • Hepatitis B Immune Globulin (Human) Immune Globulin Intravenous (Human) or IVIG Immune Globulin Injection (Human) Gri-fill® System 3.0 for compounding sterile preparations Misterium® modular clean room solution Grifols-SencorpWhite inventory management system solutions Phocus® Rx: remote pharmacist validation system for compounding IV preparations Grifols Triturus® Fully Automated EIA Analyzer

IVIG manufacturing plant in Barcelona, Spain, designed by Grifols Engineering.

Interlab G26 Clinical Agarose Gel Electrophoresis Systems A focused selection of reagents for infectious serology, autoimmunity, oncology, and celiac disease CO23-0612

Special Advertising Section Pharmacy Practice News

Corporate Profile 2013

33

ICU Medical, Inc. ICU Medical connects patients and caregivers through safe, life-saving, lifeenhancing medical devices, providing clinicians around the world with innovaAddress tive and cost-effective patient care soluICU Medical, Inc. tions for unmet clinical needs. Since the 951 Calle Amanecer 1970s, the unsafe handling of hazardSan Clemente, CA 92673 Phone: (866) 829-9025 ous drugs used to treat many forms of Fax: (949) 366-2183 cancer has been recognized as a signifiWebsite: www.icumed.com cant health hazard to health care workers, including oncology pharmacists.

Chairman of the Board, President and CEO In response to these well-documented George A. Lopez, MD risks, ICU Medical has developed the ChemoClave™ system, including the world’s only needlefree closed system transfer devices for the safe handling of hazardous drugs, and the Diana™ hazardous drug compounding system, an automated sterile compounding system for the accurate, safe and efficient preparation of hazardous drugs.

AT A GLANCE

The Diana System The Diana system is the world’s first needlefree, user-controlled automated sterile compounding system for the safe preparation and reconstitution of hazardous drugs. The Diana system takes the variation out of manual drug preparation practice and lets clinicians create a repeatable sterile preparation and safe-handling process.

The Diana system is designed to facilitate both low-volume and highvolume preparation of drugs, fits inside the pharmacy’s biological safety cabinet and complements existing pharmacy workflows. The system also provides automated checks and reminders to improve workflow efficiency and safety.

User-Controlled Automated Sterile Compounding For Maximum Accuracy and Safety Unlike automated technologies that require huge investments and do not fit into existing workflows, the Diana system cost-effectively keeps pharmacists and technicians in control of the compounding process from beginning to end. The mechanically and microbiologically closed design of the Diana system is accomplished through a series of innovative, needlefree components that attach to all con-

The affordable, easy-to-use ChemoClave system includes the world’s only needlefree closed system transfer devices for the safe handling of hazardous drugs.

tainers that are dispensing or receiving a drug in the compounding process, to protect the preparation from exposure to environmental contaminants while also protecting the clinician from both exposure to the drug and accidental needlesticks.

Reduces Risk for Repetitive Stress Injuries And Increases Efficiencies The Diana system helps free pharmacists and technicians from many of the repetitive motions required during drug preparation and reconstitution, and helps reduce the stresses and injuries that can occur as a result. Also, by helping clinicians improve the efficiency of high-volume compounding, the Diana system can deliver workflow efficiencies while reducing drug waste by extracting every drop of drug from every container. The Diana system’s proprietary enabling technology includes pre-packaged preparation sets and ICU Medical’s clinically proven simple, safe and secure ChemoClave™ needlefree closed devices to help enhance health care worker safety and comply with OSHA, NIOSH, ASHP, ISOPP, ONS, APHON and USP <797>.

The ChemoClave System ICU Medical’s ChemoClave system, designed to keep clinicians safe from dangerous exposure to hazardous drugs, provides clinicians with a variety of needlefree vial access devices, a selection of needlefree bag spikes, and primary add-on and administration sets featuring the Spiros® CSTD Male Luer. These devices work together to create and maintain a mechanically and microbiologically closed system throughout the preparation, transportation, administration and disposal of hazardous drugs.

Commitment to the Safety of Oncology Pharmacists Treating cancer patients takes compassion. It shouldn’t take your life. With limited federal regulation for devices that reduce exposure to hazardous drugs, ICU Medical has taken on the responsibility of increasing clinical awareness of the dangers of exposure to these chemicals and improving safety throughout the oncology drug–handling process. ICU Medical is committed to providing easy-to-use needlefree solutions that generate less biohazardous waste and lower costs, while helping keep clinicians and patients safe.

For more information on how to improve the accuracy, safety and efficiency of the hazardous drug–compounding process, visit us at www.icumed.com/oncology or call (866) 829-9025.

The Diana hazardous drug compounding system is the new standard in accuracy, safety, and efficiency for the automated sterile compounding of hazardous drugs.

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Corporate Profile 2013

Special Advertising Section Pharmacy Practice News

Medi-Dose/EPS For more than 40 years, the Medi-Dose System has been used by facilities of all sizes to package solid oral, unitdose medications. Working with pharmacists and technicians, Medi-Dose has been designed to be the easiest, fastest and most cost-effective way to unit-dose and bar-code your inventory.

Inexpensive, Easy and Flexible: Because of its unique Cold-Seal technology, the Medi-Dose System is simple to use and requires no special in-service training or additional space. Medi-Cup blisters are available in a variety of sizes and styles to accommodate virtually any medication or storage system. Ultraviolet-inhibitant blisters provide additional protection from light. Plus, a combina-

tion of special blister plastics with aggressive tamper-evident label adhesives provide either six-month or one-year beyond-use dating for all your unit-dose packaging needs.

Adapts to Your Needs: With our MILT 3.0 software, you can design your labels any way you want. In addition to being able to use graphics, special fonts, tall man lettering, shapes—even logos and symbols—to better identify your medications, MILT 3.0 has been designed to easily create bar codes with the information your bar code–enabled point-of-care and bar code medication administration systems require. Popular one-dimensional and two-dimensional bar code formats can be created with National Drug Code numbers, expiration dates, lot numbers and special codes.

• Sealed units can be left in sheets or easily torn down to individual doses.

• Medi-Cup Blisters are available in five sizes to accommodate the largest medications or the smallest storage spaces.

• Lid-Label Covers are available in 8 1/2˝ × 11˝ laser sheets of 25 doses or 4˝ × 6 1/4˝ direct thermal sheets of five doses.

• Laser Lid-Label Cover Sheets are available in 12 colors to facilitate color-coding of medications.

• New Oval Blisters and Lid-Label Covers have been designed to fit your dispensing machines and storage cabinets.

• All Medi-Cup Blisters and Lid-Label Covers work with our MILT 3.0 software, which can be used for all your bar-coding and labeling needs.

AT A GLANCE Address Medi-Dose/EPS 70 Industrial Drive Ivyland, PA 18974 Phone: (800) 523-8966 Fax: (800) 323-8966 Email: info@medidose.com Website: www.medidose.com

Products Medi-Dose® (Solid) and TampAlerT® (Liquid) Oral Unit-Dose Packaging Medi-Cup® PLUS packaging for extended beyond-use dating MILT® by Medi-Dose unit-dose and bar-coding software LiquiDose® labeling, IV additive and filtration products Nultraviolet® ultraviolet light inhibitant bags Steri-Dropper sterile ophthalmic dropper bottles High Alert and IV Line Tracing Labels Resealable bags, bottles and other pharmacy supplies and disposables

To get started, all you’ll need is: 1. Medi-Cup Blisters: 13 styles to suit your packaging needs.

2. Lid-Label Covers: Laser or Direct Thermal labels to seal the blisters.

3. MILT 3.0 software: Design and manage Lid-Label Cover printing.

4. Fil-Form and Roll-E-ZY: Aligns Lid-Label Covers to the Medi-Cup Blisters and ensures positive seal between labels and blisters.

Inexpensive. Flexible. Tamper-Evident. If you are looking for a system to handle any or all of your unit-dose or bar-coding needs, then the Medi-Dose System is a perfect fit for you!

Special Advertising Section Pharmacy Practice News

Corporate Profile 2013

35

Pacira Pharmaceuticals, Inc. AT A GLANCE Address Pacira Pharmaceuticals, Inc. 5 Sylvan Way Parsippany, NJ 07054 Phone: (973) 254-3560 Fax: (973) 267-0060 Website: www.Pacira.com For more information on EXPAREL, visit www.EXPAREL.com For medical inquiries related to EXPAREL, contact Medical Information at medinfo@pacira. com or 1-855-RX-EXPAREL (1-855-793-9727)

Pacira Pharmaceuticals, Inc. is an emerging specialty pharmaceutical company focused on the clinical and commercial development of new products to address the needs of acute care practitioners and their patients. Pacira is driven by a dynamic workforce committed to optimizing patient care and satisfaction in the acute care setting, with a special focus on improving outcomes in postsurgical pain management.

A Proprietary Drug Delivery Platform

The cornerstone of the Pacira product portfolio is DepoFoam®, a proprietary drug delivery platform designed to extend a medication’s duration of action without altering its molecular structure. The DepoFoam carrier matrix is made up of multivesicular liposomes that encapsulate a drug. Each chamber is separated by lipid membranes that naturally erode to release the drug over a desired period of time.

A First of Its Kind Single-Dose Local Analgesic In 2012, Pacira successfully launched EXPAREL® (bupivacaine liposome injectable suspension), the first and only DepoFoam-based local analgesic. Indicated for administration into the surgical site to produce postsurgical analgesia, a single dose of EXPAREL provides non-opioid pain control with reduced opioid requirements for up to 72 hours* without the need for catheters or pumps.1

Shifting the Postsurgical Pain Management Paradigm The launch of EXPAREL is bolstered by a robust Phase 4 clinical program, which builds a compelling case for EXPAREL as the foundation of an opioid-sparing multimodal postsurgical pain management regimen. Recently published national and regional retrospective analyses2,3 of more than 400,000 postsurgical patients receiving opioids concluded that patients who experienced opioid-related adverse events had both longer lengths of hospital stay and higher hospitalization costs. The company’s efforts are buoyed by a groundswell movement led by governmental and independent health care organizations to mitigate potentially fatal side effects related to the use of opioids by recommending a shift toward opioid-sparing pain regimens, especially in high-risk postsurgical patients.

36

Pacira recently presented data supporting the administration of EXPAREL via infiltration into the transversus abdominis plane to produce up to 72 hours of postsurgical analgesia. The company is also advancing its Phase 3 nerve block program studying the safety and efficacy of EXPAREL administered as a femoral or intercostal nerve block.

The Pacira Advantage Discovery, innovation and proprietary expertise are the hallmarks of the Pacira competitive advantage. The company not only holds the exclusive rights and expertise to DepoFoam, but owns the unique distinction of being the only company in the world with the ability to manufacture DepoFoam-based products, such as EXPAREL, on a large commercial scale. With steadily increasing demand and a growing list of potential clinical applications, Pacira and EXPAREL are poised to become vital fixtures in the postsurgical pain management arena.

For more information about Pacira Pharmaceuticals Inc., visit www.pacira.com.

Important Safety Information for EXPAREL EXPAREL is contraindicated in obstetrical paracervical block anesthesia.

EXPAREL has not been studied for use in patients younger than 18 years of age.

Non-bupivacaine-based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more.

Other formulations of bupivacaine should not be administered within 96 hours following administration of EXPAREL. Monitoring of cardiovascular and neurological status, as well as vital signs, should occur during and after injection of EXPAREL as with other local anesthetic products. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk for developing toxic plasma concentrations. In clinical trials, the most common adverse reactions (incidence ≥10%) following the administration of EXPAREL were nausea, constipation and vomiting. *Pivotal studies have demonstrated the safety and efficacy of EXPAREL in patients undergoing bunionectomy and hemorrhoidectomy procedures.

References 1. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Dis Colon Rectum. 2011;54:1552-1559.

Clinical Utility Across a Broad Range of Potential Applications

2. Oderda GM, Gan TJ, Johnson BH, Robinson SB. J Pain Palliat Care Pharmacother. 2013;27:62-70.

EXPAREL has broad applications across multiple surgical specialties, as well as in the anesthesiology arena.

3. Kessler ER, Shah M, Gruschkus SK, Raju A. Pharmacotherapy.

2013;33:383-391.

Corporate Profile 2013

Special Advertising Section Pharmacy Practice News

Clinical 37

Pharmacy Practice News • August 2013

Infectious Disease

Universal Decolonization Gets Nod for Halting ICU Infections

I

n a large study of intensive care units (ICUs), universal decolonization proved more effective than rival strategies in reducing methicillin-resistant Staphylococcus aureus (MRSA)-positive clinical cultures and bloodstream infections from any pathogen.

In the REDUCE MRSA (Randomized Evaluation of Decolonization versus Universal Clearance to Eliminate MRSA) trial ((N Engl J Med 2013;368:2255-2265), 43 hospitals (including 74 ICUs) were randomized to one of three groups. In the universal decolonization group, all patients underwent daily bathing with chlorhexidine-impregnated cloths and received twice-daily intranasal mupirocin for five days. In the screening and isolation group, patients’ nostrils were screened for MRSA on admission, and contact precautions were taken for patients with a history of MRSA or a positive MRSA test. In the targeted decolonization group, only patients known to have MRSA colonization or infection received a five-day decolonization regimen with mupirocin and chlorhexidine.

Compared with the 12-month baseline period, during the 18-month intervention period hazard ratios (HRs) for MRSA clinical isolates were 0.92 for screening and isolation, 0.75 for targeted decolonization and 0.63 for universal decolonization ((P=0.01). In the intervention versus baseline periods, HRs for bloodstream infection with any pathogen were 0.99, 0.78 and 0.56, respectively ((P<0.001). Universal decolonization significantly reduced MRSA-

Copper May Be Helpful Against Hospital-Acquired Infections

D

oes copper have a place in lowering the risk for hospital-acquired infections (HAIs)? Two recent studies suggest that it might.

Schmidt MG et al compared the bacterial burden on copper-covered and standard plastic bedrails in an intensive care unit (ICU) over three months (Infect Control Hosp Epidemioll 2013;34:530-533). The mean bacterial burden as sampled just before room cleaning was significantly lower for copper-covered bedrails than standard ones: 698 versus 6,102 colony-forming units (cfu) per 100 cm2.

Salgado CD et al performed a randomized controlled trial in the ICUs of three hospitals to assess acquisition of HAIs and methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE; Infect Control Hosp Epidemiol 2013;34:479-486). In the study, 614 patients were randomly placed in rooms with or without copper alloy surfaces on objects such as bedrails and chair arms. The rate of HAI and/or MRSA or VRE colonization in ICU rooms with copper alloy surfaces was significantly lower than in standard ICU rooms (0.071 vs. 0.123; P=0.020).

“There have been papers about the use of copper in a variety of ways,” said Susan S. Huang, MD, MPH, an associate professor in the Division of Infectious Diseases at the Health Policy Research Institute, University of California Irvine School of Medicine, who was not an author of either study. “To determine whether a type of surface can reduce infections, you’d need a large number of hospitals and certainty that other prevention activities were not changing.

Definitive evidence is still pending.”

—G.O.

positive clinical cultures by 37% and bloodstream infections from any pathogen by 44%. There were seven adverse events, all mild (pruritus or rash) and related to chlorhexidine.

“The REDUCE MRSA trial helps answer a long-standing debate about how best to prevent superbugs,” lead author Susan S. Huang, MD, MPH, an associate professor in the Division of Infectious Diseases at the Health Policy Research Institute, University of California, Irvine School of Medicine, told Pharmacy Practice News. “One approach

Simeprevir Shines in Hep C Trial Orlando, Fla.—Triple therapy with peginterferon (PEG-IFN)-2a, ribavirin (RBV) and simeprevir, an experimental once-daily, oral protease inhibitor (PI), resulted in rapid and sustained virologic response in 80% of a group of patients who relapsed following treatment with PEG-IFN-based therapy for chronic genotype 1 (GT1) HCV infection. These results, from the Phase III PROMISE study, were presented at the 2013 Digestive Disease Week meeting (abstract 869b).

The findings led Gregory Gores, MD, the executive dean for research at Mayo Clinic in Rochester, Minn., to speculate that simeprevir will soon be added to the clinician’s HCV treatment toolbox. “The surprising efficacy of simeprevir triple therapy in patients who had relapsed

after prior RBV plus PEG-IFN therapy and in patients with advanced liver fibrosis, along with its once-daily dosing, minimal drug–drug interactions and good safety profile, make it likely the drug will be approved by the FDA for use in HCV patients,” said Dr. Gores, who was not involved in the research.

A team led by Eric Lawitz, MD, a professor of medicine at the University of Texas Health Science Center and the vice president of scientific and research development at the Texas Liver Institute, in San Antonio, randomized 260 patients with HCV GT1 to receive the triple therapy and 133 similar patients to receive an oral placebo with PEG-IFN/RBV, both for 12 weeks, in a double-blind fashion.

Simeprevir recipients who experienced a drop in HCV RNA below 25 IU/mL

is to target high-risk bacteria—screen patients, find those who carry the superbugs and do something for them.

Another approach is to target high-risk patients like those in ICUs and treat all of them as if they might have worrisome bacteria. We found that targeting all high-risk patients was the best strategy.”

The paper by Dr. Huang and her colleagues acknowledges that widespread use of chlorhexidine and mupirocin could promote resistance due to partial killing of colonizing organisms, with the surviving strains becoming resis-

after four weeks of treatment and who had undetectable HCV RNA at 12 weeks received an additional 12 weeks of PEGIFN/RBV alone, whereas those who did not meet these criteria received an additional 36 weeks of PEG-IFN/RBV treatment, for a total of 48 weeks. All placebo recipients received 36 weeks of PEGIFN/RBV after the initial 12 weeks of placebo plus PEG-IFN/RBV treatment.

Rapid Virologic Response Dr. Lawitz reported that 77% of patients who received simeprevir experienced a rapid virologic response (RVR), and 79% had a sustained virologic response 12 weeks after treatment completion (SVR12). In contrast, 3% of placebo recipients achieved RVR, and 37% achieved SVR12 ((P<0.001). Only 7% of simeprevir recipients required 48 weeks of treatment, and rates of on-treatment failure and post-treatment relapse with

tant to future bactericidal treatments.

This is the “biggest concern” of Kerry LaPlante, PharmD, an associate professor in the Department of Pharmacy Practice at the The University of Rhode Island College of Pharmacy, in Kingston. Dr. LaPlante, who was not associated with the study, said the authors’ findings “are thought-provoking in many ways. But we must also stop and think about how the antimicrobials we recommend for a patient today directly impact how effective the same drug will be in another patient tomorrow.

We have to be cautious and strategic in how we use antimicrobial agents. Basically, I don’t like universal anything when it comes to antimicrobial use—it stops thought processes.”

Dr. LaPlante added, “I feel these authors have a responsibility to the community to conduct a follow-up study in three to four years, showing what the MRSA chlorhexidine and mupirocin resistance rates are. Not until these data are published will I feel fully comfortable seeing this regimen used.”

In Dr. Huang’s view, “the question is whether we actually will breed resistance. We need to be attentive to this and monitor for it. But so far, resistance to mupirocin is infrequent and resistance to chlorhexidine is rare. If we do develop resistance, it’s important to remember that these topical products are only used to temporarily remove bacteria from the body, not to treat infections. We will not lose a therapeutic agent.”

—George Ochoa Drs. Huang and LaPlante reported no relevant financial conflicts of interest.

the drug were 3% and 19%, respectively, compared with 27% and 48% with placebo. There were no differences in serious adverse events in the simeprevir and placebo groups.

Noting that the study participants were a difficult-to-treat population, including patients with prior treatment failure and compensated and fibrotic liver disease, Dr. Lawitz said, “hepatitis C is a complex disease, and we need multiple treatment options in order to provide our patients with the best possible chance of successful therapy.”

—David Wild Dr. Lawitz has received research support from Abbott, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix, Idera, Intercept, Janssen, Medtronic, Merck, Novartis, Presidio, Roche, Santaris, Scynexis and Vertex. Dr. Gores reported no relevant financial conflicts of interest.

38 Clinical

Pharmacy Practice News • August 2013

Educational Review

The Future of Antibiotics: Preserving a Precious Commodity DOROTHY MCCOY, PHARMD, BCPS-ID Clinical Associate Professor Ernest Mario School of Pharmacy Piscataway, New Jersey Clinical Pharmacist, Infectious Diseases Hackensack University Medical Center Hackensack, New Jersey

T

he perception of antibiotics has changed significantly since their initial

availability in the 1940s. Many of us have

become desensitized to their value as we either have forgotten or are unaware of the morbidity and mortality that were associated with infections in the pre-antibiotic era.

The mortality rate for Staphylococcus aureus bacteremia, for example, was 82% in the 1940s1 compared with 1.3% to 23.4% for methicillin-susceptible and methicillin-resistant S. aureus, respectively, in the early 2000s 2 (Figure).

Another illustration is the dramatic 97% decrease in pediatric pneumonia-related mortality between 1939 and 1996,3 which was made possible by the availability of new antibiotics, expanded access to medical care, and immunizations. These examples demonstrate the lifesaving capacity of antibiotics.

Very few other drugs are able to affect mortality in a similar fashion. Unfortunately, these lifesaving drugs have been taken for granted, and as a society we have become complacent about their overuse and abuse.

Misuse/Overuse of Antibiotics Antibiotics have become an ordinary part of life, with most people having taken an antibiotic at one point in time, whether it was truly necessary or not. Examples of inappropriate antibiotic use abound in the literature. One prime example is the inappropriate use of antibiotics to treat viral infections.4-7 Patients may have the perception that their “cold” went away because they might have started taking an antibiotic a few days after the cold symptoms began. This false sense of “response” makes patients want to get an antibiotic the next time they have the same symptoms.8 Studies in the United States have found that

antibiotics are used for viral infections between 15% and 72% of the time.4,7,9,10 Other practices, such as the continued use of broad-spectrum agents when narrower ones could be used, prolonged durations of therapy, unnecessary use of antibiotics to treat colonization, and inappropriate dosing, also have been reported.11-15 Additionally, misuse of antibiotics may lead to adverse effects, such as Clostridium difficile infection.16 The general public, patients, and prescribers have been focused on individual reasons for antibiotic use rather than the effect their decisions about antibiotics have on society as a whole,8,17 despite the well-established connection between abuse of antibiotics, resistance, and unnecessary adverse effects.18 As early as 1945, the medical literature included reports about antibiotic resistance and its implications,19 and as early as the 1960s, studies evaluating the appropriateness of antibiotic use began to surface.20 Guidelines published by the Infectious Diseases Society of America (IDSA) in the late 1980s described mechanisms to improve antibiotic use in hospitals.21 Approximately 20 years later, IDSA and the Society for Healthcare Epidemiology of America reiterated those recommendations in their guidelines for developing an antimicrobial stewardship program.22 Although these concerns about overuse and resistance are longstanding, the push to implement changes in practice only recently has gained momentum on societal, national, and

global levels.23 Two critical factors impeding the acceptance and employment of judicious antibiotic use are the depreciation of the value of antibiotics and lack of education.

The Value of Antibiotics How much are we willing to pay for antibiotics?

Most payors want these agents at a low price, but there is no consensus on an appropriate cost for these agents. There is a wide discrepancy in the range of prices for various antibiotics. For example, the cost of a course of therapy for a C. difficile infection may be $12.99 for a 10-day course of generic oral metronidazole (500 mg every 8 hours) versus $3,273.60 for a 10-day course of oral fidaxomicin (Dificid, Optimer) (200 mg every 12 hours).24 In comparison, the chemotherapeutic agent ipilimumab (Yervoy, Bristol-Myers Squibb), which is used for metastatic melanoma, costs approximately $120,000 for a course of therapy (4 infusions over 3 months).25 It is acceptable to pay more for a chemotherapeutic agent that may extend life by 3 to 4 months, but payors are not willing to pay for an antibiotic that can extend life indefinitely.26 This discrepancy may be due to the fact that the morbidity and mortality from infections differ from those due to an oncologic diagnosis that has the end result of death if left untreated. Not all infections are immediately “lifethreatening,” and even within the same type of infection, the spectrum of disease severity varies

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100

82

Percent ?????????

80 60 40

23.4 20 0

1940s

2000s

Figure 1. Staphylococcus aureus bacteremia mortality rate.

Based on references 1 and 2.

(mild vs severe, complicated C. difficile infection).

Moreover, when comparing some of the “older” antibiotics with the newer ones, paying more for the new agent may not be justified if it is not more efficacious or superior to the older drug.

This variability in possible outcomes lends itself to the inconsistency with respect to the price people are willing to pay for antibiotics.

Further influencing the value of antibiotics are the recent programs by various pharmacies to give out free or very low-cost antibiotics to patients.26,27 These programs have been used as a mechanism to get patients into the store as well as to assist those who otherwise might not be able to afford the antibiotics.28 Many pharmacies are able to provide these programs because antibiotics only are given for a short period of time (5-14 days), and many generic antibiotics are inexpensive for the pharmacy to acquire.28 The effect (or lack of effect) this may have on patients’ perspective on the value of antibiotics and their misuse is very controversial. The providers of these programs argue that caregivers will prescribe as they see fit and these programs do not influence patients to ask for antibiotics just because they are free.29 However, others conjecture that these programs are not as altruistic as they seem because they promote inappropriate use of antibiotics. For example, many programs run concurrently with the cold and influenza season, which may give patients the misperception that antibiotics may be useful for those types of viral infections.27 Free antibiotic programs may be sending patients a message that underscores their value by promulgating the idea that antibiotics should be inexpensive, or that because they are inexpensive they are not valuable. Additionally, these programs may be counteracting campaigns that have been initiated to educate patients about appropriate antibiotic use. Instead of promoting free antibiotics, pharmacies should promote appropriate use of antibiotics and provide patients with free immunizations.30

Many additional factors have to be considered when evaluating the costs of antibiotics. Treating an antibiotic-resistant infection is more costly than treating an antibiotic-susceptible infection.

For example, one study of 138 patients found a mean difference in attributable cost of $21,000 between antibiotic-resistant infections and nonresistant ones.31 Another study found that the average cost of hospitalization for patients with extended-spectrum β-lactamase (ESBL)–producing Escherichia colii bloodstream infections (BSIs) was $19,758.77 compared with $12,514.80 for nonESBL E. colii BSIs.32 This same study also reported an increased average hospital length of stay for patients with ESBL E. coli BSIs (20 vs 13 days).32 Furthermore, cost may have an effect on resistance rates. A study conducted in Denmark found that the use of ciprofloxacin increased when it became available as a generic at a lower cost, and this correlated with an increase in ciprofloxacinresistant E. colii from urinary isolates.33 All of these issues must be considered when weighing in on how much antibiotics are worth.

Lack of Education Lack of education is another factor that contributes to the misuse of antibiotics. Many patients mistakenly believe that antibiotics should be prescribed for viral illnesses, that symptoms should be gone within 3 days, and that antibiotics should be discontinued once symptoms are resolved, and saved for future use.34 These patients do not realize that poor adherence to therapy (skipping doses, stopping therapy because they feel better) is linked to resistance.35,36 In a study of parents of children with respiratory tract infections, 63.8% expected an antibiotic prescription.9 Patients also have the misperception that taking an antibiotic will speed the process of recovery (from a viral illness) rather than waiting for the natural evolution of a viral infection to occur, and directto-consumer advertising also may give patients inappropriate expectations about antibiotics.37 For instance, in 1997, Zithromax (azithromycin; Pfizer) was ranked as one of the top 20 prescription drug products with the highest spending on direct-to-consumer advertising.38 Furthermore, in 2000, the branded products Augmentin (amoxicillin/clavulanate potassium), Cipro (ciprofloxacin; Bayer/Schering), Levaquin (levofloxacin; Janssen), and Zithromax were among the top 50 drugs by dollar sales to pharmacies and high direct-to-consumer advertising spending.38 This type of advertising may affect patient behavior.

In one survey, 30% of consumers reported speaking with their physicians about a medication after seeing an ad.38 This might then put pressure on the prescriber to give antibiotics.

Prescribers also need additional education to encourage them toward more appropriate prescribing patterns. Unlike in specialties such as oncology or transplantation, where the prescribed drugs (chemotherapeutic agents, immunosuppressives) are predominantly limited to specialists in those areas, the prescribing of antibiotics is not solely limited to infectious diseases specialists. The availability of antibiotics to all clinicians

may give the false perception that there are minimal risks to using them inappropriately or that the information learned about antibiotics during training still applies today. Prescribers may feel obligated to give antibiotics so that patients will return for future visits and to avoid medicolegal ramifications if a bacterial infection was missed and patients suffered consequences.37 International medical graduates, increased time in practice, and high practice volume were found to be associated with an increased likelihood of inappropriate antibiotic prescribing in one study.39 Studies have shown that trainees are less likely to abuse antibiotics.37 They perceive less of a medicolegal risk in the protected academic environment and/or are more familiar with recent guidelines in comparison with prescribers in practice for many years.37 For infectious diseases physicians who participate in antimicrobial stewardship programs, there also is the feared ramification of creating antagonistic relationships with fellow clinicians who are using antibiotics inappropriately, which could possibly result in decreased consultations.

This belief was more frequent in nonteaching institutions.40 Clinicians in private practices may have limited access to current guidelines, unbiased medical information, real-time data about resistance patterns in the local area, and patient-specific information (diagnostic testing limitations, inability to follow up with patients).37 These issues may limit their ability to differentiate between bacterial and viral infections or to select among antibiotics.37 One study assessed the decision-making process for generalists in comparison with infectious diseases specialists. The prescribers had to choose between antibiotic A (an older drug available for many years, with reported resistance) and antibiotic B (a recently marketed drug, with no reported resistance) for community-acquired pneumonia due to Streptococcus pneumoniae.

The study found that for outpatients, most prescribers would choose antibiotic B if the resistance to antibiotic A was above 5%. However, for hospitalized patients and patients in an ICU, the prescribers would choose antibiotic B even if there were low levels of resistance to antibiotic A.41 It is important for all clinicians to remain up to date and continue to receive education about antibiotics and the collateral damage (resistance, C. difficile infection, and other adverse drug reactions) of using them inappropriately, so that they can make informed decisions in their clinical practices regarding antibiotics.

How To Make the Change There are multiple ways clinicians can be advocates for appropriate antibiotic use (Table). One role is in educating patients regarding adherence to antibiotics, the role of antibiotics in common infections, resistance, and untoward adverse effects such as C. difficile infection or other super-infections secondary to antibiotic exposure.22,37 Health professionals can use tools such as posters, pamphlets, one-on-one counseling, and participation in community health events.

Prescribers can tell patients to fill an antibiotic Text continues on page 40

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prescription only if they don’t feel better within the next few days, allow free return visits if the patients need to come back, make followup phone calls to decrease patient hesitation about not taking antibiotics, and provide information about over-the-counter medications for symptom relief.8,37 Guidelines and clinical support tools are available in the United States and other countries that support holding or delaying antibiotics, as well as appropriate use of antibiotics for common infections such as acute otitis media, acute sore throat/acute pharyngitis/acute tonsillitis, common cold, acute rhinosinusitis, and acute cough/acute bronchitis.42-44 Additional actions clinicians can take are getting involved in infection control and immunization efforts and antimicrobial stewardship programs.22,45 Finally, improvements in diagnostic testing methods to assist clinicians in making treatment decisions are imperative. Ideally, in the future, testing methods will be able to assist in the rapid identification of specific pathogens and differentiation of viral and bacterial infections in the community and in hospitals.22 On a national level, government organizations have developed campaigns to promote appropriate antibiotic use. The Centers for Disease Control and Prevention (CDC) has resources available online for patients and health care providers, including the “National MRSA education initiative” and the “Hand Hygiene Saves Lives” campaign.46 The recognition of antibiotic resistance as a public health threat in the 1990s led to the creation of the Interagency Task Force on Antimicrobial Resistance (ITFAR). The ITFAR was created in 1999 and includes members from the CDC, FDA, National Institutes of Health, Agency for Healthcare Research and Quality, Centers for Medicare & Medicaid Services, Health Resources and Services Administration, Department of Agriculture, Department of Defense, Department of Veterans Affairs, and Environmental Protection Agency. This collaboration resulted in the development of a public health action plan to combat antibiotic resistance, which proposes measures for surveillance, prevention and control, research, and product development.45 The IDSA has published a position paper on combating antibiotic resistance that includes proposals for legislative action. The position paper includes recommendations for economic incentives and support for antibiotic development, new regulatory approaches to aid in antibiotic development and approval, coordination of federal agencies, improvement in resistance surveillance systems, strengthening methods to prevent and control resistance, investing in antibiotic and diagnostics research, and eradicating nonjudicious use of antibiotics in animal, plant, and marine habitats.47 Furthermore, state governments also have passed legislation to control or prevent resistance. One landmark example is California, which has a statewide initiative to require antimicrobial stewardship programs.48 Furthermore, 3 bills have been proposed to Congress to address antimicrobial use and resistance. One bill, titled Generating Antibiotic Incentives Now Act (GAIN), seeks to amend the Food, Drug, and Cosmetic Act to extend exclusivity for new qualified infectious diseases products by

Table. Initiatives To Help Preserve Antibiotics for the Future Antimicrobial Stewardship Programs Educating Patients/Patient Actions • Adherence to antibiotics • Role of antibiotics in common infections • Resistance • Untoward adverse effects, such as Clostridium difficile or other super-infections • Immunizations • Posters, pamphlets, one-on-one counseling, community health events

Educating Health Care Providers/Provider Actions • Adherence to antibiotics • Role of antibiotics in common infections • Resistance • Untoward adverse effects, such as Clostridium difficile or other super-infections • Journals, newsletters, continuing medical education, conferences, best practice alerts, guidelines, one-on-one discussions • Delayed antibiotic prescriptions • Free return visits • Follow-up phone calls • Providing information about symptom relief for viral infections • Using guidelines and clinical support tools • Involvement in infection control, immunization, and antimicrobial stewardship programs

Immunization Programs Professional Organizations (not a complete list) • Infectious Diseases Society of America • Society for Healthcare Epidemiology of America • Pediatric Infectious Diseases Society • Society of Infectious Diseases Pharmacists

Centers for Disease Control and Prevention Campaigns • Get Smart • Get Smart: Know When Antibiotics Work • Get Smart for Healthcare: Know When Antibiotics Work • Get Smart: Know When Antibiotics Work on the Farm • National MRSA Education Initiative • Hand Hygiene Saves Lives

National Institutes of Health • National Institute of Allergy and Infectious Diseases

Interagency Task Force on Antimicrobial Resistance Legislation • Food and Drug Administration Safety and Innovation Act (FDASIA) • Generating Antibiotic Incentives Now Act (GAIN Act) • Strategies to Address Antimicrobial Resistance Act (STAAR Act) • Preservation of Antibiotics for Medical Treatment Act (PAMTA) MRSA, methicillin-resistant Staphylococcus aureus Based ased o on references e e e ces 8, 22,, 37, 3 , and a d 42-52.

5

5 years.49 The GAIN Act also proposes priority review for qualified infectious diseases products, a revision of the FDA guidelines for clinical trials for antibiotics, and a study to evaluate the need for incentives for qualified infectious disease biologic products. The GAIN Act was passed on July 9, 2012 as Title VIII to the Food and Drug Administration Safety and Innovation Act (FDASIA).50 The second bill is Strategies to Address Antimicrobial Resistance (STAAR) Act.51 This public health service act proposes the establishment of an Antimicrobial Resistance Office and a Public Health Antimicrobial Advisory Board. The goal for these 2 groups is to update the public health action plan created by the ITFAR and to meet, discuss, and review antimicrobial issues as necessary. This bill was referred to the House

Subcommittee on Health on June 7, 2013. A third bill, Preservation of Antibiotics for Medical Treatment Act (PAMTA), will amend the Food, Drug, and Cosmetic Act to maintain effectiveness of medically important antibiotics in humans and animals.52 This bill was referred to the Subcommittee on Health on March 15, 2013. These examples demonstrate the various methods that are being proposed on a governmental level to tackle the future outlook of antibiotics.

Conclusion In summary, the attitudes regarding the value of antibiotics in society may slowly be starting to change, although there is still a long road ahead.

It is concerning that this change in attitudes Text continues on page 42

For patients with invasive fungal infections who are refractory to, or intolerant of conventional amphotericin B therapy

ABELCET saves money

ABELCET saves time

ABELCET saves resources

ABELCET saves.

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.

Contact your Abelcet national account manager to learn about the new Abelcet contract pricing. That’s why Abelcet saves.

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 To contact an Abelcet National Account Manager please call 1-800-447-0169, select option 1 and enter 572.

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

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may almost be too late in the game as we are getting very close to the edge of losing this valuable resource.

Luckily, the examples of actions that already have been taken are laying the groundwork for gaining the momentum necessary to accomplish the task of maintaining the effectiveness of antibiotics for the future.

References 1.

Skinner D, Keefer CS. Significance of bacteremia caused by Staphylococcus aureus. Arch Intern Med. 1941;68:851-875.

2. Blot SI, Vandewoude KH, Hoste ER, Colardyn FA. Outcome and attributable mortality in critically ill patients with bacteremia involving methicillinsusceptible and methicillin-resistant Staphylococcus aureus. Arch Intern Med. 2002;162(19):2229-2235.

3. Dowell SF, Kupronis BA, Zell ER, Shay DK. Mortality for pneumonia in children in the United States, 1939 through 1996. N Engl J Med. 2000;342:1399-1407.

4. Gaur AH, Hare ME, Shorr RI. Provider and practice characteristics associated with antibiotic use in children with presumed vial respiratory tract infections. Pediatrics.

2005;115(3):635-641.

5. Misurski DA, Lipson DA, Changolkar AK. Inappropriate antibiotic prescribing in

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).

managed care subjects with influenza.

Am J Manag Care. 2011;17(9):601-608.

6. Wang EE, Einarson TR, Kellner JD, Conly JM. Antibiotic prescribing for Canadian preschool children: evidence of overprescribing for viral respiratory infections. Clin Infect Dis. 1999;29(1):155-160.

7.

Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the US. Clin Infect Dis. 2001;33(6):757-762.

8. McDonnell Norms Group. Antibiotic overuse: the influence of social norms.

J Am Coll Surg. 2008;207(2):265-275.

9. Mangione-Smith R, Elliott MN, Stivers T, McDonald LL, Heritage J. Ruling out the

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.

need for antibiotics: are we sending the right message? Arch Pediatr Adolesc Med. 2006;160(9):945-952.

10. Gonzales R, Camargo CA, MacKenzie T, et al. Antibiotic treatment of acute respiratory infections in acute care settings. Acad Emerg Med. 2006;13(3):288-294.

11. Kollef MH, Morrow LE, Niederman MS, et al. Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Chest.

2006;129(5):1210-1218.

12. Chastre J, Wolff M, Fagon JY, et al.

Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial.

JAMA. 2003;290(19):2588-2598.

13. Rotjanapan P, Dosa D, Thomas KS. Potentially inappropriate treatment of urinary tract infections in two Rhode Island nursing homes. Arch Intern Med. 2011;171(5):438-443.

14. Hall RG 2nd, Payne KD, Bain AM, et al.

Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med. 2008;121(6):515-518.

15. Leekha S, Terrell C, Edson RS. General principles of antimicrobial therapy. Mayo Clin Proc. 2011;86(2):156-167.

16. Cohen SH, Gerding DN, Johnson S, et al.

Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Infect Control Hosp Epidemiol. 2010;31(5):431-455.

17. Eggleston K, Zhang R, Zeckhauser RJ. The global challenge of antimicrobial resistance: insights from economic analysis. Int J Environ Res Public Health.

2010;7(8):3141-3149.

18. Shlaes DM, Gerding DN, John JF Jr, et al. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals.

Clin Infect Dis. 1997;25(3):584-599.

19. Plough HH. Penicillin resistance of Staphylococcus aureus and its clinical implications. Am J Clin Pathol.

1945;15:446-451.

20. Reimann HA, D’Ambola J. The use and cost of antimicrobics in hospitals. Arch Environ Health. 1966;13(5):631-636.

21. Marr JJ, Moffet HL, Kunin CM. Guidelines for improving the use of antimicrobial agents in hospitals: a statement by the Infectious Diseases Society of America.

J Infect Dis. 1988;157(5):869-876.

22. Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-177.

23. Chatterjee P, Fleck F. Mobilizing political will to contain antimicrobial resistance. Bull World Health Organ. 2011;89(3):168-169.

24. Fidaxomicin (Dificid) for Clostridium difficile infection. Med Lett Drugs Ther.

2011;53(1373):73-74.

25. Ipilimumab (Yervoy) for metastatic melanoma. Med Lett Drugs Ther.

2011;53(1367):51-52.

26. White AR; BSAC Working Party on The Urgent Need: Regenerating Antibacterial Drug Discovery and Development.

Effective antibacterials: at what cost?

The economics of antibacterial resistance and its control. J Antimicrob Chemother.

2011;66(9):1948-1953.

Clinical 43

Pharmacy Practice News • August 2013

Educational Review 27. No authors listed. US supermarkets redefine antibiotic misuse. Lancet Infect Dis. 2009;9(5):265.

28. Santa J. The real cost of free antibiotics.

Consumer News. January 9, 2009. http://news.consumerreports.org/ health/2009/01/free-antibiotic.html.

Accessed July 15, 2013.

29. Ellis AN. Experts: no such thing as free antibiotics. The Star-Ledger. Jan. 10, 2009.

Updated Jan. 11, 2009. http://www.nj.com/ news/index.ssf/2009/01/experts_no_such_ thing_as_free.html. Accessed July 15, 2013.

30. Parker-Pope T. Free antibiotics may contribute to drug resistance, officials say. March 4, 2009. http://www.nytimes. com/2009/03/05/health/policy/05drugs. html?adxnnl=1&adxnnlx=1310676972tvP9dkArVamKzx48IdOD8w. Accessed July 15, 2013.

44. National Institute for Health and Care Excellence. CG69 respiratory tract infections: NICE guideline. Prescribing of antibiotics for self-limiting upper respiratory tract infections in adults and children in primary care. July 2008. http:// guidance.nice.org.uk/CG69/NICEGuidance/ pdf/English. Accessed July 15, 2013.

45. Interagency Task Force on Antimicrobial Resistance. A public health action plan to combat antimicrobial resistance.

2012 update. http://www.cdc.gov/ drugresistance/pdf/action-plan-2012.pdf.

Accessed July 15, 2013.

46. Centers for Disease Control and Prevention.

Education campaigns. http://www.cdc.gov/

drugresistance/campaigns.html. Accessed July 15, 2013.

47. Infectious Diseases Society of America.

Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis. 2011;52(suppl 5):s397-s428.

z?d112:SN01734:@@@X. Accessed July 15, 2013.

50. Food and Drug Administration Safety and Innovation Act, S.3187/112th Congress. http://www.govtrack.us/congress/bills/112/ s3187/text. Accessed July 15, 2013.

51. Strategies to Address Antimicrobial Resistance Act, H.R. 2285/113th Congress. http://thomas.loc.gov/cgi-bin/bdquery/ z?d113:HR02285:@@@X. Accessed July 15, 2013.

48. California Department of Public Health.

The California antimicrobial stewardship program initiative. www.cdph.ca.gov/ programs/hai/Pages/Anti-microbialStewardshipProgramInitiative.aspx.

Accessed July 15, 2013.

52. Preservation of Antibiotics for Medical Treatment Act, H.R. 1150/113th Congress. http://thomas.loc.gov/cgi-bin/bdquery/ z?d113:HR01150:@@@X. Accessed July 15, 2013.

49. Generating Antibiotic Incentives Now Act of 2011, H.R. 2182/112th Congress. http://thomas.loc.gov/cgi-bin/bdquery/

31. Roberts RR, Hota B, Ahmad I, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009;49(8):1175-1184.

32. Tumbarello M, Spanu T, Di Bidino R, et al.

Costs of bloodstream infections caused by Escherichia colii and influence of extendedspectrum-β-lactamase production and inadequate initial antibiotic therapy. Antimicrob Agents Chemother.

2010;54(10):4085-4091.

33. Jensen US, Muller A, Brandt CT, et al.

Effect of generics on price and consumption of ciprofloxacin in primary healthcare: the relationship to increasing resistance. J Antimicrob Chemother.

2010;65(6):1286-1291.

34. Branthwaite A, Pechere JC. Pan-European survey of patients’ attitudes to antibiotics and antibiotic use. J Int Med Res. 1996;24(3)229-238.

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35. Craig WA. Pharmacokinetic/ pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.

Clin Infect Dis. 1998;26(1):1-12.

36. McKinnon PS, Davis SL. Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases. Eur J Clin Microbiol Infect Dis. 2004;23(4):271-288.

37. Gaur AH, English BK. The judicious use of antibiotics—an investment towards optimized health care. Indian J Pediatr.

2006;73(4):343-350.

38. Frank R, Berndt ER, Donohue J, Epstein A, Rosenthal M. Trends in direct-to-consumer advertising of prescription drugs.

Washington, DC: The Henry J. Kaiser Family Foundation; February 2002.

39. Cadieux G, Tamblyn R, Dauphinee D, Libman M. Predictors of inappropriate antibiotic prescribing among primary care physicians. CMAJ. 2007;177(8):877-883.

40. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18(4):638-656.

41. Metlay JP, Shea JA, Asch DA. Antibiotic prescribing decisions of generalists and infectious diseases specialists: thresholds for adopting new drug therapies. Med Decis Making. 2002;22(6):498-505.

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42. Wlodover CG, May C. Antibiotic stewardship: using clinical guidelines to control antibiotic overuse and deter microbial adaptation. Infect Dis Clin Pract.

2012;20:12-17.

43. Centers for Disease Control and Prevention.

Get Smart: know when antibiotics work. treatment guidelines for upper respiratory tract infections. http://www.cdc.gov/ getsmart/campaign-materials/treatmentguidelines.html. Accessed July 15, 2013.

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44 Clinical

Pharmacy Practice News • August 2013

Infectious Disease

Antibiotic Hypersensitivity: Yes or No to Offending Drug?

PharmD, a clinical pharmacist in infectious diseases at Sinai-Grace Hospital of the Detroit Medical Center. “If you don’t use an antibiotic when you can, you’re probably going to give your patient a second-line, inferior regimen, and if you do use a drug that you shouldn’t, then you need to worry about that patient having an adverse reaction.”

Central to making these decisions is determining whether the patient’s

Minneapolis—Whether rounding, verifying orders or working in the community, pharmacists are likely to encounter patients with hypersensitivity to antiinfectives, and they need to know when they can and cannot use other similar drugs, according to a presentation at the American Society of Health-System Pharmacists 2013 Summer Meeting.

The scenario has major clinical implications, said presenter Jason M. Pogue,

drug reaction was immunoglobulin (Ig) E-mediated, Dr. Pogue said, because these reactions can lead to anaphylaxis.

Of the four major types of allergic reactions, it is the type I reaction, immediatetype hypersensitivity, that involves the formation of drug-specific IgE. The reaction can occur without previous exposure to the drug, particularly if the patient has been exposed to a medication or other compound that is structurally similar.

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The drug binds to IgE mast cells, creating a pathway that leads to degranulation, the release of inflammatory mediators, and an urticarial rash (Figure 1) with a characteristic wheal and flare pattern of bumps with surrounding redness.

Knowing how to identify this type of rash and differentiate it from the more common, usually delayed-onset and self-limiting maculopapular rash (Figure 2) characteristic of type IV drug reactions is essential in assessing whether other agents can be given, Dr. Pogue said. Treating the patient who has had an IgE-mediated response with the same drug or anything structurally similar could be setting the patient up for a more severe reaction and anaphylaxis.

In contrast, with a maculopapular rash, “stop the drug and the patient moves on,” Dr. Pogue said.

t

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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

urticarialrashpictures.com

in this issue

see SUPERBUGS, pag ge 6

Figure 1. Urticarial rash.

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-

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.

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See page 27.

Dr. Pogue also highlighted another major type IV skin reaction, StevensJohnson syndrome (SJS), a very severe reaction associated with high morbidity and mortality, marked by sloughing of the skin, that typically begins several weeks after administration. If a patient has had SJS, “you’re going to know about it. It’s going to be in their medical record,” he said. A severe reaction to begin with, SJS can worsen if the drug is given again.

“We see this with drugs like Bactrim [trimethoprim-sulfamethoxazole; Mutual]. Whenever people talk about desensitizing to Bactrim, I get a little queasy because I know they’re potentially talking about this type of reaction, and if they try to desensitize them, they’re going to give them a worse reaction,” he said.

Allergic reactions to penicillin occur in about 2% of patients—fewer than previously thought—although about 10% of patients report being allergic. “When you probe, you find out things like ‘My mom told me that 30 years ago,’ or ‘I had diarrhea for a week with this drug,’” Dr. Pogue said. One study found that 90% of patients who reported a penicillin allergy were skin-test negative ((Ann Emerg Med d 2009;54:72-77). About 99% of patients with negative skin tests will tolerate penicillin, he said. “So not only do you need to know what type of allergy it was, you need to know wheth-

Clinical 45

Pharmacy Practice News • August 2013

Infectious Disease http://sanjeevsamalasr.blogspot.com/2012/08/maculopapularrash-its-henoch-scholein.html

‘Not only do you need to know what type of allergy it was, you need to know whether it really was an allergy.’

—Jason M. Pogue, PharmD 2008;7:295-304). Cefadroxil has the same side-chain structure as penicillin; cefamandole does not.

An analysis of 41 patients with penicillin or amoxicillin allergies found no cross-reactivity with cefazolin, cefuroxime or ceftriaxone, all of which have

Figure 2. Maculopapular rash.

er it really was an allergy.”

When a patient has experienced an allergic reaction to penicillin, assessing the type of allergic reaction will determine whether that patient can be given other β-lactams, Dr. Pogue said. Patients with a reaction to penicillin can have either a maculopapular or an urticarial rash. “You need to know the type of rash.

Look in the chart. Talk to the physicians.

You want to see, is it a true IgE-mediated reaction, with characteristics like hives, throat closing and anaphylaxis, or was it SJS, which you wouldn’t want to mess around with either. If it was a maculopapular rash, you will feel much more comfortable using another agent.” Probing to see whether the onset was immediate or delayed, the agents with which a reaction has occurred and whether other agents have been tolerated are also key. “You’re trying to pick out those IgEmediated reactions,” he stressed.

In cases in which a suspected penicillin reaction turns out not to have been a true allergy, he recommended noting in the chart that penicillin was tolerated “so you know that going forward.”

Dr. Pogue stressed the central role of molecular side-chain structures in determining the likelihood of crossreactivity among antibiotics. In general, cross-reactivity between penicillin and cephalosporins is less likely than previously thought. Initial numbers were elevated because the early literature included non-allergic adverse drug reactions and early cephalosporins were often contaminated with penicillin.

Additionally, the original cephalosporins on the market had side chains that were similar or identical to those of the penicillins. The likelihood of cross-reactivity depends on the side chains. Crossreactivity rates of up to approximately 40% have been seen when related agents with similar or identical molecular side chains are used. One study found crossreactivity rates for amoxicillin with cefadroxil and cefamandole of 38% and 0%, respectively ((Expert Opin Drug Saf

different side chains than penicillin ((J Am Pharm Assoc 2008;48:530-540). For patients who have had life-threatening or severe allergic reactions to penicillin or amoxicillin, “it’s very important to note that there’s no reason you can’t give cefazolin, particularly if you have

a patient with a life-threatening infection due to methicillin-sensitive Staphylococcus aureus, where β-lactams are superior to drugs like vancomycin,” Dr. Pogue said. “It’s important to know the [side-chain] structures.”

Adding further evidence to the significance of side chains is a study that found a 40% cross-reactivity rate between cephalosporins; however, these agents had nearly identical R1 side chains ((J Allergy Clin Immunol 2006;117:404-409). “You are seeing

•

see HYPERSENSITIVE, page 56

REMEDIES

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46 Clinical

Pharmacy Practice News • August 2013

Medication Safety

BIG IDEAS continued from page 1

causes of ADEs was random and not collected centrally.

The change began in 2009, when BJC integrated the Institute for Healthcare Improvement (IHI) Trigger Tool into its clinical decision support system.

When trigger rules are met—primarily toxic drug levels, antidote orders and dangerous lab values—the system generates an ADE alert, which also displays pertinent clinical factors, drug orders and lab values. Each alert is independently reviewed at the hospital for harm and causality at the time that it was created, followed by a central review of the electronic medical record after patient discharge. When harm and causality were determined, reviewers chose from a set of frequently identified, actionable causes of harm (e.g., wrong drug, wrong dose, insufficient glucose monitoring, etc.). Approximately 150 pharmacists and 25 nurses and certified diabetes educators were trained to complete the trigger reviews.

After this review, “we knew what the top harm events were, what caused them and where they were occurring,” Dr. Milligan said. “That allowed us to focus quality efforts on the hospital—and often individual floors and units—with higher ADE rates ... [using] the best practices from the high-performing hospitals.”

The results have been dramatic. The

rate of severe hypoglycemia dropped from a baseline of 2.44 events per 1,000 patient-days in 2009 to 1.31 events per 1,000 patient-days in 2012. Over the same period, the annual rate of all ADEs fell from 3.09 to 1.83 events per 1,000 patient-days—a 41% drop, Dr. Milligan and his colleagues reported (poster 13-M). (For related outcomes based on at-risk patient-days, see Figure.)

Information about the number, type and causes of ADEs is posted on data dashboards for hospital leaders, which allows them to compare the ADE rates and causes among various hospitals and track their progress. Similar information is displayed on an interactive SharePoint website for clinicians. The website also contains best-practice recommendations and interventions that are specific to each causative factor for the most common types of ADEs. “This systematic process supports continuous improvement,” Dr. Milligan said. “It’s like whack-a-mole: For example, we fixed many of the issues related to insulin dose timing at the point of care. Now that’s less of a problem, so new causative factors rise to the top.”

“Too many hospitals focus on purely quantitative measures of adverse drug events,” said Matthew Grissinger, RPh, FASCP, the director of error reporting programs with the Institute for Safe Medication Practices (ISMP). “But that’s not a very good measure for error reporting, and Dr. Milligan recognizes that. His

hospital system is now actually measuring harm to patients, and that’s very important. All of their key triggers—toxic drug levels, antidote orders and dangerous lab values—indicate that the patient was or could have been harmed. I’m also glad to see that the results are shared with hospital leaders because it’s important that they understand what type of harm can affect their patients and how often.”

Wrong-Patient Drug Errors Another poster (11-M) exploded some common misconceptions about wrongpatient drug errors (events in which a patient receives or almost receives a medication intended for another). “Many people automatically think that wrongpatient errors almost always occur because a nurse misidentifies a patient at the point of care,” said lead author Annie Yang, PharmD, BCPS, who was a safe medication management fellow at ISMP at the time she presented her work. “While many errors or near misses do occur during drug administration, we also found that many also occur at other points in the medication use process.”

Dr. Yang and a colleague reviewed reports of wrong-patient medication errors that occurred at Pennsylvania health care facilities in 2011. (Pennsylvania requires hospitals to report all medical errors to the state’s Patient Safety Authority.) Of the 813 distinct medication errors that met the criteria for a wrong-patient error, most occurred during adminis-

tration (n=353; 43.4%) and transcribing (n=311; 38.3%). The medication types most commonly associated with wrongpatient events were anti-infectives (104 reports; 12.8%); opioids (61 reports; 7.5%); anticoagulants (49 reports; 6%); and insulin (35 reports; 4.3%). For a more detailed data analysis, see Table, page 48.

The predominant contributing factors for errors during drug administration were two patients being prescribed the same medication and inadequate patient identification. The most common contributing factors for transcribing-related errors were the use of verbal orders, similar patient names and the same or similar room numbers. Among all wrong-patient event reports that involved a single drug, almost 30% (n=169) were associated with high-alert medications.

Some of the reports surprised Dr. Yang, particularly those in which a current patient was confused with one who had occupied the same bed but had been discharged. One report described a physician who wrote a prescription based on an ECG strip that belonged to a discharged patient who had occupied the same room.

The mistake was discovered when another clinician noticed that the inpatient had no cardiac issues. “We found multiple reports along that theme,” she said.

Dr. Yang also offered some general risk reduction strategies: • Improve patient verification for all patient encounters (e.g., standardize

•

see BIG IDEAS, page 48

9 00 9.00

8.00

7.00

Hypoglycemia, %

6.00

5.00

4.00

3.00

2.00

1.00

Dec 09 — Jan 10 — Feb 10 — Mar 10 — Apr 10 — May 10 — Jun 10 — July 10 — Aug 10 — Sep 10 — Oct 10 — Nov 10 — Dec 10 — Jan 11 — Feb 11 — Mar 11 — Apr 11 — May 11 — Jun 11 — Jul 11 — Aug 11 — Sep 11 — Oct 11 — Nov 11 — Dec 11 — Jan 12 — Feb 12 — Mar 12 — Apr 12 — May 12 — Jun 12 — Jul 12 — Aug 12 — Sep 12 — Oct 12 — Nov 12 — Dec 12 — Jan 13 — Feb 13

0.00

Figure. Severe hypoglycemia rates and interventions to reduce harm, BJC Healthcare.a,b a

The time line shows rates based on at-risk patient-days and thus does not match the data cited in the text, which reflect total patient days; bRolling six-month/year-to-date rate

PES, Pharmacy Expert System (proprietary clinical decision support software); RIE, rapid improvement event

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48 Clinical

Pharmacy Practice News • August 2013

Medication Safety

PILL SERVICE continued from page 1

program saved the health system nearly $90,000, according to Allison Paquin, PharmD, a clinical pharmacy specialist at VABHS, who presented the results during a session at the 2013 Summer Meeting of the American Society of Health-System Pharmacists (ASHP).

Phone Calls, Clinic Visits At Heart of PILL Service Launched in 2006, the pharmacist-led PILL Service program is designed to identify and resolve medication-related

problems and discrepancies in elderly patients through post-discharge phone calls and clinic visits, Dr. Paquin noted.

These vulnerable patients are at high risk for medication-related safety issues after hospital discharge, she explained, in part because they often face long and confusing medication regimens that are difficult to follow as instructed. Additionally, discrepancies between their discharge medication list and actual medication orders are common ((Arch Intern Med d 2005;165:424; Ann Pharmacother 2008;42:1373).

These factors can create a perfect

•

continued from page 46

Meeting Drug Shortages Head-on Because of ongoing drug shortages, the Lehigh Valley Health Network (LVHN) Pharmacy, in Allentown, Pa., ratcheted up production in its own sterile compounding room to prevent interruptions of essential medications. But everything changed at the three-hospital system when sterility testing found a batch of sodium bicarbonate syringes contaminated with Streptococcus sanguis. The batch was still well within its beyond-use date as stipulated by U.S. Pharmacopeia

—Allison Paquin, q , PharmD

see PILL SERVICE, page 50

BIG IDEAS the prescribing and communicating of drug information between providers).

• Ensure proper storage of medications and patient-specific documents.

• Use health care technology fully and properly (e.g., take advantage of the built-in safety checks of automated dispensing cabinets [ADCs]; hospitals often use ADCs as secure storage units for medications without fully using the system’s safety capabilities).

• Limit the use of verbal orders.

• Empower patients to prevent and detect medication errors (e.g., if the facility uses bar-code identification, encourage patients to speak up if their armband is not scanned prior to medication administration).

“This work does a good job of describing the systems nature of wrong-patient errors,” rather than looking to first cast blame on an individual, said Bob Feroli, PharmD, a medication safety officer at The Johns Hopkins Hospital Department of Pharmacy, in Baltimore. For example, “[the ISMP initiative] doesn’t shine a light on the nurse making a mistake when administering the drug,” Dr. Feroli said. “There’s a tendency that when a medication is given to the wrong patient, people automatically assume that it’s because the nurse wasn’t paying attention. This poster clearly highlights the multifactorial nature of the process and that you can’t just focus on the end point.”

‘We were able to reach more patients by phone during the critical window and found that working through some of the medication issues is feasible by phone.’

Streptococcus sanguis.

(USP) Chapter <797> guidelines, so sterility testing was not required.

“We chose to test it anyway,” said primary author Cindy L. Mitman, PharmD, the assistant director of pharmacy with LVHN. “There was a lot of activity in our IV room and we felt more comfortable conducting extra sterility tests for added safety.” But when the contaminated batch was discovered on an off shift, she and her infection control colleagues realized that there was no standing policy the pharmacy staff could turn to that

would direct their response. “We had no written policy—nothing in place telling us which staff members should be notified when a batch of sterile compounded drugs tested positive.”

Representatives from pharmacy, infection control and prevention, infectious diseases and the microbiology laboratory met and identified gaps in the existing policies and procedures. The action plan that arose from their collaboration (poster 2-M) stipulated what departments the pharmacy must alert under a given set of circumstances. For example, if a compounded sterile product that has tested positive for contamination has reached patients, infection control, risk management and pharmacy managers must be alerted. But in cases when the contaminated batch has not reached patients, there is no need to contact risk

Table. ISMP/PPSA Medication Error Analysis Administration

No. of Reports

% of Reports

Medication administration

286

81.0

Medication procurement

55

15.6

Monitoring

12

3.4

Patients prescribed the same medication

41

14.3

Inadequate identification check

37

12.9

Rooming issues

35

12.2

Transcribing

No. of Reports

% of Reports

253

81.4

Processes

Contributing Factors

Processes Wrong chart Wrong label

57

18.3

Wrong chart and wrong label

1

0.3

Verbal orders

23

7.4

Similar patient names

8

2.6

Same/similar room numbers

5

1.6

Contributing Factors

ISMP, Institute for Safe Medication Practices; PPSA, Pennsylvania Patient Safety Authority

management. In either case, the pharmacy will consult with infection control to investigate possible causes of the contamination. “We’re now constantly in contact with our infection control and prevention teams,” Dr. Mitman said.

Additionally, the pharmacy re-educated the clean room staff about proper garbing (such as the importance of wearing surgical masks correctly and consistently when compounding, along with changing them regularly); limiting talking in the clean room; limiting traffic in the clean room; and reiterating aseptic technique during drug production and while obtaining sterility test samples. The clean room staff also incorporated monthly volumetric air sampling instead of using monthly settling plates.

The Engineering Department also was part of the quality improvement effort, with members asked to correct recurring temperature fluctuations in the clean room instead of waiting to be called by clean room staff. To bolster such efforts, the microbiology lab was to ensure that the proper media and incubation guidelines were followed based on USP Chapters <797> and <71> standards.

Dr. Mitman and her colleagues concluded that “definition of formal policies and procedures is needed to safely prepare and recall sterile products for patient use, and clear communication and swift response to positive sterility test results is critically important to mitigate patient harm.”

“This is a good example of an organization that didn’t realize it didn’t have the necessary safety controls in place after something went wrong,” Mr. Grissinger said. “Then they acted on that information to prevent a similar event from happening again. It also shows how we’ve entered a new era in which pharmacists have to interact with infection prevention departments and other departments they’re not used to dealing with.”

—Steve Frandzel Drs. Milligan, Yang, Mitman and Feroli, and Mr. Grissinger reported no relevant financial conflicts of interest.

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50 Clinical

Pharmacy Practice News • August 2013

Medication Safety

PILL SERVICE continued from page 48

storm for medication misadventures that too frequently lead to an emergency room visit or hospital readmission, Dr. Paquin pointed out. In one widely cited study, she noted, older adults were found to be nearly seven times more likely than younger persons to have adverse drug events that require hospitalization ((JAMA 2006;296:1558).

“For most of us, we may look at a medication list and think it’s simple.

But we have to put ourselves in the shoes of elderly patients,” Dr. Paquin said. “Those who are cognitively impaired face even greater challenges; they may forget which medicines to take and when, or may have difficulty incorporating regimen changes. Physically, it may be very difficult for older adults to split a tablet or use an inhaler because of limited dexterity. What we may think is simple, some folks will struggle with.”

Patients who are 65 years or older, have evidence of cognitive impairment and who are discharged directly home after an inpatient stay are eligible for the PILL Service. To identify patients with cognitive difficulties, a PILL Service pharmacist searches the pharmacy database for orders for dementia medications (e.g., galantamine, donepezil, rivastigmine or memantine). Pharmacists also are electronically alerted to patients noted to be at high risk for delirium at the time of inpatient screening.

‘Taking medications is a learnable skill, but we don’t do a good job of teaching it.’

—James Rudolph, MD Individuals with mild cognitive deficits may need a little more coaching or help with their medications, Dr. Paquin said. At the other end of the spectrum are patients with severe neurocognitive deficits who require a caregiver to manage their medications as well as other activities of daily living.

“We’re finding that medication management is a very complex activity,” said another speaker, Tia R. Kostas, MD, a staff physician at the VABHS. “Even when people are functioning well in other realms of their lives, if they have even mild cognitive difficulties, taking medications as prescribed is one of the first daily living activities that begins to decline. Sometimes it’s one of the first signs that someone has cognitive impairment.”

“We have to consider how these patients are going to handle so many

‘Even when people are functioning well in other realms of their lives, if they have even mild cognitive difficulties, taking medications as prescribed is one of the first daily living activities that begins to decline. Sometimes it’s one of the first signs that someone has cognitive impairment.’

—Tia R. Kostas, MD

medications,” added James Rudolph, MD, the chief of geriatrics and palliative care at VABHS, who also spoke at the ASHP session. “We don’t know if they’re taking everything we prescribe properly. Taking medications is a learnable skill, but we don’t do a good job of teaching it.”

Every patient presents a unique challenge along a spectrum, Dr. Rudolph added. Managing the cognitively impaired patient who is taking only four medications, for example, may turn out to be a big challenge because those could be lifesaving drugs. At the same time, a patient with minimal cognitive deficiency who is taking 15 to 20 drugs presents a big task in itself.

The Pharmacist’s Role Detailed Once a high-risk patient has been identified, a pharmacist critically evaluates that individual’s drug regimen for potential problems, such as contraindications to any of the drugs; medications that may impair cognition or are prescribed with no matching indication; inappropriate dosing; drug allergies; potential drug– drug interactions; ineffective agents; discrepancies between the discharge medication list and actual orders; and opportunities to whittle down the number of drugs. If necessary, the pharmacist contacts the patient’s primary care or specialty physician to suggest changes that are intended to decrease the risk for drug toxicity and other adverse events and simplify the regimen.

Three to five days after discharge, a PILL Service pharmacist phones the patients and conducts, essentially, medication reconciliation to ensure that the patients’ stock of medications matches the list they received at the time of hospital discharge. The pharmacist also educates the patients (or

a caregiver) about proper medication use and addresses any confusion or uncertainty about the regimen. Patients with complex medication needs are referred to the outpatient PILL clinic.

During a typical visit, patient and caregiver sit down with a PILL pharmacist and physician, who clarify the patient’s medication history, develop treatment plans and coordinate additional patient follow-up and monitoring.

“Phone calls aren’t as intensive as a clinic visit, but they work as a triage point,” Dr. Paquin said. “We were able to reach more patients by phone during the critical window and found that working through some of the medication issues is feasible by phone. If a case is very complex, if red flags pop up or if a patient needs more guidance, we’ll schedule them into the clinic.”

A Smart Compromise “This program does a good job of targeting an at-risk, vulnerable population,” said Kelechi C. Ogbonna, PharmD, CGP, an assistant professor in the Department of Pharmacotherapy & Outcomes Science at Virginia Commonwealth University (VCU) School of Pharmacy, in Richmond, who specializes in geriatric pharmacotherapy. “Trying to reach out to patients via telephone and providing an opportunity for them to meet with a clinician is a great way to compromise, but there are limitations with phone interactions, such as the inability to provide visual cues. A dual approach would be more beneficial, but you can’t do that with every patient.”

Dr. Ogbonna added that the program leaders have demonstrated not only that the initiative results in improved patient outcomes but also that it saves money.

“To be able to prove [all of ] those [outcomes] is extremely important.”

More kudos for the PILL Service were offered by geriatric pharmacology expert Emily Peron, PharmD, MS, an assistant professor in the Department of Pharmacotherapy & Outcomes Science at VCU School of Pharmacy.

“There are certainly pharmacists who [focus on] patients such as those targeted by the PILL Service, independent of any formal program, but putting a protocol into place for identifying and caring for these patients ensures that they’ll get the best possible treatment,” Dr. Peron said. “That sets the program apart. It’s also a worthwhile and impressive investment on the part of the Boston VA. I hope it serves as a model for other health systems seeking to improve care for older adults.”

Dr. Paquin said that she is flattered by the idea that because of these initial successes, the PILL Service may serve as a model for other hospitals. She added that those successes were largely due to the initiative’s multidisciplinary nature. “The importance of the team approach in geriatrics cannot be overstated,” she said. “I work with frontline physicians, other pharmacists, nurse practitioners and social workers, whose insights are very important when dealing with this vulnerable population.”

Other At-Risk Patients Up Next As for next steps, VABHS is in the midst of applying variations of the PILL Service to other populations, including patients with congestive heart failure (a cohort known to require numerous medications) and patients who are discharged to a rehabilitation center before returning home, and who therefore must pass through two transition points where drug information can get muddled or lost.

—Steve Frandzel

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52 Clinical

Pharmacy Practice News • August 2013

Critical Care

ICU GLUCOSE

tight glycemic control was used (Chest 2006;129:644-650).

“Furthermore, applying strict glucose targets can definitely result in good clinical outcomes, as has been previously reported in daily ICU practice—but on the condition that accurate glucose sensors and adequate glucose control systems are used,” Dr. Van Herpe asserted.

continued from page 1

clinicians should keep the harms of hypoglycemia in mind when managing glucose aggressively,” Dr. Qaseem told Pharmacy Practice News.

In the ACP report, Dr. Qaseem and his team cited a previous systematic literature review that concluded that shortterm mortality rates did not differ when MICU or SICU patients underwent IIT with strict blood glucose targets of 80 to 110 mg/dL or when they were managed using a higher target range ((Ann Intern Med 2011;154:268-282). That review found only slim evidence of a “marginally significant reduction in the risk of sepsis and a nonsignificant reduction in the incidence of infection,” Dr. Qaseem’s team wrote.

They concluded that the risks for hypoglycemia with IIT outweighed any slight potential benefits, pointing to a 2011 literature review they conducted in which they found that targeting normoglycemia significantly increased the risk for hypoglycemia (risk ratio, 5.32; 95% confidence interval, 3.21-6.73; Ann Intern Med 2011;154:260-267).

SCCM Guidelines Author: Hypoglycemia a Known Risk Judith Jacobi, PharmD, a critical care pharmacist at Indiana University Health Methodist Hospital, in Indianapolis, and the lead author of the Society of Critical Care Medicine’s (SCCM) 2012 insulin infusion guidelines for critically ill patients (Crit Care Med 2012;40:32513276), agreed that “when clinicians attempt to improve glucose control, there is a risk of hypoglycemia.” That finding “is consistent among all published guidelines and analyses,” commented Dr. Jacobi, who was not involved in the ACP review. “Despite this risk, new data suggest that moderate glucose control is associated with increased mortality compared with tighter glucose control in critically ill patients without diabetes,”

Costs (dollars)

200,000

182,488

150,000

‘Most centers will create their own individualized protocols based on their specific institutional environment, their own patient populations and their specific cost constraints.’

—Cynthia Phillips, PharmD, CDE she said, referring to a study published in Chest ((2013;143:1226-1234).

The SCCM guidelines she co-authored state that “the benefits of tight glycemic control have not been definitive” and that “the limited available literature has narrowed the scope of [these recommendations] and the ability to make recommendations for specific populations.”

Therefore, the SCCM guidelines focus on the need to avoid hypoglycemia and recommend an absolute lower limit of 70 mg/dL for most patients, which means that “infusion insulin should be stopped in most settings if glucose is less than 100 mg/dL consistently,” Dr. Jacobi said.

Her team recommended an absolute lower limit of 100 mg/dL blood glucose in those with neurologic injury. However, again, Dr. Jacobi said, “There is no direct evidence to support this recommendation—it is for safety only.”

The Chest study supporting IIT emerged after publication of the SCCM guidelines, Dr. Jacobi pointed out. The study, which included 3,529 diabetic and nondiabetic patients in 12 ICUs, found blood glucose targets of 80-110 mg/dL were associated with lower rates of mortality in critically ill patients without diabetes than targets of 90-140 mg/dL. “What we might need are different approaches to patients based on whether they are diabetic or not,” Dr. Jacobi suggested.

Technology May Help 100,000 58,000

50,000

0

Supplies Nursing salary

Figure. Increased health care costs related to intensive insulin therapy.

She said she anticipates that the risks of hypoglycemia using IIT will drop as advances in the monitoring and administration of insulin emerge. Indeed, a recent randomized controlled study showed that, compared with use of a pump with a standard sensor, a novel sensor-controlled insulin pump reduced the incidence of overnight hypoglycemia by 32% in 247 non-ICU patients with type 1 diabetes treated using tight glucose targets ((N Engl J Med d 2013 June 22 [Epub ahead of print]).

“Introduction of robust glucose sen-

sors for continuous readings, as well as the development of sophisticated insulin titration algorithms are hoped to increase the safety of insulin therapy,” Dr. Jacobi said, pointing to algorithms published by LDS Hospital in Salt Lake City ((J Diabetes Sci Technol 2008;2:357368) as examples.

Tight Control May Work, But at What Financial Cost?

Digging deeper into the ACP’s stance on tight control, the group’s review also concluded that IIT increased health care costs, adding the caveat that few costeffectiveness studies of the treatment have been conducted. The 2006 study they cited showed IIT-related hourly glucose monitoring and insulin-dose adjustments added $182,488 in nursing salary costs and $58,000 in supplies over a one-year period compared with a previous one-year period when more conservative targets were used in the ICU setting ((Am J Crit Care 2006;15:370-377; Figure). “Aside from the costs associated with implementation of IIT in a hospital, there are also downstream costs that are incurred with the management of consequent harms,” they said.

Tom Van Herpe, PhD, MSc, a member of the Belgian team that reported in 2001 that IIT targets of 80 to 110 mg/dL reduced overall in-hospital mortality among ICU patients by 34% ((N Engl J Med 2001;345:1359-1367), disagreed with the authors’ cost–benefit conclusions. “Large cost-analysis studies have already shown that tight glycemic control in the ICU reduces costs due to shortened stay in the ICU, reduced periods of mechanical ventilation and reduced antibiotic treatment due to fewer infections and complications,” argued Dr. Van Herpe, who is a postdoctoral researcher at Catholic University of Leuven, in Belgium. He pointed to a singlecenter, 800-patient study, in which he was not involved, that showed an annual savings of $1,580 per ICU patient when

ACP Guidelines Largely Similar to Others The ACP guidelines are consistent with those issued jointly by the American Association of Clinical Endocrinology (AACE) and the American Diabetes Association (ADA), noted Cynthia Phillips, PharmD, CDE, an assistant professor in the Department of Clinical Pharmacy Practice and Outcomes Sciences at the University of South Carolina’s College of Pharmacy, in Columbia. However, she said that although the ACP is recommending an upper limit of 200 mg/dL, the AACE/ADA recommend an upper limit of 180 mg/dL ((Diabetes Care 2009;32:11191131). Dr. Phillips said that the discrepancy might partly reflect differences in the composition of the respective organizations’ review teams. “This group was very physician-specific,” she said, stopping short of arguing that one threshold is more appropriate than another. “The ADA/AACE, in contrast, created a multidisciplinary team to conduct a more comprehensive review of the evidence.”

Best practices come from a multidisciplinary approach, Dr. Phillips said.

“We don’t operate in a vacuum: When a range of specialties is involved in guideline creation, the results are more representative and more robust.”

Weak Evidence Makes For Weak Guidelines Dr. Phillips believes the dearth of evidence on the safety and efficacy of IIT as well as the contradictory nature of available findings mean professional guidelines are, in turn, not as comprehensive and authoritative as they could be. “Many centers will conduct their own literature review and draw on the ACP and other guidelines as well as input from medical staff, nursing, pharmacy, nutrition and quality improvement personnel,” she said. “Most centers will create their own individualized protocols based on their specific institutional environment, their own patient populations and their specific cost constraints.”

Dr. Qaseem, however, said he expects to see centers slowly transition away from IIT. He said, “People have definitely started recognizing that overly strict targets are being used.”

—David Wild Drs. Van Herpe, Jacobi, Phillips and Qaseem reported no relevant financial conflicts of interest.

TRANEXAMIC ACID INJECTION • AP Rated to Cyklokapron®1 • Preservative Free NDC 0517

Strength

Size

Shelf Pack

0960-10

1000 mg/10 mL

10 mL

10

(100 mg/mL)

Single Dose Vial

Vial stoppers are not made with natural rubber latex 1 Cyklokapron® is a registered trademark of Pfizer Health AB

Customer Service

Growth

Quality

Partnership

IMPORTANT SAFETY INFORMATION Tranexamic acid d injec injectio tion n is is cont contrai raindi ndicat cated: ed 1. In patients with th acquired d def defect ective ive co color lor vi visio sion, since this prohibits measuring one endpoint that should be followed as a measure of toxicity.

2. In patients with h sub subara a chn hnoid oid he hemor morrha rhage. ge. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid injection in such patients.

3. In patients with h active ive intra ravas vascul cular ar clo clotti ttin ng.

4. In patients with h hyp hypers ersens ensiti itivit vityy to to tran tranexa examic m acid or any of the ingredients.

Focal areas of ret etina inal dege egeneration have developed in cats, dogs and rats following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times the recommended usual human dose) from 6 days to 1 year. The incidence of such lesions has varied from 25% to 100% of animals treated and was dose-related. At lower doses some lesions have appeared to be reversible.

Limited data in cats and rabbits showed retinal changes in some animals with doses as low as 126 mg/kg/day (only about 3 times the recommended human dose) administered for several days to two weeks. No retinal changes have been reported or noted in eye examinations in patients treated with tranexamic acid for weeks to months in clinical trials.

However, visual abnormalities, often poorly characterized, represent the most frequently reported postmarketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, color vision, eye-ground and visual fields, is advised, before commencing and at regular intervals during the course of treatment. Tranexamic acid should be discontinued if changes in examination results are found.

Convulsions have been reported in association with tranexamic acid treatment.

The dose of tranexamic acid injection should be reduced in patients with renal insufficiency because of the risk of accumulation.

Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with tranexamic acid.

Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid injection. Central retinal artery and central retinal vein obstruction have been reported.

Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis.

Tranexamic acid injection should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased.

Patients with disseminated intravascular coagulation (DIC), who require treatment with tranexamic acid, must be under strict supervision of a physician experienced in treating this disorder.

Tranexamic acid may cause dizziness and therefore may influence the ability to drive or use machines.

Pregnancy Category B: Reproduction studies performed in mice, rats, and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid.

There are no adequate and well-controlled studies in pregnant women. However tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid. To avoid this response, the solution should not be injected more rapidly than 1 mL per minute.

Worldwide Postmarketing Reports: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined.

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TRANEXAMIC ACID INJECTION

Rx Only

DRUG DESCRIPTION Tranexamic acid is an antifibrinolytic agent. Each mL of the sterile solution for intravenous injection contains Tranexamic Acid 100 mg and Water for Injection to 1 mL.

54 Clinical

Cardiovascular disease

INDICATIONS Tranexamic acid injection is indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction.

CONTRAINDICATIONS Tranexamic acid injection is contraindicated in patients with acquired defective color vision, since this prohibits measuring one endpoint that should be followed as a measure of toxicity (see WARNINGS); in patients with subarachnoid hemorrhage.

Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid injection in such patients; in patients with active intravascular clotting; and in patients with hypersensitivity to tranexamic acid or any of its ingredients.

WARNINGS Focal areas of retinal degeneration have developed in cats, dogs and rats following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times the recommended usual human dose) from 6 days to 1 year. The incidence of such lesions has varied from 25% to 100% of animals treated and was dose-related. At lower doses, some lesions have appeared to be reversible.

Limited data in cats and rabbits showed retinal changes in some animals with doses as low as 126 mg/kg/day (only about 3 times the recommended human dose) administered for several days to two weeks. No retinal changes have been reported or noted in eye examinations in patients treated with tranexamic acid for weeks to months in clinical trials.

However, visual abnormalities, often poorly characterized, represent the most frequently reported postmarketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, color vision, eye-ground and visual fields, is advised, before commencing and at regular intervals during the course of treatment. Tranexamic acid should be discontinued if changes in examination results are found.

Convulsions have been reported in association with tranexamic acid treatment.

PRECAUTIONS General: The dose of tranexamic acid injection should be reduced in patients with renal insufficiency because of the risk of accumulation. Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with tranexamic acid injection. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid injection. In addition, cases of central retinal artery and central retinal vein obstruction have been reported. Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis.

Tranexamic acid injection should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Patients with disseminated intravascular coagulation (DIC), who require treatment with tranexamic acid injection, must be under strict supervision of a physician experienced in treating this disorder. Tranexamic acid may cause dizziness and therefore may influence the ability to drive or use machines.

BP GOALS continued from page 24

She also pointed out that “the pharmacists we worked with in the study are employed by HealthPartners as MTM pharmacists. They work right in the primary care clinics as part of the care teams. Since MTM is a nationwide program covered by Medicare, that makes it easier for other health care systems to adapt some of our methods.”

Kari Olson, PharmD, BCPS (AQ Cardiology), a clinical pharmacy specialist at Kaiser Permanente Colorado and a clinical associate professor at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Aurora, said, “The study

by Dr. Margolis and her team is yet another well-designed clinical trial in

Pregnancy Category B Reproduction studies performed in mice, rats, and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. There are no adequate and well-controlled studies in pregnant women. However, tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery (See above under Pregnancy).

Nursing Mothers: Tranexamic acid is present in the mother’s milk at a concentration of about a hundredth of the corresponding serum levels. Caution should be exercised when tranexamic acid injection is administered to a nursing woman.

Pediatric Use: The drug has had limited use in pediatric patients, principally in connection with tooth extraction. The limited data suggest that dosing instructions for adults can be used for pediatric patients needing tranexamic acid injection therapy.

Geriatric Use: Clinical studies of tranexamic acid injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic 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.

ADVERSE REACTIONS Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid. To avoid this response, the solution should not be injected more rapidly than 1 mL per minute.

Worldwide Postmarketing Reports: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined.

OVERDOSAGE Cases of overdosage of tranexamic acid injection have been reported. Based on these reports, symptoms of overdosage may be gastrointestinal, e.g., nausea, vomiting, diarrhea; hypotensive, e.g., orthostatic symptoms; thromboembolic, e.g., arterial, venous, embolic; visual impairment; convulsions, mental status changes; myoclonus, and rash.

DOSAGE AND ADMINISTRATION Immediately before tooth extraction in patients with hemophilia, administer 10 mg per kg body weight of tranexamic acid injection intravenously together with replacement therapy (see PRECAUTIONS). Following tooth extraction, intravenous therapy, at a dose of 10 mg per kg body weight three to four times daily, may be used for 2 to 8 days. For dosing in patients with moderate to severe impaired renal function, see Full Prescribing Information.

For intravenous infusion, tranexamic acid injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions and Dextran solutions. The mixture should be prepared the same day the solution is to be used. Heparin may be added to tranexamic acid injection. Tranexamic acid injection should NOT be mixed with blood.

The drug is a synthetic amino acid, and should NOT be mixed with solutions containing penicillin.

HOW SUPPLIED Tranexamic Acid Injection, 100 mg/mL, is a clear, colorless solution STORAGE Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Discard unused portion.

AR117 Iss. Date 9/2011

the growing armamentarium demonstrating the value of clinical pharmacists working in conjunction with the medical team and incorporating patient home blood pressure monitoring on improving blood pressure control. Hypertension management often requires multiple medications along with appropriate laboratory monitoring. This study along with others highlight the important role clinical pharmacists, as medication experts, can play in improving hypertension control in the U.S. Pharmacy communities should take the results of these studies and determine how best to incorporate hypertension management into the care of the patients they serve.”

—Bruce and Joan Buckley

FDA WATCH

DRUG INTERACTIONS No studies of interactions between tranexamic acid and other drugs have been conducted.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY An increased incidence of leukemia in male mice receiving tranexamic acid in food at a concentration of 4.8% (equivalent to doses as high as 5 g/kg/day) may have been related to treatment. Female mice were not included in this experiment.

Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic/neoplastic changes in the liver. No mutagenic activity has been demonstrated in several in vitroo and in vivo test systems. There are no clinical or nonclinical data to assess the effects of tranexamic acid on fertility.

Pharmacy Practice News • August 2013

New Indication

Telavancin Approved for Nosocomial Pneumonia

O

n June 21, the FDA expanded its approval of telavancin (Vibativ, Theravance) to include treatment of patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP or nosocomial pneumonia) caused by Staphylococcus aureus. In a press release, the FDA specified that telavancin should be used to treat nosocomial pneumonia only when alternative treatments are not suitable.

According to a Theravance press release, telavancin is an injectable, once-daily, bactericidal, lipoglycopeptide antibiotic with a dual mechanism of action: It inhibits bacterial cell wall synthesis and disrupts bacterial cell membrane function. It is already approved for the treatment of complicated skin and skin structure infections caused by susceptible gram-positive bacteria.

Telavancin’s safety and effectiveness in the treatment of nosocomial pneumonia were established in two trials (Clin Infect Dis 2011;52:31-40). The studies randomized 1,532 patients with HABP suspected or proven to be caused by gram-positive bacteria. Of the patients, 1,503 received telavancin or vancomycin. The primary end point of each study was noninferiority of telavancin versus vancomycin in clinical cure rate at the test-of-cure visit. Cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% confidence interval for the difference, –4.3% to 7.7%) in the pooled clinically evaluable population (N=654). The trials also measured all-cause mortality 28 days after initiation of treatment in patients presumed to test positive for S. aureus at baseline. Mortality rates were comparable between telavancin and vancomycin treatment arms, except that more patients with preexisting kidney problems died in the telavancin arm than in the vancomycin arm.

Telavancin can cause new or worsening kidney problems, a fact that has been added to the drug’s boxed warning. According to the FDA press release, the most common adverse event associated with telavancin in the clinical trials was diarrhea.

—George Ochoa

Olmesartan Label Changes To Warn Of Sprue-like Enteropathy

O

n July 3, the FDA warned that the angiotensin II receptor blocker (ARB) olmesartan medoxomil (marketed as Benicar, Benicar HCT, Azor and Tribenzor by Daiichi-Sankyo and available in generic formulations) can cause intestinal problems known as sprue-like enteropathy, with symptoms including severe, chronic diarrhea with substantial weight loss.

Reports of sprue-like enteropathy associated with olmesartan had been increasing during the past year, with physicians presenting data on the topic at last year’s American College of Gastroenterology meeting and this year’s Digestive Disease Week meeting, among other reports (Pharmacy Practice News 2013;40[7]:22; Mayo Clin Proc 2012;87:732-738). Other ARBs have not been associated with this finding.

In a press release, the FDA recommended that health care professionals should tell patients to contact them if they develop severe, chronic diarrhea with substantial weight loss while taking an olmesartan-containing product, even if it takes months or years for symptoms to develop.

The FDA will continue to evaluate the safety of olmesartan-containing products.

Health care professionals and patients are encouraged to report adverse effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program at (800) 332-1088 or www.fda.gov/medwatch/ report.htm.

Clinical 55

Pharmacy Practice News • August 2013

IVIG FAQ

Immunoglobulins and Obesity: Dosing Considerations I

’ve been involved with the development and management of intravenous immunoglobulin (IVIG) therapy for more than 30 years, and questions about the optimal use of IVIG are emailed to me on an almost daily basis. Many of those queries touch on safety issues, such as the review and monitoring of adverse reactions.

I want to make this column as relevant as possible, so please send me your questions on IVIG therapy via email to Jerry.siegel.rx@ gmail.com (cc: ppneditor@mcmahonmed.com), and I will do my best to answer them.

Q

: How do you dose intravenous immunoglobulin in morbidly obese patients?

A: For more than 30 years, intravenous immunoglobulin (IVIG) has been used as replacement therapy for patients with primary immunodeficiency.1 More recently, the product has been used for a wide array of autoimmune-mediated diseases and for the treatment of antibody rejection in solid organ transplantation.2,3 IVIG works via several mechanisms of action including the modulation of the Fc receptors of phagocytic cells, complement activation, inhibition of cytokine release, and interaction with B- and T-cell receptors.4

Debate About Dosing IVIG is supplied in lyophilized and liquid dosage forms and is supplied as vials with varying increments. Different manufacturers provide 1-, 2.5-, 3-, 5-, 6-, 10-, 12-, 20-, 25-, and 30-g vials.5 The concentrations of IVIG are usually 5%, 6%, or 10%, depending on the reconstitution or liquid product selected. The dose of IVIG prescribed varies depending on the indication, but the appropriate dosing regimen in obese patients has long been unclear; studies have traditionally excluded this population.2,3 Recently, there has been a national and international debate about the “ide-

al” way to dose IVIG by weight. The drivers for this controversy have not been evidence-based studies definitively showing that using actual body weight (ABW) for dosing calculations will have a negative effect on outcome; rather, there has been concern among practitioners that the higher doses of immunoglobulin given to morbidly obese patients dosed using ABW may result in a higher risk for adverse events than that observed with dosing based on ideal body weight (IBW). Over the years, IVIG shortages also have influenced decisions about appropriate indications and dosing. There also are cost pressures that may weigh into the decision.

A utilization review by the Australian Red Cross evaluated patients treated in that country between 2006 and 2009: 37.2% weighed at least 80 kg, 26% weighed at least 90 kg, and 12.6% weighed at least 100 kg. With 75.8% of the IVIG population being greater than 80 kg, changing to IBW dosing would result in a significant decrease in Australia’s IVIG use, and thus cost.6 This applies in other countries as well, and several other US and international groups have evaluated and made recommendations supporting the use of IBW. However, if you start with IBW dosing, it is vital that you pay attention to clinical outcome and adjust the dose accordingly.

At the Cleveland Clinic, dosing and use guidelines for IVIG dosing follow 3 key

points. First, the dose of IVIG is calculated based on IBW, not ABW. If the person is 30% to 40% above IBW, then an adjusted body weight will be used, making it important to have the current weight of the patient. Second, the total dose of IVIG should be no more than 2 g/kg (eg, 0.4 g/ kg per day for 3 to 5 days or 1 g/kg per day for 2 days). All doses greater than 1 g/kg must be approved by the Drug Information Center. Third, IVIG should not be dosed any more frequently than every 4 to 6 weeks.7 The policy at Hospital Corporation of America is to base all doses of IVIG (except for in neonates) on patient’s IBW and round to the nearest whole vial size.8 IVIG dosing adjustment also has been evaluated in pregnancy. Canadian investigators studied the pharmacokinetics of IVIG before and during pregnancy in healthy women with poor obstetrical histories and found that with a weightadjusted dosage of IVIG, drug exposure, based on area under the curve calculations, was maintained at the pre-pregnancy level. This team recommended “a weight-adjusted dosage of IVIG during the first and second trimesters.”9 The Department of Health of the United Kingdom clinical guidelines for immunoglobulin use dose-determining weight (DDW) derived from IBW for patients who are morbidly obese.10 The Ohio State University Medical Center uses an approach that takes into account the pharmacokinetic properties of the drug, as well as the product packaging variability to dose IVIG in obese patients. Although IVIG has been shown to have very little distribution into the fat,11 there is an increased volume of distribution (Vd) in patients with obesity due to their increased volume of body fluids. Thus, although in general, IVIG should be dosed using ABW W in patients weighing up to 100 kg with a body mass index (BMI) less than 30 kg/m2, in obese patients, an adjusted body weightt should

Jerry Siegel, PharmD, FASHP Clinical Associate Professor The Ohio State University College of Pharmacy Columbus, Ohio

be used to account for the increased Vd into their extra body fluids, without accounting for the increase in fat. It is recommended that dosing be calculated using an adjusted body weight if a patient has a BMI of 30 kg/m2 or higher, or if the patient’s ABW is more than 20% over his or her IBW. A practical and cost-efficient formula for dosing IVIG in morbidly obese patients using an adjusted body weight can be calculated considering the equations in Table 1.10 The dosing equation in the Table will provide values that account for the extra Vd in obese patients.

It is not uncommon for calculated doses to fall between vial sizes. Such doses should be rounded to the nearest whole vial size available to prevent unnecessary waste. Generally, the goal is to target the rounded doses to be within 10% of calculated doses. The dosing equation in Table 1 provides values that easily can be rounded to manufacturer’s vial sizes.

Table 2 demonstrates the importance of dosing patients with obesity using an adjusted body weight. In the first example, IVIG is ordered for a 5-ft 4-in., 120-kg woman with primary immunodeficiency. The ordering physician considers giving the patient a dose of 500 mg/ kg. To calculate the dose of drug that the patient will require, her BMI must be calculated first.

Patient’s weight = 120 kg × 2.2 = 264 lb Patient’s height = 64 in.

BMI = 703 × [(264 lb)/(64 in. × 64 in.)] = 45 kg/m2 Because the patient’s BMI is greater than 30 kg/m2, the IVIG should be dosed using an adjusted body weight. To

•

see IVIG DOSING, page 56

Table 1. Equations IVIG Dosing Calculation = Adjusted Body Weight = IBW + 0.5 (actual body weight – IBW)

Table 2. Examples of Dosing of IVIG in Morbidly Obese Patients Patient

Dose

Height, Weight, in. kg

Dosing BW, kg

BMI

% Body Weight Above IBW

Dose Using Actual BW, g

Dose Using Adjusted BW, g

No. Vials Needed For Rounded Adjusted BW Dose

Female 48 y

500 mg/kg

64

120

87.4

45

37.5

60

43.7

If 6-g, use 7 vials (42 g) 6% solution = 700 mL

Male 24 y

1,000 mg/kg

74

150

116

42

45.2

150

116

If 20-g, use 6 vials (120 g) 10% solution = 1,200 mL

BMI = 703 × (weight in pounds/height in inches2) IBW (kg) for males = 50 + [2.3 × (height in inches – 60)] IBW (kg) for females = 45.5 + [2.3 × (height in inches – 60)] IVIG Adjusted Body Weight = IBW + 0.5 (actual body weight – IBW) IBW, ideal body weight; IVIG, intravenous immunoglobulin

BMI, body mass index; BW, body weight; IBW, ideal body weight

56 Clinical

Pharmacy Practice News • August 2013

IVIG FAQ

IVIG DOSING continued from page 55

calculate an adjusted body weight, first calculate the patient’s IBW. IBW = 45.5 × [2.3 × (64 in. – 60 in.)] = 54.7 kg Using that IBW, an adjusted body weight can then be calculated.

Adjusted body weight = IBW (54.7 kg) + 0.5 × (actual body weight [120 kg] – IBW [54.7 kg]) = 87.4 kg To calculate the total dose, the dose that the physician ordered (500 mg/kg) is then multiplied by the adjusted body weight (87.4 kg), yielding 43,700 mg, or 43.7 g.

For a calculated dose of 43.7 g, the dose should be rounded to 42 g. After dose escalation, the maximum tolerated infusion rate was 2 mg/kg per hour.

The infusion rate of a 6% preparation in this case would be calculated as follows: The maximum tolerated infusion rate: (2 mg/kg per minute) × adjusted body weight (87.4 kg) × (1 g/1,000 mg) × 700 mL/42 g (6 g/100 mL in 6% preparation, ie, 700 mL/42 g) × (60 min/1 h) = 174.8 (175) mL per hour.

The second example also highlights the importance of using an adjusted body weight in the dosing of IVIG in patients who are obese. IVIG is ordered for a 6-ft 2-in., 150-kg male professional football player for the treatment of idiopathic thrombocytopenic purpura. The dosing

options vary from 400 mg/kg per day for 5 days to 500 mg/kg per day for 4 days or 1,000 mg/kg per day for 2 days. At the highest dose-per-day option (1,000 mg/kg per day), he would receive 150 g of IVIG per day if the ABW were used. If a 5% solution were used, this would be 3,000 mL of IVIG fluid per day (5 g/100 mL in 5% preparation, ie, 3,000 mL/150 g). The volume and time for infusion may be difficult for the patient to tolerate.

To address this problem, a 10% solution is selected for administration. Additionally, because his BMI is greater than 30 kg/m2 and the ABW is more than 20% above the patients’ IBW, the IVIG should be dosed using an adjusted body weight.

To calculate an adjusted body weight, first calculate the patient’s IBW. IBW = 50 + [2.3 × (74 in. – 60 in.)] = 82.2 kg Adjusted body weight = 82.2 kg + 0.5 × (150 kg – 82.2 kg) = 116 kg Using adjusted body weight (116 kg), the calculated dose of IVIG is 116 g, and this dose should be rounded to 120 g, allowing for the use of six 20-g vials. At a maximum infusion rate of 2 mg/kg per minute, the rate would be 140 mL per hour, not the 180 mL per hour that would be calculated using actual body weight.

The maximum tolerated infusion rate: (2 mg/kg per minute) × adjusted body weight (116 kg) × (1 g/1,000 mg) × 1,200 mL/120 g (10 g/100 mL in 10%

preparation, ie, 1,200 mL/120 g) × (60 min/1 h) = 140 mL per hour.

Conclusion IVIG should be dosed using adjusted body weight in obese patients to account for distribution into extra body fluids.

Adjusted body weight should be used if a patient has a BMI of 30 kg/m2 or greater or if the patient’s ABW is more than 20% over IBW. At our institution, we recommend using the equation, adjusted body weight = IBW + 0.5 × (ABW – IBW) for ease of calculation.

More important than using IBW or ABW for IVIG is the clinical outcome. For replacement therapy, monitoring the IVIG level and the clinical response of prevention of infections is the most important outcome and will vary from patient to patient. For immunomodulation, the ideal dose is not known and IVIG levels are less important than outcome. For ITP, the surrogate marker is the platelet count, whereas for neurologic disorders such as chronic inflammatory demyelinating polyneuropathy, it is the patient’s performance level.

Guidelines for determining the most appropriate dose for each patient should be based on the patient demographics and monitoring of clinical outcomes, with dosage adjustments made as needed.

References 1. Boros P, Gondolesi G, Bromberg JS. High dose intravenous immunoglobulin treat-

ment: mechanisms of action. Liver Transpl.

2005;11(12):1469-1480.

2. Privigen Immune Globulin Intravenous (Human) 10% Liquid [package insert].

Kankakee, IL: CSL Behring LLC; May 2012.

3. Immune Globulin Intravenous (Human), Carimune NF, Nanofiltered [package insert].

Kankakee, IL: CSL Behring LLC; June 2012.

4. Crow A, Lazarus A. The mechanisms of action of intravenous immunoglobulin and polyclonal anti-D immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know? Transfus Med Rev. 2008;22(2):103-116.

5. Siegel J. Intravenous immune globulins: therapeutic, pharmaceutical, administration, and cost considerations. Pharmacy Practice News.

2013;40(1 suppl):1-8.

6. http://www.transfusion.com.au/sites/default/ files/Aston%20Less%20is%20the%20new%20 more.pdf.

7.

Standard Cleveland Clinic Foundation clinical practice.

8. IVIG HCA Pharmacy Protocol. www.ashp. org/s_ashp/.../DShort_IVIGHCAPharmacyProtocol.doc.

9. Ensom MH, Stevenson MD. A two-center study on the pharmacokinetics of intravenous immunoglobulin before and during pregnancy in healthy women with poor obstetrical histories.

Hum Reprod. 2011;26(9):2283-2288.

10. Wemperis J, Lunn M, Jones A, et al. National Health Service. Clinical guidelines for the use of immunoglobulin use: second edition update. https://www.gov.uk/government/uploads/ system/uploads/attachment_data/file/153238/ dh_131107.pdf.pdf.

11. Koleba T, Ensom MH. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy. 2006;26(6);813-827.

Infectious Disease

HYPERSENSITIVE continued from page 45

that cross-reactivity even within the same class due to the side chain,” Dr. Pogue said. “Always remember that with cephalosporins, there’s a second side chain, R2 (C3). Different cephalosporins have the same R2 [side chains], so if [a patient has] an allergy to one, I might caution you from using another.

The bottom line with cephalosporin is that the cross-reactivity might be less than we thought, but if you have structurally similar agents, it can be high.”

Dr. Pogue noted that because ceftazidime and aztreonam have identical side chains, “if a patient has a ceftazidime allergy, giving aztreonam is probably one of the worst things you can do.”

The data on using carbapenems in patients with a history of penicillin allergy are conflicting, with studies showing cross-reactivity rates of from 1% to nearly 50% ((Ann Pharmacother 2009;43:304-315). “In general, clinicians are more likely to give carbapenems than cephalosporins, but it isn’t what I would recommend,” Dr. Pogue said. “There is a potential for cross-reactivity, even if we

don’t know what the mechanism is precisely. For my money, it looks to be a little higher than the cephalosporins.”

Dr. Pogue stressed that it’s important to keep in mind that “hypersensitive patients are hypersensitive. So, even if it’s not a cross-reactivity, you still need to be aware that they might have a higher propensity to having a reaction in general.”

In cases for which there is no choice but to administer a drug to a patient who has had a previous type I reaction, antibiotic desensitization—the induction of temporary tolerance to the allergen— can be used. With antibiotic desensitization, small, gradually increasing doses of the target medication are given, usually intravenously, until the patient can tolerate the full dose. Dr. Pogue emphasized that the procedure is appropriate only for patients with IgE-mediated hypersensitivity. “If the patient has had SJS and you try to desensitize them, you are going to give them an awful reaction,” he said. It’s also important to remember that the tolerance is temporary. “If the patient needs this drug again in the future, they are still allergic to this drug and you would need to do this [desensitization] again.”

Although the mechanism behind anti-

biotic desensitization is unclear, “there is some evidence that if you give a little bit of a drug, that you can actually set up a negative feedback loop that depletes those signal transducers that tell the cell they need to release [inflammatory mediators],” he said. This induces tolerance. When the drug leaves the system, the feedback loop is turned off and the allergy remains.

Dr. Pogue said he favors the ICU for performing antibiotic desensitization because close monitoring is more readily available there, but the location is not as critical as having one-on-one monitoring by a caregiver who knows how to assess the patient and administer lifesaving medications. If the patient experiences a mild reaction to the medication, the reaction can be managed and then administration of the proper dose can be resumed. With more severe reactions, however, he said, if at all possible, “you would abort the process.”

David J. Amrol, MD, an associate professor of clinical internal medicine and director of the division of allergy and immunology at the University of South Carolina School of Medicine, in Columbia, reviewed a recent study by

Macy et al on penicillin allergy in the NEJM Journal Watch. Noting, as did Dr. Pogue that penicillin allergy is often overstated, he wrote, “In this study, [[J All Clin Immunol Prac 2013;1:258-263] fewer than 1 in 50 patients with penicillin allergy histories were truly allergic. We should stop accepting penicillin allergy history as a reason for lifelong avoidance. All drug reactions should be documented carefully. Patients with severe delayed reactions such as Stevens Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), or hemolytic anemia should never be challenged or tested; those with mild delayed reactions probably can undergo oral challenges. For those with potential IgE-mediated reactions (i.e., hives, edema, or other symptoms of anaphylaxis occurring within 1–2 hours), penicillin testing followed by oral challenge is safe and effective.”

—Susan Birk Dr. Pogue is on the speakers bureau for Merck, Pfizer and Forest, is a consultant for Cubist and has received grant support from Merck and Forest.

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58 Operations & Management

Pharmacy Practice News • August 2013

Leadership in Action

Are You Really in Charge?

A

s a pharmacy manager, you have probably agonized over developing the perfect plan to implement a new clinical or operational program. You research the best design. You search the literature and the websites of the American Society of Health-System Pharmacists and ASHP Connect. You speak with countless others who have rolled out similar initiatives. What you likely will determine is that there is no one best plan to accomplish the same clinical or operational goal. After all, why do we have so many different drug distribution programs in hospital pharmacy?

There is a valuable lesson on leadership to be culled from such an exercise, and it is this: Success hinges not so much on method, but rather on how well your program will be designed and implemented by your team, as opposed to individuals working in silos. In fact, even highly talented people can fail because they cannot work together. As Henry Cloud wrote in his book “Boundaries for Leaders” (HarperCollins Publishers, 2013), “Ultimately, leadership is about producing real results in the real world.

And that is only done through people doing what it takes to make it happen.”

Over the next several columns we will explore, based in part on the writings of Henry Cloud, what leaders need to do to help their pharmacy managers and staffers develop a vision for what they want to achieve. We’ll also explore how you can relate that vision to the evolving practice of pharmacy. It’s all about leading the right people in the right ways to do the right things at the right times.

Is that type of leadership in evidence at your health system? Are you getting the results you are looking for in your department? If not, perhaps the principles we will review will help set you on the right path. Remember, as the leader, you are in charge and you can change!

Setting Boundaries The first decision a leader has to make is how to set effective boundaries, with an eye toward not only establishing the vision, goals and purposes of your department, but also determining who will be included in the journey toward achieving those goals. I would strongly advise against making that determination on your own. In fact, I recommend you do it as a team. In my former role as a pharmacy director, we set the vision collectively, and my role was to then hold the various managers to that direction. If I needed to jump in with an individual “problem” employee, I would take my cues from the managers; I was more than happy to do so. I held them accountable and they held their folks accountable.

I set the tone for “no bickering or pet-

tiness” between individuals; it was just not to be tolerated. We were a professional department and we needed to act that way. We needed to treat others with respect if we were to get respect.

In setting that tone, I often found myself drawing on some of the core concepts behind Henry Cloud’s teachings.

He identifies several key areas that the leader must define and own: • The vision and focus to create forward movement • The emotional climate of the department • The unity and connectedness of the department and teams • The thinking and beliefs of the department • The amount and type of control and empowerment people are given and required • The performance and development of their direct reports and teams • The leadership of oneself, establishing one’s own boundaries To further establish this culture of shared accomplishments, I held weekly meetings of the managers to be sure we were all on the same page and to allow each manager to review what was going on in his or her area of responsibility. This process increased awareness across the various sections of the pharmacy and encouraged synergy, where individuals would help each other when possible and appropriate. I also encouraged directors to surround themselves with people different from themselves.

This creates a complementary group of pharmacy managers, each of whom brings different personal and professional strengths. Additionally, I empow-

ered managers to take responsibility and control of their areas. I also met individually with most of my managers on a weekly basis to foster communication and development. All of these efforts were systematic and intentional. The more successful you are in managing the people, the more successful you are in accomplishing the vision.

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, of Brockton, Mass.

Mr. Anderson welcomes your input on leadership issues, at anderson489@ comcast.net.

Ernest R. Anderson Jr., MS, RPh

Maximizing Brain Functionality As leaders we also need to create a setting that enables our employees to maximize their abilities, particularly in the case of managers who need to develop sharp skills leading others. According to Cloud, this is another area where the concept of boundaries can be helpful.

He notes, for example, that we need to set boundaries to enable our brains to function in several essential processes: • Attention: the ability to focus on relevant stimuli and block out what is not relevant. So pay attention.

• Inhibition: the ability to “not do” certain actions that could be distracting. So don’t do that.

• Working memory: the ability to retain and access relevant information for reasoning, decision making and taking future actions. So remember and build on relevant information.

Our brains need to be able to focus on something specific without being distracted by other data inputs. But we also need to be continuously aware of other relevant information at all times. High-performance leaders do this cognitive balancing act very well; they can lead in a way that ensures that energy will be spent on what is important and drives results, while

‘High-performance leaders ... can lead in a way that ensures that energy will be spent on what is important and drives results, while limiting distractions or intrusions.’

limiting distractions or intrusions.

Pharmacy Renovation Puts A Ceiling on Distractions Several years ago we were renovating our central pharmacy. In the design we established what we called the “bull pen.” This was an area of four workstations in a square surrounded by five-foot walls. These workstations enabled the pharmacists to perform their order verification processes while minimizing distractions. We set up a phone triage system where the technicians handled the incoming calls unless a pharmacist was truly needed. We also set up a morning huddle to set the priorities of the day for the entire central pharmacy staff.

The pharmacists worked efficiently yet cooperatively with their co-workers.

They collaborated on clinical questions in an effort to benefit from the expertise of others and were able to focus without unnecessary interruptions.

The key here is to create an atmosphere in which your pharmacists can focus on a specific area of practice. In effect, it is the opposite of multitasking, which Cloud feels is an overrated measure of efficiency. In fact, he cites data showing that multitasking actually detracts from optimal brain function. So we need to set up our systems and processes recognizing this fact.

Summary Ask yourself this key question: As the pharmacy director or chief pharmacy officer, is my overall vision and strategy clear? If not, begin by focusing your managers on figuring out what is important and what is not. Allow them to set goals and plans through persistence, adaptability and flexibility. Set good boundaries in terms of allowing managers the leeway to assign responsibility in achieving the shared vision. Such an approach produces freedom, not control, and allows your managers to work to the best of their abilities and to produce the results you seek. At the same time, be attuned to what is going on not only in the pharmacy but also in the larger circle of the health care profession, so you can adapt to change and propel your department and the profession forward.

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Available in three sizes: 10 oz. NDC# 65628-070-10 5 oz. NDC# 65628-070-05 3 oz. NDC# 65628-070-03

Many more Kits are available. Visit www.CutisPharma.com

www.cutispharma.com

facebook.com/CutisPharma 68 Cummings Park, Woburn MA 01801 Tel: 781-935-8141 Fax: 781-935-8395

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