PPN - February 2015

The Pharmacist’s News Source

pharmacypracticenews.com

Volume 42 • Number 2 • February 2015

Printer-friendly versions available online

in this issue UP FRONT

3

Opioids increase risk for androgen deficiency.

TECHNOLOGY

4

Innovative drug packaging boosts compliance.

OPERATIONS & MGMT

10 12

Pharmacists make their mark in ambulatory care.

Hospitals that have won the war against drug diversion.

CLINICAL

15

Tips for thwarting drug-induced bowel dysfunction in the ICU.

POLICY

22 26

FDA Watch: New drugs for plaque psoriasis, afib, DVT and PE. Sterile compounding: Are you in compliance with DQSA?

EDUCATIONAL REVIEW

Glycemic Control and the Hospitalized Patient: From Bedside to Beyond See insert after page 28

Mystery Illness Causes Paralysis In 107 Children

T

More than 200 lives saved per year

Is ‘Code Sepsis’ the Secret To Better Patient Outcomes?

he Centers for Disease Control and Prevention (CDC) is investigating reports of children who developed a sudden onset of limb weakness to determine whether the cases represent a second manifestation of the U.S. enterovirus D-68 (EV-D68) respiratory outbreak that ran from August to November 2014.

Experts say it will be difficult to definitively link this illness, called acute flaccid myelitis (AFM), to EV-D68 infection because the evidence is circumstantial. “There is [some] evidence suggesting an association, but we are still a bit away from making a direct link,” said James Sejvar, MD, a neuroepidemiologist with the CDC. One telling trend, Dr. Sejvar noted, was the fact that the AFM spike coincided with the national outbreak of respiratory illness caused by EV-D68.

“As these cases of respiratory illness decline, we have seen a similar rapid decline in the [incidence of AFM].”

Anaheim, Calif.—A sepsis management protocol based on the “code” responses used to treat patients with cardiopulmonary arrest or stroke has cut mortality rates by more than 50% at one North Carolina health system.

The Code Sepsis initiative, which garnered an American Society of HealthSystem Pharmacists (ASHP) Best Practices Award at the ASHP’s 2014 Midyear Clinical Meeting, markedly reduced the time between a positive sepsis screen and administration of antibiotics in both ICUs and non-ICUs. Jeremy Degrado, PharmD, a clinical pharmacy specialist in critical care in the Department of Pharmacy Services at Brigham and Women’s Hospital in Boston, applauded the initiative. “There are many interventions that have been attempted and tested in septic patients, but few have proven to make as much of a difference as this one has,” said Dr. Degrado, who was not involved in the study.

The protocol was developed after staff at Wake

see MYSTERY ILLNESS, page 20

see CODE SEPSIS, page 14

•

Delirium Consult Service Pinpoints Offending Drugs

•

An Inside Job: Hospital Adds $1.6 Million in Billables Via MTM

Anaheim, Calif.—Pharmacists at an Illinois hospital have implemented a first-of-its-kind automatic delirium pharmacy consult service.

Nearly two-thirds (65%) of the pharmacist consults conducted over an 18-month period resulted in a drug being identified as a possible or definite cause of inpatient delirium, and pharmacist recommendations were widely accepted by

Anaheim, Calif.—An Oregon hospital has demonstrated that inpatient medication therapy management (MTM)—traditionally thought of as an outpatient pharmacy service—is financially lucrative as well as a boon to clinical pharmacists.

The project’s researchers said the success of their inpatient MTM service nearly doubled the number of clinical consultations they conducted over a four-year period and generated approximately $1.6 million in billable pharmacy services in 2014.

“This is truly a one-of-a-kind program,” said Karen Trenkler, PharmD, MS, who is the clinical coordinator of pharmacy services at Mt. Sinai Hospital in Chicago, and was not involved in the project. “Inpatient pharmacists have been providing MTM interventions for decades but financial reimbursement remains rare.”

The program, one of several to win an American Society of Health-System Pharmacists (ASHP) Best Practices Award at the ASHP 2014 Midyear Clinical Meeting, was presented at the

see DELIRIUM, page 16

see MTM MILLIONS, page 8

•

•

New Product Teva Pharmaceuticals introduces Linezolid Injection.

See page 24

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Up Front 3

Pharmacy Practice News • February 2015

Capsules

Opioids Boost Risk for Androgen Deficiency

Web Exclusives

O

Visit us online for Web-exclusive content.

Links to all of the articles below can be found at pharmacypracticenews.com/ webex0215 or via your smart phone by scanning the adjacent 2D barcode. Be sure to check the Pharmacy Practice News site every day for late-breaking news!

Common Drugs May Increase Risk of Dementia

H

igh-dose anticholinergic agents that are taken for extended periods place patients at an increased risk for developing dementia, including Alzheimer’s disease, according to new data from researchers in Seattle.

CMS Makes a Move To Reward Value, Not Volume

T

he Centers for Medicare & Medicaid Services (CMS) has announced a timeline to move the Medicare program, and the health care system at large, toward paying providers based on the quality, rather than the quantity of care they give patients. Such programs have already saved 50,000 lives and $12 billion in health spending from 2010 to 2013, according to the agency.

PPIs + Diuretics = Low Magnesium, Hospitalizations

P

atients taking a combination of proton pump inhibitors (PPIs) and diuretics are at increased risk for low magnesium levels severe enough to warrant hospitalization, a new study suggests. Patients taking the drug combination were 73% more likely to require hospitalization for hypomagnesemia than those not on the medications. The risk for all outpatients taking PPIs was 43% greater than for those not on the reflux agents.

pioids may increase the risk for androgen deficiency (AD) in men— m depending on the type of opioid, dosage and the patient’s phy ysical health—so checking testosterone levels before considering opioid therapy may have benefit, a new retrospective cohort study suggests.

Lead study author Andrea L. Rubinstein, MD, head of the Chronic Pain Department at The Permanente Medical Group in Santa Rosa, Calif., and her team identified 1,121 men on stable doses of a single opioid for daily use to determine whether low testosterone levels are related to opioid dose (Am J Med d 2014;127:1195-1201). The men were found using the Kaiser Permanente Northern California administrative databases.

All study participants were taking one of the following opioids in the 100 days before the testosterone test: fentanyl (in transdermal form), hydrocodone, morphine, methadone or oxycodone. The authors used logistic regression to assess the association between individual opioids and AD, controlling for dose, obesity, age, hypertension and hyperlipidemia.

Hydrocodone was used as the referent for the regression analysis because it was associated with the lowest incidence of AD among the opioids examined during preliminary analyses.

Dr. Rubinstein and her team found that men on fentanyl (odds ratio [OR], 26.40), methadone (OR, 7.39) and oxycodone (OR, 3.17) were more likely to be androgen-deficient than those on hydrocodone. Morphine was also associated with a significantly higher risk for AD than hydrocodone—the sample included only 48 men taking morphine alone.

Dose was associated with an increased risk for AD for men on hydrocodone and oxycodone. Higher dose was not associated with an increased risk for AD among men on fentanyl, methadone or morphine. Men 50 years of age or older who had diabetes, hypertension and/ or hyperlipidemia were more likely to be androgen-deficient than men who were younger than 50 years old and did not have these conditions. Obese men were also more likely to be androgen-deficient than those who were not obese.

“Androgen deficiency needs to be a part of the total equation for each patient when deciding if [an opioid] is good therapy,” Dr. Rubinstein said. “The high incidence [of deficiency] merits testing [testosterone levels] in every [male patient] on opioids. When the opioid risks outweigh the benefits, it is time to seek alternative therapy options.”

Chong Hwan Kim, MD, who works at the West Virginia University Pain Clinic, Morgantown, and has a research interest in AD among opioid users, agreed that Dr. Rubinstein’s findings highlight the importance of checking androgen levels among men undergoing treatment for chronic pain. However, he said further research is needed before this issue becomes a key driver in pushing practitioners to alternative therapeutic options.

“We have little evidence for the mechanism of action or causation of androgen deficiency in opioid use,” said Dr. Kim, who was not involved in Dr. Rubinstein’s research. “Conclusive associations between duration, dosage or even specific risk factors for development of androgen deficiency with opioid use are also unclear. Additionally, most of the clinical symptoms are commonly seen in the chronic pain population even prior to opioid initiation. For now, prescribers should consider testing based on clinical judgment and continue appropriate monitoring. Further studies are needed before any recommendations can be made such as for baseline testing or screening criteria.”

The findings were presented in Las Vegas during PAINWeek in September.

—Brian Dunleavy

EDITORIAL BOARD

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Volume 42 • Number 2 • February 2015 • pharmacypracticenews.com

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INTERNAL MEDICINE

EDITORIAL STAFF

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BIOTECHNOLOGY

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ONCOLOGY

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CARDIOLOGY

Robert Ignoffo, PharmD, San Francisco, CA

C. Michael White, PharmD, Storrs, s CT CNS/PSYCHIATRY Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, Texas Larry Ereshefsky, PharmD, San Antonio, T Texas COMPLEMENTARY AND ALTERNATIVE MEDICINE

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4 Technology

Pharmacy Practice News • February 2015

Drug Handling

Compliance Packaging Lessens Adherence Gamble T

wo new medication adherence initiatives show the power of giving caregivers and patients the tools they need in order to understand their postdischarge medications and to take them as prescribed. In the process, hospital readmission rates are falling and positive health outcomes are on the rise.

A case in point is the medication adherence program at the Desert Hospital outpatient pharmacy, in Palm Springs, Calif.

By using compliance drug packaging, the hospital has shaved 30-day hospital readmission rates for discharged congestive heart failure (CHF) patients to less than 12% from 25% a year ago.

Pharmacist-in-charge Ramesh Upadhyayula, RPh, said the program has grown to nearly 70 patients, adds one to three patients per week on average and potentially saves the health care system $12,000 for every patient who stays home rather than lands in a hospital bed again.

These results help qualify the hospital for the Advanced Heart Failure Management Certification from the American Heart Association, Mr. Upadhyayula told Pharmacy Practice News.

In his view, CHF “has the potential for the highest ROI [return on investment] of the diseases for which CMS [Centers for Medicare & Medicaid Services] imposes readmission penalties. CHF patients can be a revolving door. Desert had one [patient] return 24 times, but [has come back] only once since joining our adherence program.”

The CHF program extends the hospital’s commitment to improve transitions of care. Direct patient contact begins at hospital discharge, when a clinical pharmacist from the outpatient pharmacy, with medications in hand, visits the bedside with a nurse to explain dose, time and rate of administration for each drug, as well as the importance of the patient taking the medications post-discharge. These medications come in strips of clear plastic packaging designed to simplify adherence—organized, labeled and dispensed on Parata PASS, Check PASS and Safe Loader technology. Desert Hospital “covers all costs of all CHF meds for the first 30 days,” explained Mr. Upadhyayula. “The hospital considers it an investment to help avoid readmission and thus CMS penalties.

The cost is about $50 for medications such as Lasix [furosemide], metoprolol and lisinopril.”

At discharge, CHF patients also receive a $19 scale free so “they can monitor [their] weight, which directly relates to fluid buildup,” he noted. “We have a standing protocol for a patient to take an additional Lasix [dose] and call the

Shailaja Karanti, PharmD, a clinical pharmacist at the Desert Hospital Outpatient Pharmacy, in Palm Springs, Calif., demonstrates how to use the Parata Packaging system for better compliance.

‘Our goal is to move toward a multidisciplinary team led by physicians working closely with pharmacists and nurses to facilitate rapid and effective interventions, and thus improve [patient] outcomes.’

—Ramesh Upadhyayula, RPh doctor right away if he or she gains 3 to 5 pounds from base weight.”

The Desert pharmacy synchronizes a patient’s prescriptions to renew simultaneously, so they can be shipped together just as the prior month’s inventory winds down. Before each renewal, pharmacists call patients for a medication therapy management (MTM) consult; the pharmacy also issues patient surveys to monitor patient behavior and prompt interventions when necessary. Patients who follow through with the CHF MTM program comply in excess of 95%, according to Mr. Upadhyayula.

“Our goal is to move toward a multidisciplinary team led by physicians working closely with pharmacists and nurses to facilitate rapid and effective interventions, and thus improve outcomes. This is where the true value of the pharmacist is—being part of the team.”

MedAssist and Wagner Pharmacy Meanwhile, data from the proprietary MedAssist program launched in February by Wagner Pharmacy Company, in Clinton, Iowa, show adherence gains in 50 patients studied. Each had taken five or more chronic medications daily for at least six months to treat dia-

Parata’s PASS multidrug adherence packaging comes in strips of clear plastic designed to simplify medication adherence.

betes, hypertension, hyperlipidemia, coronary artery disease (CAD) or CHF. They also received initial and follow-up comprehensive reviews from clinical pharmacists, medications from Wagner in barcoded strip packets, organized sequentially by when to take them, and had refills synchronized to be picked up at the same time each month.

The aggregate adherence rate of the study group (as measured by proportion of days covered [PDC]) jumped to 99% from a 72% baseline before the

start of MedAssist. Wagner co-owners Tim and Nora Wright, both PharmD, BCACP, devised the MedAssist practice model to raise adherence rates above what their MTM counseling could achieve alone. MedAssist began at Wagner Clinic Pharmacy, which serves patients from a consortium of 50 medical practitioners in the same building.

Subgroup findings include patients from the company’s three sites since program rollout: • Diabetes (n=21): baseline PDC adherence of 69% rose on average by 43% • Hypertension (n=45): baseline PDC adherence of 71% rose on average by 39% • Hyperlipidemia (n=40): baseline PDC adherence of 73% rose on average by 35% • CAD (n=16): baseline PDC adherence of 68% rose on average by 45% • CHF (n=12): baseline PDC adherence of 67% rose on average by 47% The clinical team at Wagner—led

by Dr. Nora Wright, vice president and clinical director of MedAssist— includes two other clinical pharmacists: Ashley Byrd, PharmD, and Aekta Vasavada, PharmD. Key components of MedAssist are the comprehensive medication reviews performed by board-certified pharmacists, Parata’s PASS multidrug adherence packaging and Ateb’s TimeMyMeds synchronization software. These elements work with QS/1 PrimeCare software, which the Wrights leveraged to create custom reports to aid in identifying patients as candidates for the program.

Participants see the three-pronged MedAssist program as an “empowering solution” that improves patient outcomes. “We are keeping patients out of nursing homes longer, improving adherence and preventing medication adverse events,” Dr. Nora Wright told Pharmacy Practice News.

Wagner Clinic Pharmacy has grown MedAssist to serve 125 patients overall, and has just a 4.6% attrition rate, according to Dr. Tim Wright. “We know the day is coming when our profession will have to show this type of efficacy and practice model,” he said. “It is unreasonable to think independent medical practitioners will effectively fulfill the care mission without effective pharmacist partners.”

To fulfill that mission, a change in mindset regarding discharge planning is needed, he added. The service “is typically a one-time event today,” he explained. A better approach would be for hospitals to “focus on transition of care and collaboration with field practitioners who can play a continuing role in

•

see PACKAGING, page 7

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LINEZOLID Injection 1 INDICATIONS AND USAGE Linezolid Injection is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Linezolid Injection is not indicated for the treatment of Gram-negative infections.

It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gramnegative pathogen is documented or suspected [see Warnings and Precautions (5.4)].

1.1 Pneumonia Nosocomial pneumonia caused by Staphylococcus aureuss (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [see Clinical Studies (14)].

Community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only) [see Clinical Studies (14)].

1.2 Skin and Skin Structure Infections Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureuss (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid Injection has not been studied in the treatment of decubitus ulcers [see Clinical Studies (14)].

Uncomplicated skin and skin structure infections caused by Staphylococcus aureuss (methicillinsusceptible isolates only) or Streptococcus pyogenes [see Clinical Studies (14)].

1.3 Vancomycin-resistant Enterococcus faecium m Infections Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia [see Clinical Studies (14)].

1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Linezolid Injection and other antibacterial drugs, Linezolid Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

The safety and efficacy of Linezolid Injection formulations given for longer than 28 days have not been evaluated in controlled clinical trials.

4.1 CONTRAINDICATIONS 4.1 Hypersensitivity Linezolid formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.

4.2 Monoamine Oxidase Inhibitors Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.

5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.

5.2 Peripheral and Optic Neuropathy Peripheral and optic neuropathies have been reported in patients treated with linezolid, primarily in those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with linezolid for less than 28 days. Peripheral and optic neuropathy has also been reported in children.

If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking linezolid for extended periods (≥ 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients should be weighed against the potential risks.

5.3 Serotonin Syndrome Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration

of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported.

Unless clinically appropriate and patients are carefully observed for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMSlike) reactions, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine, bupropion, or buspirone [see Drug Interactions (7)) and Clinical Pharmacology (12.3)]. ] In some cases, a patient already receiving a serotonergic antidepressant or buspirone may require urgent treatment with linezolid. If alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for two weeks (five weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Symptoms of serotonin syndrome or NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The patient should also be monitored for discontinuation symptoms of the antidepressant (see package insert of the specified agent(s) for a description of the associated discontinuation symptoms).

5.4 Mortality Imbalance in an Investigational Study in Patients with Catheter-Related Bloodstream Infections, including those with catheter-site infections An imbalance in mortality was seen in patients treated with linezolid relative to vancomycin/dicloxacillin/oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs. 58/363 (16%); odds ratio 1.426, 95% CI 0.970, 2.098]. While causality has not been established, this observed imbalance occurred primarily in linezolidtreated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only.

Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections.

Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Indications and Usage (1)].

5.5 Clostridium difficilee Associated Diarrhea Clostridium difficilee associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficilee produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficilee cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficilee may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.6 Potential Interactions Producing Elevation of Blood Pressure Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine) [see Drug Interactions (7)) and Clinical Pharmacology (12.3)].

5.7 Lactic Acidosis Lactic acidosis has been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving linezolid should receive immediate medical evaluation.

5.8 Convulsions Convulsions have been reported in patients when treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.

5.9 Hypoglycemia Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus

receiving insulin or oral hypoglycemic agents when treated with linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents.

While a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be cautioned of potential hypoglycemic reactions when treated with linezolid.

If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required.

5.10 Development of Drug-Resistant Bacteria Prescribing linezolid in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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.

Adults: The safety of linezolid formulations was evaluated in 2046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days.

Of the patients treated for uncomplicated skin and skin structure infections (uSSSIs), 25.4% of linezolid-treated and 19.6% of comparator-treated patients experienced at least one drug-related adverse event. For all other indications, 20.4% of linezolidtreated and 14.3% of comparator-treated patients experienced at least one drug-related adverse event.

Table 2 shows the incidence of all-causality, treatmentemergent adverse reactions reported in at least 1% of adult patients in these trials by dose of linezolid.

Table 2. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in >1% of Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials ADVERSE Uncomplicated Skin and All Other Indications REACTIONS Skin Structure Infections Linezolid Clarithromycin Linezolid All Other 250 mg by 400 mg 600 mg Comparatorsa by mouth mouth every every (n=1464) 12 hours every 12 hours (n=537) 12 hours (n=1498) (n=548) Headache 8.8 8.4 5.7 4.4 Diarrhea 8.2 6.1 8.3 6.4 Nausea 5.1 4.5 6.6 4.6 Vomiting 2 1.5 4.3 2.3 Dizziness 2.6 3 1.8 1.5 Rash 1.1 1.1 2.3 2.6 Anemia 0.4 0 2.1 1.4 Taste 1.8 2 1 0.3 alteration Vaginal 1.8 1.3 1.1 0.5 moniliasis Oral 0.5 0 1.7 1 moniliasis 0.4 0.2 1.6 0.8 Abnormal liver function tests Fungal 1.5 0.2 0.3 0.2 infection Tongue 1.3 0 0.3 0 discoloration 1.3 0.6 1.2 0.8 Localized abdominal pain 0.9 0.4 1.2 1 Generalized abdominal pain a

Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours.

Of the patients treated for uSSSIs, 3.5% of linezolidtreated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 2.1% of linezolid-treated and 1.7% of comparator-treated patients. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting.

Pediatric Patients: The safety of linezolid formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 3 comparatorcontrolled clinical trials and were treated for up to 28 days. In the study of hospitalized pediatric patients (birth through 11 years) with Gram-positive infections, who were randomized 2 to 1 (linezolid: vancomycin), mortality was 6% (13/215) in the linezolid arm and 3% (3/101) in the vancomycin arm.

However, given the severe underlying illness in the patient population, no causality could be established.

Of the pediatric patients treated for uSSSIs, 19.2% of linezolid-treated and 14.1% of comparator-treated

patients experienced at least one drug-related adverse event. For all other indications, 18.8% of linezolid-treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event.

Table 3 shows the incidence of all-causality, treatment-emergent adverse reactions reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled Phase 3 trials.

Table 3. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in > 1% of Pediatric Patients (and >1 Patient) in Either Treatment Group in Comparator-Controlled Clinical Trials Uncomplicated Skin All Other Indicationsb and Skin Structure ADVERSE Infectionsa REACTIONS Linezolid Cefadroxil Linezolid Vancomycin (n=248) (n=251) (n=215) (n=101) Diarrhea 7.8 8 10.8 12.1 Vomiting 2.9 6.4 9.4 9.1 Headache 6.5 4 0.9 0 Anemia 0 0 5.6 7.1 Thrombocytopenia 0 0 4.7 2 Nausea 3.7 3.2 1.9 0 Generalized 2.4 2.8 0.9 2 abdominal pain Localized 2.4 2.8 0.5 1 abdominal pain Loose stools 1.6 0.8 2.3 3 Eosinophilia 0.4 0.8 1.9 1 Pruritus at non0.8 0.4 1.4 2 application site Vertigo 1.2 0.4 0 0 a

Patients 5 through 11 years of age received linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours.

Patients 12 years or older received linezolid 600 mg by mouth every 12 hours or cefadroxil 500 mg by mouth every 12 hours. b Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance.

Of the pediatric patients treated for uSSSIs, 1.6% of linezolid-treated and 2.4% of comparator-treated patients discontinued treatment due to drugrelated adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 0.9% of linezolid-treated and 6.1% of comparator-treated patients.

Laboratoryy Abnormalities: Linezolid has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hours for up to 28 days. In Phase 3 comparatorcontrolled trials, the percentage of adult patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3 to 10%) with linezolid and 1.5% (range among studies: 0.4 to 7%) with a comparator. In a study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with linezolid and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with linezolid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of linezolid appears to be dependent on duration of therapy (generally greater than 2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in Phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for linezolid; the role of linezolid in these events cannot be determined [see Warning and Precautions (5.1)].

Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between linezolid and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 4, 5, 6, and 7.

Table 4. Percent of Adult Patients who Experienced at Least One Substantially Abnormala Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Uncomplicated Skin and All Other Indications Skin Structure Infections Laboratory Linezolid Clarithromycin Linezolid All Other Assay 400 mg 250 mg every 600 mg Comparatorsb every 12 hours every 12 hours 12 hours Hemoglobin 0.9 0 7.1 6.6 (g/dL) Platelet 0.7 0.8 3 1.8 count 3 3 (× 10 /mm ) WBC 0.2 0.6 2.2 1.3 (× 103/mm3) Neutrophils 0 0.2 1.1 1.2 (× 103/mm3)

Technology 7 a

b

<75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; <75% (<50% for neutrophils) of LLN and of baseline for values abnormal at baseline.

Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours.

Table 5. Percent of Adult Patients who Experienced at Least One Substantially Abnormala Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Uncomplicated Skin and All Other Indications Skin Structure Infections Laboratory Linezolid Clarithromycin Linezolid All Other Assay 400 mg 250 mg every 600 mg Comparatorsb every 12 hours every 12 hours 12 hours AST (U/L) 1.7 1.3 5 6.8 ALT (U/L) 1.7 1.7 9.6 9.3 LDH (U/L) 0.2 0.2 1.8 1.5 Alkaline 0.2 0.2 3.5 3.1 phosphatase (U/L) Lipase (U/L) 2.8 2.6 4.3 4.2 Amylase 0.2 0.2 2.4 2 (U/L) 0.2 0 0.9 1.1 Total bilirubin (mg/dL) BUN 0.2 0 2.1 1.5 (mg/dL) Creatinine 0.2 0 0.2 0.6 (mg/dL) a

b

>2 × Upper Limit of Normal (ULN) for values normal at baseline; >2 × ULN and >2 × baseline for values abnormal at baseline.

Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours.

Table 6. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormala Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Uncomplicated Skin All Other Indicationsc and Skin Structure Laboratory Infectionsb Assay Linezolid Cefadroxil Linezolid Vancomycin Hemoglobin 0 0 15.7 12.4 (g/dL) Platelet count 0 0.4 12.9 13.4 (× 103/mm3) 0.8 0.8 12.4 10.3 WBC (× 103/mm3) Neutrophils 1.2 0.8 5.9 4.3 (× 103/mm3) a

b

c

<75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; <75% (<50% for neutrophils) of LLN and <75% (<50% for neutrophils, <90% for hemoglobin if baseline <LLN) of baseline for values abnormal at baseline.

Patients 5 through 11 years of age received linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours.

Patients 12 years or older received linezolid 600 mg by mouth every 12 hours or cefadroxil 500 mg by mouth every 12 hours.

Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance.

Table 7. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormala Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Uncomplicated Skin and All Other Indicationsc Laboratory Skin Structure Infectionsb Assay Linezolid Cefadroxil Linezolid Vancomycin ALT (U/L) 0 0 10.1 12.5 Lipase (U/L) 0.4 1.2 ----Amylase ----0.6 1.3 (U/L) ----6.3 5.2 Total bilirubin (mg/dL) Creatinine 0.4 0 2.4 1 (mg/dL) a

>2 × Upper Limit of Normal (ULN) for values normal at baseline; >2 × ULN and >2 (>1.5 for total bilirubin) × baseline for values abnormal at baseline. b Patients 5 through 11 years of age received linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours. Patients 12 years or older received linezolid 600 mg mouth every 12 hours or cefadroxil 500 mg by mouth every 12 hours. c Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously/by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of linezolid. 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.

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been

reported during postmarketing use of linezolid [see Warnings and Precautions (5.1)]. ] Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with linezolid [see Warnings and Precautions (5.2)]. Lactic acidosis has been reported with the use of linezolid [see Warnings and Precautions (5.7)]. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy. Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and linezolid [see Warnings and Precautions (5.3)]. Convulsions have been reported with the use of linezolid [see Warnings and Precautions (5.8)]. ] Anaphylaxis, angioedema, and bullous skin disorders such as those described as Stevens-Johnson syndrome have been reported.

Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome. Hypoglycemia, including symptomatic episodes, has been reported [see Warnings and Precautions (5.9)].

7 DRUG INTERACTIONS 7.1 Monoamine Oxidase Inhibitors Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. [see Contraindications (4.2)) and Clinical Pharmacology (12.3)].

7.2 Adrenergic and Serotonergic Agents Linezolid has the potential for interaction with adrenergic and serotonergic agents. [see Warnings and Precautions (5.3, 5.6) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects Pregnancy g y Category g yC Linezolid was not teratogenic in mice, rats, or rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.06-fold (in rabbits) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen (see Non-teratogenic Effectss ). There are no adequate and well-controlled studies in pregnant women.

Linezolid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-teratogenic g Effects In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). A dose of 450 mg/kg/day (6.5-fold the estimated human exposure level based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion.

In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights.

Slight maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day.

In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at a dose of 15 mg/kg/day (0.06-fold the estimated human exposure based on AUCs).

When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation, survival of pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.

8.3 Nursing Mothers Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when linezolid is administered to a nursing woman.

8.4 Pediatric Use The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years [see Indications and Usage (1), Clinical Pharmacology (12.3) and Clinical Studies (14)]: • nosocomial pneumonia • complicated skin and skin structure infections • community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years) • vancomycin-resistant Enterococcus faecium infections

The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infection have been established in a comparatorcontrolled study in pediatric patients ranging in age from 5 through 17 years [see Clinical Studies (14)]: • uncomplicated skin and skin structure infections caused by Staphylococcus aureuss (methicillinsusceptible strains only) or Streptococcus pyogenes Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.

The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients.

However, in preterm (gestational age < 34 weeks) neonates < 7 days of age, linezolid clearance is often lower than in full-term neonates < 7 days of age.

Consequently, preterm neonates < 7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. ] In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with linezolid had clinical cures.

However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response [see Clinical Pharmacology (12.3)) and Dosage and Administration (2)]. ] 8.5 Geriatric Use Of the 2046 patients treated with linezolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Manufactured In Hungary By: Teva Pharmaceutical Works Ltd. Hungary H-2100 Gödöllö Táncsics M. út 82 Hungary Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. A 1/2014

Drug Handling

PACKAGING continued from page 4

patient care post-discharge, because that is when medication nonadherence will land patients right back in the hospital.”

To take data further, the Wrights want to assess the affects of MedAssist on the health outcomes of at-risk patients, such as those with medication adherence rates below 60%. They want to determine the economic burden of rehospitalizations for specific subpopulations, such as nonadherent patients with diabetes, and assess the program’s ability to reduce hospitalizations to quantify the program’s dollar effect. “This is the language payors speak,” Dr. Tim Wright said. “Our aim is to lower their beneficiaries’ risk for rehospitalizations for certain diseases.”

—Al Heller The sources reported no relevant financial conflicts of interest.

Your Letters

Benefits of Robotics Seen in Outpatient Pharmacies As Well Re: “$1 Million Reasons To Invest In Robots” (January 2015, page 1).

This article, which focused on robotic dispensing in inpatient pharmacies, was spot-on. It covered all the right reasons why fully automated dispensing brings a positive return on investment (ROI), the most important being improved patient safety, efficient distribution of pharmacy staff and yes, hard-number cost savings.

I’d also like to point out that those same compelling ROI factors (safety, staffing, cost savings and error prevention) are just as important and measurable in outpatient/ambulatory pharmacies. Latest estimates show that almost one-third of U.S. health systems are operating or planning to open an outpatient pharmacy. Unfortunately, funding automation for the outpatient pharmacy can, in my experience, take a back seat to inpatient needs. As the trend continues upward for outpatient pharmacy, the need for safety and efficiency also rises there, as well. So yes, there are $1 million reasons to invest in dispensing technology when you are filling prescriptions for discharged patients, ambulatory care patients and your health system’s employees.

Mike Stotz Senior Marketing Manager Kirby Lester, LLC Lake Forest, Ill.

8 Operations & Management

Pharmacy Practice News • February 2015

Finance 9000 8000

continued from page 1

meeting by Sarah White, PharmD, RPh, and Deborah Sanchez, PharmD, BCPS, both membesr of the pharmacy management team at Asante Rogue Regional Medical Center in Medford, Oregon. Dr. White is a co-faculty associate professor at Pacific University in Forest Grove, and Dr. Sanchez is the residency director.

Dr. White said her team was motivated to design a mechanism for getting reimbursed for the same types of MTM services that are offered in a community setting, “where they do qualify for MTM charges,” she said. Those services included patient education, dosage recommendations and changes and laboratory test result assessments.

The Asante model uses Centers for Medicare & Medicaid (CMS) Evaluate and Manage (E/M) codes 99211-99215, Dr. Sanchez noted. These codes stipulate that a pharmacist must provide an order or have a protocol in place for each MTM consultation, and they must conduct a face-to-face visit. The specific code used can vary based on the complexity of care provided, she pointed out (Table).

For private insurers, the process is somewhat different: for both inpatient and outpatient MTM care, the hospital uses Revenue Code 940, which captures “other therapeutic services.”

Additionally, as per Oregon Board of Pharmacy requirements, each consultation is documented and traceable. At Asante that is done in the electronic medical record progress notes.

Targeting the Right Patients The MTM billing process at Asante was first implemented for patients needing pharmacokinetic dosing, falls consults or renal dosing, Dr. White noted, and the initial success with those patients led to the program’s expansion to automatic consults for patients on vancomycin, aminoglycosides, warfarin and parenteral nutri-

7000 6000 5000 4000 3000 2000 1000 0 2009

2010

2

2012

2013

2014

MTM, medication therapy management

A Transformation Implementation of the MTM program transformed how pharmacists conducted their daily practice at Asante, its developers noted. For example, pharmacists began visiting their patients and documenting their clinical services daily. “This change, like any major change, was stressful at first,” Dr. White said. “Over time the process has become well integrated into daily practice.”

Dr. Sanchez added another valuable lesson learned: the need to bill CMS for MTM inpatient clinical services even though those services won’t be paid for.

“Bill for it anyway,” she stressed, “because all claims are taken into consideration when CMS sets its base rates for DRGs paid to hospitals.”

Another useful tip, she noted, is to remember that pharmacists can bill for one MTM consultation a day for as long as the patient is receiving the specific treatment the provider has asked them to manage.

Not Only About Revenue But the MTM initiative isn’t focused solely on revenue, Dr. White noted. “I suspect our services also are improving HCAHPS [Hospital Consumer Assessment of Healthcare Providers and Systems] scores, because there is now an added layer of patient–pharmacist inter-

1.8 1.6 1.4 1.2 1.0 8 6 4 2 0 2009

2010

2011

2012

2013

2014

Figure 2. Annual MTM billing.

MTM, medication therapy management

action,” she said. “And we have a greater presence on the care team because we write full-page SOAP notes,” she said, adding that the medical center is continually evolving and expanding the MTM program. (SOAP is an acronym for subjective, objective, assessment, and plan.)

Dr. White did not have data on clinical outcomes related to MTM, but said there are indications the added consultations have been beneficial. “For example, for calendar year 2014, we only had

Table. A Complexity-Based Approach to MTM Reimbursement MTM Level

2011

Figure 1. Number of MTMs billed annually.

Millions, $

MTM MILLIONS

tion. “The program has even grown to encompass antimicrobial stewardship, a critical care collaborative agreement and multiple educational protocols,” she said.

A total of 4,236 MTM consultations were billed for in 2009, translating to roughly $224,000 in added claims. By 2013, the number of billable MTM consultations rose to 8,090, with related charges rising to $1.6 million (Figures 1 and 2). About $250,000 of the $1.6 million in claims has been paid by CMS and private insurers, Dr. Sanchez reported. The percentage of successful claims is highest from the privates—about 80% of those claims resulted in payments, she said.

Reimbursement Codes

Description

Example

Simple assessment; presenting problems are minimal

• Simple falls consult • Medication reviews or reconciliations

99211

Low complexity; presenting problems are of low or moderate severity

• Brief assessment • Renal evaluation • IV to oral conversion

99212

3

Moderate complexity; presenting problems are of moderate severity

• Kinetic, warfarin or oral monitoring • TPN follow-up • Patient education

99213

4

High complexity; presenting problems are high severity

• New starts on warfarin, kinetics or TPN • High-complexity pharmacotherapy consult

99214

5

Very complex; multiple high-severity problems

• Multiple critical issues • Typically not billable due to need for a head-to-toe physical, per CMS guidelines

99215

CMS, Cente Centers ers for Medicare & Medicaid Services; MTM, medication therapy management; mana agement; TPN, total parenteral nutrition

four patients receiving warfarin management by pharmacists in the entire hospital who had an INR [international normalized ratio] greater than 6.” Those INR results, she noted, “suggest a high level of care provided by pharmacists in managing patients on warfarin.”

Dr. Trenkler believes the program demonstrates how inpatient MTM services can be billed using a “stepwise approach, including evaluation of state and federal regulations, determination of patient severities and, finally, through collaboration with the finance department to formulate a charging scheme.”

—David Wild Drs. White, Sanchez and Trenkler reported no relevant financial conflicts of interest.

More on Reimbursement This month, Bonnie Kirschenbaum’s Reimbursement Matters column is an on-line exclusive! To access her latest tips for navigating new payment rules from CMS, scan the adjacent 2D barcode or load pharmacypracticenews.com/ FebPayment into your browser.

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10 Operations & Management

Pharmacy Practice News • February 2015

Ambulatory Pharmacy

PCMH Pharmacists Bring Home Value of Their Interventions Austin, Texas—Many hospitals appreciate the value of involving the pharmacist in the clinical care of patients to reduce medication errors, boost adherence and reduce 30-day readmissions.

Now, facilities are looking at whether the same strategy could work in the ambulatory care setting.

There are many advantages in having medication management performed by a pharmacist post-discharge, such as

in the patient-centered medical home (PCMH), Tamara S. Lallier, PharmD, MBA, told Pharmacy Practice News.

“Pharmacists are more adept at identifying problematic medication combinations and inappropriate doses for specific patients, so I think this is an area with great potential,” said Dr. Lallier, who was completing her postgraduate year 1 residency at Northeast Iowa Medical Education Foundation/

Waverly Health Center, in Waterloo, at the time of the study.

In a study (abstract 249) presented at the 2014 annual meeting of the American College of Clinical Pharmacy (ACCP), Dr. Lallier, who is now the director of pharmacy at Adair County Hospital in Greenfield, Iowa, and her colleagues reviewed the electronic medical records (EMRs) of 3,394 patients in a PCMH and found 752

medication issues. They made recommendations to rectify the problems and then looked at the acceptance of the recommendations by the prescriber.

Each week, the pharmacists and pharmacy students reviewed the EMR of patients scheduled to visit the Waverly Health Center to identify medication-related problems and record pharmacy recommendations in the EMR and on the patient’s pre-visit “huddle sheet.” The huddle sheet contained specific information about the patient that was reviewed by the nurse, physician and pharmacist on the day of the patient encounter.

Dr. Lallier’s project was a continuation of a study by Megan Mormann, PharmD, who had reviewed 60% of the patient records. In the five months that Dr. Lallier worked on the project, she was able to review nearly half of the patient charts before the patient visit.

Physicians reported that the recommendations were helpful, but the acceptance rate was modest (47.7%), according to Dr. Lallier, who said the lower acceptance rate might be due to the fact that the recommendations were made after a chart review, rather than face-to-face interviews with patients, and then were put into the EMR and on the huddle sheet.

The most common reason for the physician not following the recommendation was that the physician “did not see the recommendation [24%].”

When email reminders were distributed to physicians, the acceptance rate improved, she said.

Dr. Lallier said the study resulted in two changes in the process: making the recommendations on the huddle sheet more pronounced by bolding them, and focusing chart reviews on patients who were seeing the physician that day for routine physician, health maintenance or chronic disease follow-up, instead of an acute condition.

As they reviewed the charts, the investigators also were able to identify a subset of higher-risk patients—those taking six or more medications or who had a diagnosis of heart failure or diabetes—and schedule time to talk with them about their medication and disease management. “The face-to-face encounters allow for the pharmacists to gain additional perspective from the patient regarding how they are taking their medication and their preferences,” Dr. Lallier said, adding that the encounters also provided “an opportunity to verbally communicate newly identified drug therapy recommendations to the physician as they enter the exam room.”

A prospective review of the records is key, according to Brigid K. Long,

Operations & Management 11

Pharmacy Practice News • February 2015

Ambulatory Pharmacy PharmD, MS, a pharmacist care coordinator in transitions of care at Dublin Patient Care Center-Kroger Pharmacy, in Dublin, Ohio, who was not involved in the study. “When a pharmacist performs a prospective drug review and assesses for the drug-related problem prospectively, it maximizes the providers’ time with the patient because recommendations will be in place prior to the patient’s visit,” she said.

A Phone Call Away In the second PCMH-focused study presented at the meeting, Amanda Wojtusik, PharmD, PCPS, in the Department of Medical Education, University of Pittsburgh Medical Center (UPMC) St. Margaret, evaluated the effect of a post-discharge telephone intervention made by a pharmacist within a PCMH on hospital readmissions, outpatient follow-up, emergency department (ED) use and medication discrepancies (abstract 248E).

“Our aim was to reach [patients] within four days of discharge from the hospital,” Dr. Wojtusik said. “First and foremost, we want to make sure that they are doing OK after being home.

Second, we want to reconcile their medicines and make sure there were not any errors, check their adherence, make sure they did not have any questions, check to see what medicines had changed, update their medication lists and then make sure they got into their doctor’s office to see their primary care doctor for follow-up.”

The researchers included all the adults discharged from the hospital inpatient family medicine service between July 2013 and January 2014. They identified 316 patients and called 289. Of those, they spoke to 183 (58%). Forty-three patients were readmitted to the hospital within 30 days of discharge. Of those, the pharmacists spoke with 25 (13.7%) and failed to reach 18 (13.5%).

Forty-six patients went to the ED at least once. Of those, the pharmacists spoke with 24 (13.1%) and did not speak with 22 (16.5%).

The post-discharge care team had more success with primary care followup. Of the patients that they spoke with, 96 (52.5%) saw their primary care doctor within seven days, and 44 (33.1%) who did not speak with a pharmacist saw their primary care doctor.

“In my experience, patients have many questions after discharge,” Dr. Long said. “Having pharmacists perform telephonic transition of care follow-up calls is an effective method of ensuring patients have their questions answered and assessing for drug-related problems or changing conditions prior to them becoming a significant issue.”

The patients were not the only ones to benefit from pharmacy involvement,

according to Dr. Wojtusik. “I was able to facilitate a nice warm handoff to the physician in the office because I had talked to them on the phone and knew what medications had changed, so I was able to follow up in the office when they came to see their primary care doctor,” she said.

Early Interventions Transitions of care can be difficult at discharge because patients are not always receptive; they just want to go home, she said. In addition, they haven’t experienced the medication

regimen changes, so they don’t know if there are problems, such as not being able to afford their medications. “What we do is different because we initiate this from the outpatient setting,” Dr. Wojtusik said. As a result, all of the pharmacist’s interventions are documented in the same EMR as the primary care doctor. If a correction needs to be made, she explained, the pharmacist and the physician have a common basis for collaboration and can make the correction immediately.

In Dr. Long’s view, the proactive

nature of the ambulatory clinic–based approach was a key factor in the program’s success. Such pharmacists, she noted, “have the opportunity to perform medication reviews by collecting patient-specific information, assessing and identifying medications for drugrelated problems, prioritizing these problems and then creating a plan to solve these [issues].”

—Marie Rosenthal The sources reported no relevant financial conflicts of interest.

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12 Operations & Management

Pharmacy Practice News • February 2015

Supply Chain Cases nearly eliminated after 70% boost in audit follow-up

Worksheet Thwarts Drug Diversion Anaheim, Calif.—In November 2013, a health care worker was caught redhanded at her hospital self-injecting hydromorphone that was intended for a patient. That same caregiver, just two months earlier, had been red-flagged during an audit for an unusually high number of withdrawals of the drug from the institution’s automated dispensing

cabinets (ADCs). Her manager, however, never completed the audit.

Despite increasingly widespread use of ADCs, and coupled software that mines data from ADCs, diversions continue to threaten the lives of patients and health care workers (HCWs)—in addition to hospital bottom lines.

“Drug diversions are a common prob-

lem for every hospital, every pharmacy department, every nursing department,” said Allison Cannon, PharmD, MS, a manager of controlled drugs and surgical services with the Cleveland Clinic pharmacy in Ohio. “It’s just a matter of how hard you’re looking for them.”

The Cleveland Clinic is among several centers with new programs that bolster

GLYDO (lidocaine HCl jelly USP, 2%) Brief Summary of Prescribing Information

INDICATIONS AND USAGE GLYDO (lidocaine HCl jelly USP, 2%) is indicated for prevention and control of pain in procedures involving the male and female urethra, for topical treatment of painful urethritis, and as an anesthetic lubricant for endotracheal intubation (oral and nasal).

CONTRAINDICATIONS Lidocaine is contraindicated in patients with a known history off hypersensitivity to local anesthetics of the amide type or to other components of GLYDO. WARNINGS EXCESSIVE DOSAGE, OR SHORT INTERVALS BETWEEN DOSES, CAN RESULT IN HIGH PLASMA LEVELS AND SERIOUS ADVERSE EFFECTS. PATIENTS SHOULD BE INSTRUCTED TO STRICTLY ADHERE TO THE RECOMMENDED DOSAGE AND ADMINISTRATION GUIDELINES AS SET FORTH IN THIS PACKAGE INSERT. THE MANAGEMENT OF SERIOUS ADVERSE REACTIONS MAY REQUIRE THE USE OF RESUSCITATIVE EQUIPMENT, OXYGEN, AND OTHER RESUSCITATIVE DRUGS. GLYDO should be used with extreme caution in the presence of sepsis or severely traumatized mucosa in the area of application, since under such conditions there is the potential for rapid systemic absorption.

When used for endotracheal tube lubrication care should be taken to avoid introducing the product into the lumen of the tube.

Do not use the jelly to lubricate the endotracheal stylettes. If allowed into the inner lumen, the jelly may dry on the inner surface leaving a residue which tends to clump with flexion, narrowing the lumen. There have been rare reports in which this residue has caused the lumen to occlude. (See also ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.) PRECAUTIONS General The safety and effectiveness of lidocaine depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. (See WARNINGS and ADVERSE REACTIONS.) The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Repeated doses of lidocaine may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical status. Lidocaine should also be used with caution in patients with severe shock or heart block.

GLYDO should be used with caution in patients with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine.

Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using).

Information for Patients When topical anesthetics are used in the mouth, the patient should be aware that the production of topical anesthesia may impair swallowing and thus enhance the danger of aspiration. For this reason, food should not be ingested for 60 minutes following use of local anesthetic preparations in the mouth or throat area. This is particularly important in children because of their frequency of eating.

Numbness of the tongue or buccal mucosa may enhance the danger of unintentional biting trauma. Food and chewing gum should not be taken while the mouth or throat area is anesthetized.

Carcinogenesiss—Long-term studies in animals have not been performed to evaluate the carcinogenic potential of lidocaine.

Mutagenesiss—The mutagenic potential of lidocaine has been tested in the Ames Salmonella reverse mutation assay, an in vitro chromosome aberrations assay in human lymphocytes and in an in vivo mouse micronucleus assay. There was no indication of any mutagenic effect in these studies.

Impairment of Fertility: The effect of lidocaine on fertility was examined in the rat model.

Administration of 30 mg/kg, s.c. (180 mg/m2) to the mating pair did not produce alterations in fertility or general reproductive performance of rats. There are no studies that examine the effect of lidocaine on sperm parameters. There was no evidence of altered fertility.

Use in Pregnancy Teratogenic Effects: Pregnancy Category B Reproduction studies for lidocaine have been performed in both rats and rabbits. There was no evidence of harm to the fetus at subcutaneous doses of up to 50 mg/kg lidocaine (300 mg/m2 on a body surface area basis) in the rat model. In the rabbit model, there was no evidence of harm to the fetus at a dose of 5 mg/kg, s.c. (60 mg/m2 on a body surface area basis). Treatment of rabbits with 25 mg/kg (300 mg/m2) produced evidence of maternal toxicity and evidence of delayed fetal development, including a non-significant decrease in fetal weight (7%) and an increase in minor skeletal anomalies (skull and sternebral defect, reduced ossification of the phalanges). The effect of lidocaine on post-natal development was examined in rats by treating pregnant female rats daily subcutaneously at doses of 2, 10, and 50 mg/kg (12, 60, and 300 mg/m2) from day 15 of pregnancy and up to 20 days post partum. No signs of adverse effects were seen either in dams or in the pups up to and including the dose of 10 mg/ kg (60 mg/m2); however, the number of surviving pups was reduced at 50 mg/kg (300 mg/m2), both at birth and the duration of lactation period, the effect most likely being secondary to maternal toxicity. No other effects on litter size, litter weight, abnormalities in the pups and physical developments of the pups were seen in this study.

A second study examined the effects of lidocaine on post-natal development in the rat that included assessment of the pups from weaning to sexual maturity.

Rats were treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine (60 mg/m2 and 180 mg/m2 on a body surface area basis, respectively). This time period encompassed 3 mating periods. There was no evidence of altered post-natal development in any offspring; however, both doses of lidocaine significantly reduced the average number of pups per litter surviving until weaning of offspring from the first 2 mating periods.

There are, however, no adequate and well-controlled studies in pregnant women. 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 Lidocaine is not contraindicated in labor and delivery. Should GLYDO be used concomitantly with other products containing lidocaine, the total dose contributed by all formulations must be kept in mind.

Nursing Mothers Lidocaine is secreted in human milk. The clinical significance of this observation is unknown. Caution should be exercised when lidocaine is administered to a nursing woman.

Pediatric Use Although, the safety and effectiveness of GLYDO in pediatric patients have not been established, a study of 19 premature neonates (gestational age <33 weeks) found no correlation between the plasma concentration of lidocaine or monoethylglycinexylidide and infant body weight when moderate amounts of lidocaine (i.e. 0.3 mL/kg of lidocaine gel 20 mg/ mL) were used for lubricating both intranasal and endotracheal tubes. No neonate had plasma levels of lidocaine above 750 mcg/L. Dosages in children should be reduced, commensurate with age, body weight, and physical condition. (See DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS Adverse experiences following the administration of lidocaine are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage or rapid absorption, or may result from a hypersensitivity, idiosyncrasy, or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported: There have been rare reports of endotracheal tube occlusion associated with the presence of dried jelly residue in the inner lumen of the tube. (See also WARNINGS and DOSAGE AND ADMINISTRATION.) Central Nervous System CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression, and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest.

Drowsiness following the administration of lidocaine is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption.

Cardiovascular System Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest.

Allergic Allergic reactions are characterized by cutaneous lesions, urticaria, edema, or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to the local anesthetic agent or to other components in the formulation. Allergic reactions as a result of sensitivity to lidocaine are extremely rare and, if they occur, should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value.

OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.) Management of Local Anesthetic Emergencies The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic administration. At the first sign of change, oxygen should be administered.

The first step in the management of convulsions consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (e.g., ephedrine).

If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted.

Dialysis is of negligible value in the treatment of acute overdosage with lidocaine.

The oral LD50 of lidocaine HCl in non-fasted female rats is 459 (346 to 773) mg/kg (as the salt) and 214 (159 to 324) mg/kg (as the salt) in fasted female rats.

Mfd. for SAGENT Pharmaceuticals Schaumburg, IL 60195 (USA) Mfd. by Klosterfrau Berlin GmbH Made in Germany ©2014 Sagent Pharmaceuticals, Inc. March 2014 You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

Please see full prescribing information for GLYDO (lidocaine HCl jelly USP, 2%).

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the ability of these technologies to ensure drugs make the full journey from pharmacy to patient. In other words, they help hospitals look harder for the problem.

Dr. Cannon presented her hospital’s new reconciliation template during the American Society of Health-System Pharmacists (ASHP) 2014 Midyear Clinical Meeting. The worksheet, which includes suggested questions for managers to consider when reconciling ADC transactions, has combined with other interdisciplinary efforts to increase manager response rates to suspicious activity raised by audits from 30% to nearly 100%.

Dispensing cabinets and software from companies such as Omnicell and Pyxis/CareFusion provide a “decent starting point,” she said, but not a “magic bullet” in deterring diversions of controlled substances, high-cost biologics and other drugs.

“These are great tools,” added John Burke, the commander of the Warren County Ohio Drug Task Force. “But they can only do so much. People who want these drugs will find ways to get them.”

Cmdr. Burke commended Cleveland Clinic’s efforts to make the data “meaningful, so that you can zero in on suspicious behavior.”

Getting a handle on the actual frequency of diversions remains difficult.

The Drug Enforcement Administration, the National Association of Boards of Pharmacy, the ASHP and a 2012 peerreviewed report ((Mayo Clin Proc 2012; 87[7]:674-682) concerning drug diversions from health care facilities all conceded a lack of hard statistics. Rates of prescription drug abuse in the general population hover around 5%, according to a national survey by the Substance Abuse and Mental Health Services Administration. But Cmdr. Burke and other experts suggest the figure is likely higher for health care providers, simply due to convenient access to the drugs.

What’s more, they say the problem is still growing—with tragic consequences for patient safety. HCWs diverting patient pain medications for their own use, according to a report published in July, have been linked to six infectious disease outbreaks over the past decade ((Mayo Clin Proc 2014;89[7]:878-887).

“There’s a staggering amount of this going on,” Cmdr. Burke said. “It’s so scary just how much it is overlooked and brushed under the table.”

He highlighted what he sees as a dangerously common response: The perpetrating drug diverter on staff is fired. “That

Operations & Management 13

Pharmacy Practice News • February 2015

Supply Chain does no good for the addicted nurse” or other implicated staffer, Cmdr. Burke said. “They just go on to the next facility, rather than to rehab. That also puts more patients in danger.”

Fortunately, in the hydromorphonediverting case, the caregiver was sent for treatment.

Still, catching cases early is far preferable. Dr. Cannon and her colleagues came to recognize their institution’s shortcomings: Cleveland Clinic managers followed up on only 30% of the 20 caregivers red-flagged for an audit each month, and they left most of those responses incomplete. So, Dr. Cannon and her team convened a group—nursing leadership, along with representatives of the employee assistance program, human resources, protective services and legal affairs—to address the roadblocks faced by auditors, such as a lack of clarity on how caregivers are selected for an audit and uncertainty over what questions to ask when reconciling the flagged activity.

‘There’s a staggering amount of [drug diversion] going on. It’s so scary just how much it is overlooked and brushed under the table.’

—Cmdr. John Burke The group would go on to launch new education programs, create a diversionresponse task force and revise the format in which controlled drug activity was sent to Cleveland Clinic managers for audit. The latter included the reconciliation template for auditors, with questions assessing the timeliness of the drug’s administration, documentations of waste and pain assessments or other clinical indicators of a patient’s appropriate response to the medication.

Shortly after the February 2014 template rollout, manager response rates across the campus rose to 40%. The addition of the task force and the support of nursing and anesthesia leadership further increased that rate to nearly 100%, Dr.

Cannon reported. Compared with just one diversion case identified through controlled drug activity audits between August 2013 and January 2014, eight were caught from February 2014 to July 2014.

“We aim to continue improving, with a focus now on prevention and early detection,” Dr. Cannon said.

Behavioral signs such as frequent bathroom breaks should be heeded and seen as red flags for diversion, she noted.

Another prevention strategy, in use at Cleveland Clinic, is to place stickers on every ADC, providing a contact number

for confidential reporting and a couple of questions: “Concerned about drug misuse?” “Are you or someone you know diverting drugs for personal use?”

Kim New, RN, a drug diversion consultant and educator based in Knoxville, Tenn., underscored the importance of including education, analytics and behavior in any diversion program. She added that it also requires constant vigilance to keep the issue “front and center.”

“Everyone is excited when a program is implemented,” she said. “But then people get distracted.”

The high-profile diversion cases over the past decade, added Ms. New, may have “never been picked up by looking at drug cabinet data alone.”

Cmdr. Burke pointed to what he sees as a dangerously common attitude: “It won’t happen to us. Well, it can happen to you,” he said. “And when it does, it can be devastating, both financially and otherwise.”

—Lynne Peeples Dr. Cannon and Cmdr. Burke reported no relevant conflicts of interest. Ms. New reported occasional consulting for Omnicell.

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14 Clinical

Pharmacy Practice News • February 2015

Critical Care

CODE SEPSIS continued from page 1

Forest Baptist Health in Winston-Salem, N.C., found that their sepsis mortality rates fell roughly in the 75th percentile of hospitals in the University Health Consortium (UHC), explained James Beardsley, PharmD, who is clinical manager at Wake Forest. “At the time, we had an Early Warning Score screening tool and a Sepsis Order Set in place, but our outcomes were still unfavorable,” Dr. Beardsley explained.

The Code Sepsis protocol follows the same systematic and structured approach used in other code responses and has improved the accuracy and speed of septic patient identification; the efficacy and clarity of communication between providers; and the speed of antibiotic administration, he said.

Dr. Beardsley said the code is initiated once a patient screens positive for possible sepsis. The positive screen triggers a Code Sepsis digital page to all team members, who begin executing a defined set of responsibilities in an ordered sequence. In the case of pharmacists, the focus is on improving three phases of the sepsis management process, Dr. Beardsley noted.

“The first stage begins when the pharmacist receiving the Code Sepsis page lets the rest of the inpatient pharmacy know to prioritize antibiotic orders for the specific Code Sepsis patient, even if the antibiotics are not ordered STAT,” he said.

Pharmacists are also more proactive now in determining whether a prescriber needs an antibiotic order, he added. “Before the project was implemented, we noticed physicians some-

Some members of the Code Sepsis team (L-R): Teresa Jackson, RN, Adam Orsborn, PharmD, MS, James Beardsley, PharmD, and Margaret Currie-Coyoy, MBA.

‘What this project demonstrates is that pharmacists can play a key role in the types of local, multidisciplinary approaches needed to improve sepsis-related outcomes.’

—Kevin Anger, PharmD times lost track of time or were busy doing procedures, so ordering antibiotics was sometimes delayed.”

preparation and delivery, Dr. Beardsley said, emphasizing the importance of clear communication. “Once the order is verified, each subsequent handoff—from verification of the order by the pharmacist, to preparation of the drug by a technician, to the pharmacist checking the medication, and the technician tubing it—is accompanied by a verbal acknowledgment that these are Code Sepsis antibiotics,” he said.

The third stage focuses on rapid drug delivery and administration. To ensure nurses are aware of the priority of sepsis drug administration, pharmacy technicians now tag the prepared medications with STAT stickers. Furthermore, because multiple antibiot-

A Multistage Process As per the new protocol, pharmacists contact prescribers 15 minutes after the code is initiated, to find out whether the patient will need any additional antibiotics. If a prescriber says there is such a need but they do not have time to determine the appropriate drug, the pharmacist selects the antibiotic based on a description of the probable source of the infection and a review of the patient’s medical record.

The second stage of the pharmacy process involves safely expediting drug

450 400 350

Time (min)

300

Implementation in select surgical ICUs

250

Implementation in remainder of surgical ICUs

200 150

Implementation in medical ICUs

100 50

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Figure. Mean time from positive sepsis screen to antibiotic administration in ICUs. Baseline: May-July 2012

ics often are required, the pharmacy has developed a set of principles to guide the order of antibiotic administration. The department also has created a compatibility chart to encourage simultaneous antibiotic administration when possible, Dr. Beardsley said.

With the protocol in place, the average time between a pharmacy Code Sepsis page and delivery of antibiotics to the nursing unit is 14.1 minutes, he reported.

More broadly, the time between a positive sepsis screen and administration of antibiotics has fallen from a mean 396 minutes to 51 minutes in non-ICUs, and from 427 minutes to 31 minutes in ICUs, Dr. Beardsley said (Figure).

Plunge in Sepsis Mortality Looking back at the concerning mortality rate that prompted the development of the Code Sepsis protocol, Dr. Beardsley said the hospital’s sepsis mortality rates are now among the 10 lowest of UHC hospitals. More specifically, the hospital’s sepsis-related mortality index, which is a measure of mortality adjusted for the expected death rate of a given condition, has dropped from 1.65 before Code Sepsis implementation to 0.8.

“At our institution, that translates to more than 200 lives saved per year,” Dr. Beardsley stressed.

It is difficult to determine the precise impact that faster antibiotic administration had on mortality reduction, but Dr. Beardsley said lower sepsis mortality rates have been linked to prompt administration of antimicrobial therapy (Crit Care Med d 2010;38[4]:1045-1053). Thus, “it is likely our process improvements had a significant impact on patient outcomes.”

Kevin Anger, PharmD, who is a clinical pharmacy specialist in critical care in the Department of Pharmacy at Brigham and Women’s Hospital, Boston, said high sepsis-related mortality rates remain common despite the availability of effective guidelines like those developed by the Surviving Sepsis Campaign (www.survivingsepsis.org).

“Institutions continue to struggle to implement best practices, including Surviving Sepsis guidelines,” said Dr. Anger, who was not involved in the Code Sepsis initiative.

“What this project demonstrates is that pharmacists can play a key role in the types of local, multidisciplinary approaches needed to improve sepsisrelated outcomes,” he said. “Continuous quality assessment and improvement initiatives like this one, which optimize available resources to provide the best patient care possible, should be a priority for all inpatient pharmacists.”

—David Wild Drs. Beardsley, Degrado and Anger reported no relevant conflicts of interest.

Clinical 15

Pharmacy Practice News • February 2015

Critical Care Prevention at core of pharmacist interventions

Taming Drug-Induced Bowel Dysfunction in the ICU Phoenix—Prevention is the best medicine for thwarting drug-induced diarrhea (DID) and constipation—two common causes of bowel dysfunction that can complicate the care of patients in the ICU, according to two experts who detailed their management tips at the 44th Annual Critical Care Congress.

The first step is to understand just how prevalent these adverse drug events are in the ICU. In the case of DID, “there are more than 700 drugs that cause diarrhea,” said Diana Esaian, PharmD, BCPS, pharmacotherapy specialist, Critical Care Postgraduate Year 1 Pharmacy Residency program coordinator at New York University Langone Medical Center, New York City. Because there is little agreement on how many bowel movements in a given time frame constitute diarrhea, the incidence of DID can be as low as 2% to as high as 95%, she noted.

But whatever the definition or frequency, DID is a potentially debilitating condition that critical care pharmacists need to meet head-on. Dr. Esaian stressed that DID can lead to malnutrition; electrolyte abnormalities; metabolic acidosis; hypovolemia; increased risk for infection; and contamination of wounds and pressure ulcers. Additionally, reduced enteral drug absorption can result from reduced mucosal contact time.

Easy Targets Although several drugs can cause diarrhea, antibiotics are the most common cause and one of the first problem areas that critical care pharmacists should review for potential interventions, Dr. Esaian noted. “Patients needing antibiotics can have diarrhea in up to 40% of cases,” she said.

Risk factors for antibiotic-associated diarrhea include the use of broad-spectrum agents, particularly those with antianaerobic and enterobacteriaceae activity. Antibiotics that have high lumen concentrations and have a longer duration of action are also problematic, as is the use of multiple antibiotics.

Breakdown in Mucosal Defense When not used optimally, anti-infectives are uniquely suited to disrupt normal gut function. The medications cause a reduction in anaerobic flora, which lessens bacterial fermentation of carbohydrates into short-chain fatty acids (responsisble for colonic health). Critically ill patients can also be deficient in these fatty acids, and there may be an impairment of the mucosal defense against bacterial adherence to colonic mucosa, Dr. Esaian explained. “Because these antibiotics decrease our normal

flora, they result in the proliferation of pathogenic microorganisms, such as Clostridium difficile,” she said. C. difficile is responsible for more than 90% of the pseudomembranous colitis cases.

Other common organisms are C. perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida and Salmonella species.

Management Prevention is best, Dr. Esaian said. She suggested avoiding the use of therapy that is likely to cause diarrhea, avoiding liquid preparations that have a high sorbitol content, especially when using multiple liquid medications, and using antibiotics judiciously. Additionally, she said laxatives and stool softeners should

ing probiotics, which suppress pathogens by restoring the gut microecology, as a means of slowing or even preventing DID. However, safety and efficacy data on these agents have been mixed, according to Dr. Esaian. In fact, one literature review documented an increased rate of infection and mortality in patients given the supplements ((Am J Clin Nutri 2010;91:687-703). She therefore urged caution when prescribing probiotics, especially in the critically ill, where very few studies on probiotics have been done.

Constipation Awareness Gap Although DID is widely recognized in the ICU, constipation is underappreciated in critically ill patients, according

drug-induced condition,” Dr. Smithburger said, but the biggest culprit is high-dose opioid regimens, which decrease motility, prolong transit time and increase fluid absorption, resulting in constipation.

A variety of treatments are available.

Emollient laxatives and stool softeners are typically well tolerated but are ineffective without adequate ingested fluids, she noted. Additionally, the efficacy of those treatments in reducing opioid-induced constipation is variable and not well studied.

Stimulant laxatives are significantly associated with a bowel movement.

Bulk laxative require large volumes of water and are not always practical in

Mechanisms of Drug-Induced Diarrhea Osmotic diarrhea (osmotically active solutes). Laxatives

Secretory diarrhea (excess fluids and electrolytes).

Stimulant laxatives

Malabsorption of fat (steatorrhoea).

Lipase inhibitors Malabsorption of carbohydrates (osmotic diarrhea). α-glucosidase inhibitors

Fat H2O

Carbohydrates

K+

Lymphocytic or collagenous colitis.

NSAIDs

L Lymphocytes C Collagen

Motility diarrhea (shortened transit time).

Erythromycin, cisap pride

Exudative diarrhea (protein-losing enteropathy).

Antineoplastics

Clostridium difficile

Pseudomembranous colitis (bacterial proliferation).

Antimicrobiotics

Source: Chassany O, et al. Drug Saf. 2000;22:53-72 000 22 53 72

not be on the patient’s medication list.

“Sometimes, we have order sets and we don’t notice these are preselected items unless we really screen through [the patient’s] medication list.”

If the diarrhea is related to enteral nutrition, she added, “slowing down the infusion rate, as well as using an infusion pump, can minimize the diarrhea.” Also, she suggested switching to a more isotonic enteral feeding formulation.

Soluble fibers can be considered; however, they should only be used in patients who are hemodynamically stable and at low risk for decreased perfusion.

First-line management should include overall supportive care, minimizing hypovolemia and electrolyte abnormalities and ruling out infectious diarrhea as a cause. “If the diarrhea still persists or is very severe, use antidiarrheal or antispasmodic agents,” Dr. Esaian said.

Some physicians have been prescrib-

to Pamela L. Smithburger, PharmD, MS, BCPS, associate professor, University of Pittsburgh, School of Pharmacy in Pennsylvania. “In one survey, only 52% of units recognize constipation as a problem and very few had a protocol for diagnosis and treatment of constipation,” she said.

Yet, there also is a high incidence of drug-induced constipation in the ICU, ranging from 15% to 83% of patients, according to Dr. Smithburger. Again, the incidence is so varied because of a lack of a clear definition. Constipation has been described as a lack of bowel movement for three to nine days.

And the problem is not benign. Constipation-related complications include prolonged ICU stay; delayed mechanical ventilator weaning; intestinal obstruction and perforation; and inability to receive enteral nutrition.

“Medications that reduce colonic motility are possible culprits of this

the ICU, according to Dr. Smithburger, and patients tend to dislike suppositories and enemas.

Several pharmacologic agents are promising for opioid-induced constipation.

Naloxone is a non-selective opioid receptor antagonist and the IV formulation is approved for complete or partial reversal of opioid depression. “When used orally, it may be effective in reversing opioid-induced bowel dysfunction.

•

see DYSFUNCTION, page 16

Web Exclusive Many drugs affect the gastrointestinal tract to cause bowel dysfunction.

For a list, go to pharmacypracticenews.com/DIDList or scan the adjacent 2D barcode.

16 Clinical

Critical Care

DELIRIUM 500

providers, according to the researchers, who presented the poster results (6-083) at the American Society of Health-System Pharmacists (ASHP) 2014 Midyear Clinical Meeting.

450

Frequency

continued from page 1

Opioids were the most common cause of delirium among patients.

441

400

Opioids

350

Benzodiazepines

300

Miscellaneous 257

250

Effect of drug withdrawal

200

Antiepileptics

150

Antidepressants

128

127 87

100

Musculoskeletal relaxants 64

64

50

“This is an interesting and innovative pharmacy service,” said Robert MacLaren, PharmD, MPH, who is a professor at the University of Colorado School of Pharmacy in Aurora, and was not involved in the initiative. “I don’t know of another service that is pharmacy-run and exclusive for delirium.”

Ed Rainville, MSPharm, who is the pharmacy clinical manager at OSF Saint Francis Medical Center in Peoria, Ill., said pharmacy and nursing staff collaborated to launch the service. On the nursing end of the program, patients aged 65 or older and younger patients who exhibit altered mental status are screened for delirium upon hospital admission or during nursing shift changes. If a patient meets the Confusion Assessment screening tool delirium criteria, the hospital’s electronic medical records (EMR) system automatically triggers an inpatient pharmacy consult.

Inpatient pharmacists like Cara Phillips, PharmD, who helped develop the service and co-authored the poster presented at the ASHP meeting, then review the patient’s EMR and determine whether a drug might be contributing to, or causing, delirium.

The pharmacist issues a recommendation within 24 hours of the consult request. If a medication is found to be possibly or definitely contributing to the patient’s delirium, the pharmacist

DYSFUNCTION continued from page 15

One of the main benefits is the limited oral bioavailability, which is important for patients to not experience opioid withdrawal when using this agent for opioid-induced constipation,” she said.

Methylnaltrexone (Relilstor, Salix) is a subcutaneously administered peripheral opioid antagonist that does not cross the blood–brain barrier, thus limiting withdrawal effects. Most of the studies have been conducted on patients with noncancer pain, but there are limited data in the ICU.

0

Drugs Identified

Figure. Common drugs identified as possible or definite causes of deliriuma,b a

For some consults, more than one drug was implicated.

b

Data derived from 1,201 consults conducted over an 18-month period (December 2012-May 2014).

can recommend reducing the drug dosage, discontinuing the medication or switching to an alternative agent.

The data Mr. Rainville presented included information from the 1,201 delirium consults conducted between December 2012 and May 2014. Consults required an average of 15 to 20 minutes of pharmacist time. Pharmacists identified a drug as a possible cause of delirium in 44.5% of cases, and as a definite cause in 20.2% of cases.

In 35.3% of cases, they determined a medication was unlikely to be at fault.

Mr. Rainville said the most common culprits were opioids, which were identified as possible or definite causes of 36.7% of delirium episodes, and benzodiazepines, which were implicated in 21.3% of cases (Figure).

An analysis of a random subset of 36 pharmacist suggestions revealed providers accepted 54.5% (12 of 22) of the proposed interventions when those recommendations identified a drug as “possibly” causing delirium, whereas they followed 92.8% (13 of 14) of pharmacists’ recommendations when a drug was deemed to

be a “definite” cause of delirium.

“The provider acceptance analysis was small, but I think it’s representative,” Mr. Rainville said, adding that the service is being used widely.

He said approximately 55% of consults were for patients in general care units, whereas 18.9% were for medical intermediate or medical ICU patients, 12.8% were for neurology intermediate or neurology ICU patients, 7.3% were for cardiology ICU patients and 6.8% were for patients receiving surgical intermediate or ICU care.

Alvimopan (Entereg, Cubist) is an orally administered peripheral μ-opioid receptor antagonist that also does not cross the blood–brain barrier. It is approved for postoperative ileus following partial large or small bowel resection surgery with primary anastomosis. Treatment of opioid-induced bowel dysfunction is an off-label use, Dr. Smithburger explained.

“Based on the literature with these opioid antagonists, we should be aware of the possibility of withdrawal and monitor them to make sure they are not withdrawing from the opioids we are giving them for their pain,” she said.

Dr. Smithburger stressed that opioids

are not the only drugs that can cause constipation. “If your patient is suffering from drug-induced constipation and is not taking opioids, it would be worthwhile to review medications to see if any have anticholinergic properties.” Other causes of constipation, she added, include shock, inadequate oral fluid intake and electrolyte disturbances.

More Study Needed Dr. MacLaren said widespread use of the service in the hospital “is commendable, since it would require a lot of awareness and buy-in.” However, he believes several questions need to be addressed to establish the cost and value of the delirium consult service.

“It’s very hard to say that the service did anything other than alter therapies,” he said. “Did the rate and duration of delirium change with the service? What were the costs of the

Importance of Prevention The constipation protocol should include risk assessment and dietary intervention; correction of fluid and electrolyte abnormalities; and minimizing drugs known to slow gastric motility. Dr.

service and the costs of drug changes?

These are important points that need to be investigated.”

Mr. Rainville said his team has been gathering cost-savings and costavoidance data, although they did not include these in their ASHP poster.

“We hope to analyze the impact on cost and patient care in a more comprehensive review of the service in the near future,” he said.

Anecdotally, however, he believes the favorable acceptance rates indicate the consults could be helping to chip away at rates of inpatient delirium or lengths of delirium episodes.

Delirium is “a significant problem associated with increased morbidity and mortality,” he said. “Physicians caring for patients may not recognize when a drug is contributing to a patient’s altered mental status, which makes our expertise valuable, and the acceptance rates support that.”

—David Wild Mr. Rainville and Dr. MacLaren reported no relevant financial conflicts of interest.

Smithburger also recommended reducing patients’ opioid use and getting them out of bed. It’s also important “to be accountable for discussing the presence or absence of bowel movements” and thus to ensure that bowel movements are charted.

To ensure success, Dr. Smithburger recommended having a standardized protocol in place for managing constipation in the ICU. “How can we correct something if we don’t know that it is happening?”

—Marie Rosenthal The sources reported no relevant financial conflicts of interest.

Take a bite out of G-CSF acquisition costs Based on whole esale acquissition cosst (WAC AC A C) of of all sho ort r -a act c in ng GG CS CSF F pr prod o uc od u ts as of November 11, 201 0 3.

3 WAC rep prese sent ntts pu publ blis bl ishe is he ed ca cata t lo ta log gue gu g e or lisst prric i es e and n may not represent acctual tra ansa action o al a pri r ce ces. s. Ple s. leas a e co con ntac actt yo your urr sup uppl plie ierr fo forr ac actu tual al pri rice ces. ce s

GRANIX® is an option in short-acting G-CSF therapy » A 71 7 % red duct ctio io on in n dur urat attio on off sev ever ere e ne n ut u rro ope p nia a vs placebo (1.1 days vs 3.8 da dayss, p<0 <0.0 000 001) 1)1 – Ef E fica cacy cy was eva cy valu l at ated e in a m ed multtin mu nat atio iona n l, m multi t ce enter, randomized, controlled, Phase III study of chem motherapy-naïve patien ents tss witth hi hig g -r gh -ris i k br is brea east stt cance er receivving do oxorubicin (60 mg/m2 IV bo olus)/docetaxel (75 mg/m2)1 » Th he sa afe etyy of GR GRA A IX was est AN sa ablishe ed in 3 Phase III trials,, with 680 p patients receiving g chemotherapy py for either breast ca anccer er,, lu lung ng g can nce er, or no nonn-Ho odgkin lympho oma (N NHL)1 » No Now w of offe ferring fe ing ng a new e pre r se s ntation for self-ad dministration

Indication » GR G AN A IX is a leukocyte ocyte growth factor indicat indicated ted forr reduction in the duration of severe ne neutropenia eutropenia in p patients atients w th non wi onm mye oid malig myel gnancies receiving myelosuppresssive anticancer drugs associated with a clinically significant i ci in cide dencce of febrile neu utropenia.

Important Safety Information » Sple Sp eni n c ru upture: Splen nic rupture, including fatal cases, can occur following the administrattion of human granulocyte colo co lony ny-stimulating facttors (hG-CSFs). Discontinue GRAN NIX and evaluate for an enlarged spleen or sp s le enic rupture in pati pa tien e ts who report up pper abdominal or shoulder pain after receiving GRANIX. » Ac Acut u e resspiratory disttress syndrome (ARDS): ARDS ca an occur in patients receiving hG-CSFs. Evaluate pa p tients t who wh o de deve elop fever and d lung infiltrates or respirator o y disstress after receiving GRANIX, forr ARDS. Disco c ntinue GRANIX X in pat a ie ients with ARDS. » Al A lergic reactions: Serrious allergic reactions, including anaphylaxis, can occur in patientts receivving hG G-CSF SFs. Rea e ctions n can ca n occurr on initial exposure. exp posure Permanentlyy discontinue GRANIX GRA ANIX in patients with serious allergic reac actions. tions D Do o no n t not administe ad er GRANIX to patients with a histo ory of serious allergic reactions to o filgrastim or pe egfilgrastim.

U e in pa atients with sickle cell disease: Severe and sometimes fatal sickle e cell crises can occur in patients with sick ckle e » Us cell diseasse receiving hG-CSFs. Consider the potential risks and benefits prrior to the administration of GRAN NIX X in p tients with sickle cell disease. Discontinu pa ue GRANIX X in patients undergoin ng a sickle cell crisis. » Ca C pillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and iss characte eriize z d byy hyp pote ensiion, hypoalbuminemia, edema and hemoconce entration. Episodes vary in freque ency, severity and may be life f -thre eatening if treatme ent is delayed. Patients who develop symptoms of CLS should be closelyy monitored and d re ece c ive e sttanda ard r symptoma atic treatment, which may include e a need for intensive care. » Potential for tumor growth stimulatory effects on malign g ant cells: The granulocyte colony-stimulating facctor (G-CSF) re eceptor, through which GRANIX acts, has been fo f und on tumor ce ell lines. The pos o sibi b lity tha hat GR G AN NIX X actss as a grow wth factor for any tumor type, inclu uding myelo oid malignancies and myelodysplasia, diseases e for which GRA ANIX i not app is proved, cannot be excluded. » Most com mmon treatment-emergent adve erse e reaction: The most common n treatment-eme ergent advers r e re ea action tha h t occurred in patients treated with GRANIX at the recommended dose with an incidence off at least 1% % or gre eat a er and t o timess more frequent than in the placebo group wass bone pain. tw Plea Pl ase s see brief summary of Full Prescribin ng Inforrmation on adjacent page.

For more information, visit GRANIXhcp.com.

Refe Re fere renc nce: e 1. GRA ANI N X® (tbo-filgrastim) Injection Prescribing g Info ormation. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva a Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved.. GRX-40582 January 2015.

18 Clinical

Pharmacy Practice News • February 2015

Oncology

Brentuximab After Transplant May Be New Standard for HL San Francisco—In high-risk Hodgkin lymphoma (HL), consolidation therapy after autologous hematopoietic cell transplant (auto-HCT) with the CD30-directed monoclonal antibody brentuximab vedotin (Adcetris, Seattle Genetics) provides a major extension of progression-free survival (PFS), according to an interim analysis of the Phase III AETHERA trial. The benefit relative to placebo was consistent

across subgroups.

Emphasizing the significance of the data, principal investigator Craig H. Moskowitz, MD, noted that it has been 20 years since any new treatment for aggressive lymphomas demonstrated a clinically significant improvement in outcome after auto-HCT. This magnitude of advantage “has never been seen before in patients with relapsed/refractory lymphoma, let alone with Hodgkin

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: UÊ -« i VÊ,Õ«ÌÕÀiÊQsee Warnings and Precautions (5.1)] UÊ VÕÌiÊ,ië À>Ì ÀÞÊ ÃÌÀiÃÃÊ-Þ `À iÊQsee Warnings and Precautions (5.2)] UÊ -iÀ ÕÃÊ iÀ} VÊ,i>VÌ ÃÊQsee Warnings and Precautions (5.3)] UÊ 1ÃiÊ Ê*>Ì i ÌÃÊÜ Ì Ê- V iÊ i Ê Ãi>ÃiÊQsee Warnings and Precautions (5.4)] UÊ >« >ÀÞÊ i> Ê-Þ `À i [see Warnings and Precautions (5.5)] UÊ * Ìi Ì > Êv ÀÊ/Õ ÀÊ À ÜÌ Ê-Ì Õ >Ì ÀÞÊ vviVÌÃÊ Ê > } > ÌÊ i ÃÊQsee Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

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 clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian.

In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

lymphoma,” said Dr. Moskowitz, the clinical director of the Division of Hematologic Oncology at Memorial SloanKettering Cancer Center (MSKCC), in New York City. “I think that once this study is published, this therapy will be the standard of care.”

Presenting the data at the 2014 annual meeting of the American Society of Hematology (ASH; abstract 673), Dr. Moskowitz described the AETHERA

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.

Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.

This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

trial as the only randomized, placebocontrolled study ever performed in HL. During the study, 329 patients were enrolled at 78 sites in North America and Europe. Most of the study population had multiple adverse prognostic risk factors, such as failure to achieve remission with front-line therapy. They were randomized to receive 16 cycles of brentuximab—an antibody-drug conjugate directed at the surface CD30 protein expressed on HL tumor cells—or placebo, administered over one year.

The median PFS, which was the primary end point of the trial, was 43 months for those receiving brentuximab and 24 months for those receiving placebo, producing a hazard ratio of 0.57 ( =0.001). At two years, the PFS rate was (P 65% in the experimental therapy group versus 45% in the control group. This difference in relative PFS at two years is particularly important because relapses after remissions of this duration in the past have been rare, Dr. Moskowitz said.

The therapy was relatively well tolerated. Brentuximab was associated with a far greater rate of peripheral neuropathy (56% vs. 16%), but Dr. Moskowitz reported that most of these events were grade 2 or lower. There were no grade 4 events in either arm of the study, and adverse events associated with brentuximab, including peripheral neuropathy, resolved when therapy was discontinued.

There was no overall survival advantage observed or expected because of a trial design that permitted placebo patients to receive brentuximab at progression, according to Dr. Moskowitz.

He noted that 85% of placebo patients crossed over.

Dr. Moskowitz concluded that these data will change practice, and Brad S. Kahl, MD, the clinical research director for hematologic malignancies at the University of Wisconsin School of Medicine, in Madison, who was invited by ASH to comment on the study, agreed.

He noted that AETHERA is “the first study to show a benefit for any posttransplant therapy” in HL, providing an opportunity to improve outcome, particularly in high-risk populations.

—Ted Bosworth Dr. Moskowitz reported financial relationships with Genentech, Merck and Seattle Genetics. Dr. Kahl reported a financial relationship with Infinity.

Clinical 19

Pharmacy Practice News • February 2015

In Brief: Oncology

FDA Approves Akynzeo for CINV

T

he FDA has approved Akynzeo (netupitant and palonosetron) to treat nausea and vomiting in patients undergoing chemotherapy.

Akynzeo is a fixed-combination capsule composed of two drugs: oral palonosetron, a product approved in 2008 to prevent nausea and vomiting during the acute phase of chemotherapy (within the first 24 hours), and netupitant, a new drug that prevents both side effects during both the acute and delayed phases of chemotherapy (from 25 to 120 hours after).

The combination drug’s effectiveness was established in two clinical trials involving 1,720 patients receiving chemotherapy. The participants were randomly assigned to receive either Akynzeo or oral palonosetron, to examine whether the drugs prevented vomiting in the acute, delayed and overall phases after the start of chemotherapy.

Results of the first trial showed that 98.5%, 90.4% and 89.6% of Akynzeotreated participants did not experience any vomiting or require medication for nausea during the acute, delayed and overall phases, respectively. In contrast, 89.7%, 80.1% and 76.5% of participants treated with oral palonosetron did not experience any vomiting or require medication for nausea during the acute, delayed and overall phases, respectively.

The second trial showed results similar to the first.

Common side effects of Akynzeo in the clinical trials were headache, weakness (asthenia), fatigue, indigestion (dyspepsia) and constipation.

FDA Approves Lanreotide To Treat GI Neuro Tumors

therapy, or for whom surgery and/or radiotherapy is not an option.

The new indication was based on demonstration of improved PFS in a multicenter, international, randomized (1:1), double-blind, placebo-controlled study (trial 2-55-52030-726) that enrolled 204 patients with unresectable, well- or moderately differentiated, locally advanced or metastatic, nonfunctioning GEP-NETs. More than half of the patients (55%) had NETs outside the pancreas. Patients were randomized to receive either lanreotide 120 mg or

placebo subcutaneously every 28 days.

The trial demonstrated a significant prolongation of PFS for the lanreotide arm (hazard ratio, 0.47; 95% confidence interval, 0.30-0.73; P< 0.001). The median PFS in the lanreotide arm had not been reached at the time of the final analysis and is at least 22 months. The

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which are characteristic of those associated with other amide-type local anesthetics.1 In clinical trials, side effects were mild and transient and may reflect the procedures, patient health status, and/or other medications used. Adverse events reported at a rate

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of *5%: hypotension, nausea, vomiting, bradycardia, fever, pain, postoperative complications, anemia, paresthesia, headache, pruritus, and back pain.

There have been adverse event reports of

T

he FDA has approved a new indication for Ipsen’s lanreotide (Somatuline Depot) for the treatment of patients with unresectable, well- or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival (PFS), the agency announced.

Lanreotide already had an indication for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radio-

median PFS in the placebo arm was 16.6 months.

Safety data were evaluated in 101 patients who received at least one dose of lanreotide. The most commonly reported adverse event (AE) in lanreotide-treated patients were abdominal and musculoskeletal pain, vomiting, headache, injection site reaction, hyperglycemia, hypertension and cholelithiasis. The most common serious AE of lanreotide observed in this trial was vomiting, which occurred in 4% of treated patients.

■

chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. NAROPIN is not approved for this use.

Reference 1. NAROPIN Prescribing Information.

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0793-NAR- 05-1/ 15

20 Clinical

Pharmacy Practice News • February 2015

Infectious Disease

MYSTERY ILLNESS continued from page 1

Additionally, some, but not all, of the children have tested positive for EV-D68 from a nonsterile site on a nasal pharyngeal swab or stool sample. “The virus is transient and not all of the children were tested, which is why we are hesitant to state that there is a direct relationship between EV-D68 and [AFM],” Dr. Sejvar said. “We want to be diligent and substantiate this, but we are also looking at other potential causes.”

The Respiratory Cases The EV-D68 respiratory symptoms caused the hospitalization of 1,153 children; 13 of them died. The infection probably affected millions of Americans, but they did not seek medical treatment for their “cold” symptoms.

Many children required intensive care that taxed the resources of children’s hospitals across the country ((Pharmacy

Case Definition To be considered a case, the patient must meet all four criteria: 1. Age: ≤21 y 2. Acute onset of focal limb weakness 3. Occurred on or after Aug. 1, 2014 4. MRI shows a spinal cord lesion largely restricted to gray matter

Practice News, November 2014, page 28).

“We had a huge surge of patients in our emergency department [ED] who were being seen for respiratory disease, primarily asthma-like illness,” said Samuel R. Dominguez, MD, of Children’s Hospital Colorado, in Aurora, the first center in the country to report the cases of paralysis. “A large proportion of patients—more so than usual—were being admitted to our hospital, both on the floors and in our ICUs as well.”

Compared with previous years, the hospital had a threefold increase in respiratory cases, he added. “We almost ran out of albuterol,” he said. “It was a pretty dramatic time for our hospital, but no different than the experiences of other hospitals around the country.”

Although enteroviruses typically occur annually in late summer and early fall, they don’t normally cause the high number of hospitalizations attributed to EV-D68, nor do they require the intensive respiratory treatments that children with EV-D68 needed to recover.

Game Changer The beginning of the AFM outbreak— the real game-changer, according to infectious disease experts—can be traced to a child who sought treatment at Colorado Children’s Hospital. The

child had a history of a febrile illness, but was not one of the young patients who presented to the ED with wheezing. His presentation was similar to the cases that would follow.

The children suffered an acute neurologic illness characterized by extremity weakness; cranial nerve dysfunction, such as diplopia, facial droop, dysphagia or dysarthria; or both. All the children had normal sensation, but some reported neck, back or extremity pain. The neurologists saw an unusual finding on the magnetic resonance imaging scan: inflammation of the gray matter (the nerve cells) in the spinal cord. In some cases, the cranial nerves also showed signs of inflammation. (Two of the Colorado patients only had inflammation of the cranial nerves; they were not included in the CDC case definition [box].)

By the time the outbreak was over, Colorado would see a dozen children with AFM. All of the children had a history of mild respiratory symptoms and fever but only one, a child with asthma, presented with respiratory symptoms so severe that she required a week’s stay in the ICU. She spent five days in the hospital for her asthma-like illness, was released and returned several weeks later with neurologic symptoms.

“For most, it was not a severe respiratory illness,” Dr. Dominguez said. “The symptoms were definitely noticed by the family, and [the children] were sick, but they did not require coming into the ED or being admitted to the hospital for that respiratory illness.”

On Sept. 12, 2014, the Colorado Department of Health and Environment reported the cases to the CDC, which has verified reports of 107 children in 34 states with AFM that meets the CDC’s case definition. The children ranged in age from 1 to 18 years (median, about 7 years), nearly all of whom were hospitalized; some were put on breathing machines and feeding tubes because they could not swallow.

Historical Perspective Every year, a few children in the United States develop neurologic illness with flaccid paralysis, but not since the polio era have so many children been struck down with neurologic symptoms at the same time, Dr. Dominguez explained.

“All of the infectious disease doctors, all of the neurologists, all of the ED docs and attendings were saying they had ‘never seen anything like this before with this many cases all at once,’” he said. “Maybe we might see one case every year or so, but to have 12 cases [in one hospital] in a month or two is really unprecedented.”

Dr. Dominguez said the MRI findings resemble those for poliomyelitis, enterovirus 71 or West Nile virus. “We don’t have a lot of MRIs from the polio era, but we do have a few, and [the images] look very similar,” he said.

A-D: Acute imaging performed at two to three days in a patient from Children’s Hospital Colorado demonstrates T2 hyperintensity in the right dorsal pons (white arrow, A) and more ill-defined central gray matter hyperintensity seen more commonly in the acute phase (white arrows, B and C; black arrows, D). E-I: Subacute imaging of the spine performed in the same patient at 38 days demonstrates contraction of the cord T2 hyperintensity to focally involve the anterior horn cells (black arrows, E; white arrows, F and H) and nerve root enhancement of ventral cervical roots (white arrows, G) and the cauda equine (white arrows, I).

Images courtesy of the American Society of Neuroradiology. First appeared in Maloney JA, et al. MRI Findings in children with acute flaccid paralysis and cranial nerve dysfunction occurring during the 2014 Enterovirus D68 Outbreak. AJNR Am J Neuroradiol. 2014 Nov 20. [Epub ahead of print].

“Poliovirus is the most common of the enteroviruses to cause this particular syndrome, but there are numerous enteroviruses that can produce the [same] exact syndrome,” Dr. Sejvar said. “One of the challenges for us since the end of the polio era is we don’t do ongoing surveillance for this type of illness. So it is difficult in any given year to say, ‘we would expect X number of these types of cases.’

Having said that, anecdotally, clinicians across the country were seeing more of these types of cases than [normal].”

Because no one knew what was causing the problem, there was no treatment. Neurologic illnesses such as this are typically treated with high-dose corticosteroids, IV immune globulins (IVIG) or plasmapheresis. Other treatments include interferon, antiviral medications and immunosuppressive medications/biologic modifiers.

“Initially, our kids got more steroids, but since we were not sure what was going on, we switched to IVIG because we were concerned about a direct viral effect,” Dr. Dominguez said.

The CDC put together an expert panel to review clinical management protocols, but found all of the therapies lacking and could not recommend any, although the panel’s report (http://goo. gl/ToKMSt) does provide information about safety and efficacy of these treatments for other conditions.

In addition to medical therapy, all the children have received or are receiving physical and occupational therapy.

Nationally, only one child has fully recovered. Two-thirds have shown some improvement; one-third has not shown any improvement.

Future Considerations The investigation continues, with the CDC testing stool, respiratory and cerebrospinal fluid samples; implementing a case–control study; and providing interim guidance on treatment options for AFM. The unknowns are many, including whether the illness is going to be a seasonal event or a one-time occurrence.

“Typically, the pattern with enteroviruses is you will have a large year with a substantial number of cases and then it [eases] for several years, presumably because [some] children [develop immunity],” said Dr. Sejvar, who added that the CDC plans to continue active surveillance for the virus as a precaution. As for the children who are currently affected, “if you look at other similar viruses, the great likelihood is that most of these children will be left with long-lasting or even permanent limb weakness and functional disability. This is clearly the most concerning aspect of this situation.”

—Marie Rosenthal None of the sources reported any relevant financial conflicts of interest.

Web Exclusive Purdue University researchers announced that they have traced the precise structure of EV-D68.

Scan the adjacent 2D bar code or visit pharmacypracticenews.com/EVBug to read about their recommendations for treating the paralysis patients.

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22 Policy

Pharmacy Practice News • February 2015

FDA Watch

FDA OKs Cosentyx For Plaque Psoriasis

T

he FDA approved secukinumab (Cosentyx, Novartis) as first-line therapy for the treatment of adults with moderate to severe plaque psoriasis.

This is the first approved human monoclonal antibody (mAb) that selectively binds to interleukin (IL)-17A, which is involved in the inflammatory process.

rent infection, and in patients with active Crohn’s disease. The most common side effects include diarrhea and upper respiratory infections.

Psoriasis affects 7.5 million Americans and more than 125 million people worldwide. Nearly 35% of psoriasis patients suffer from moderate to severe plaque psoriasis. Research shows that IL-17A plays an important role in driving the body’s immune response in disorders such as moderate to severe plaque psoriasis.

—From FDA and Novartis press materials

Savaysa Approved For Afib, DVT and PE Psoriasis is an autoimmune disorder that produces thick, red skin with flaky, silver-white patches called scales. By binding to IL-17A, secukinumab prevents the protein from binding to its receptor and inhibits its ability to trigger the inflammatory response that plays a role in the development of plaque psoriasis.

Administered as an injection under the skin, secukinumab is intended for patients who are candidates for systemic therapy, phototherapy with ultraviolet light or a combination of both.

“Plaque psoriasis can cause significant skin irritation and discomfort for patients, so it is important to have a variety of treatment options available to patients,” said Amy Egan, MD, MPH, deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research.

The safety and efficacy of secukinumab were established in four randomized, placebo-controlled, Phase III clinical trials with 2,403 participants with plaque psoriasis who were candidates for systemic or phototherapy.

The researchers examined secukinumab 300 and 150 mg. Secukinumab met all primary and key secondary end points, including Psoriasis Area and Severity Index (PASI) 75 and 90 and Investigator’s Global Assessment modified 2011 (IGA) 0/1 responses, showing significant skin clearance at week 12. PASI measures the redness, scaling and thickness of psoriatic plaques, and the extent of involvement in each region of the body.

Treatment efficacy is assessed by the reduction of the score from baseline (i.e., a 75% reduction is known as PASI 75 and a 90% reduction is known as PASI 90).

Because secukinumab is an immune modulator, patients may have a greater risk for infection. Serious allergic reactions have been reported with the use of secukinumab. Caution should be exercised when considering the use of secukinumab in patients with a chronic infection or history of recur-

T

he FDA has approved the anti-clotting drug, edoxaban tablets (Savaysa, Daiichi Sankyo), to reduce the risk for stroke and systemic embolism in patients with atrial fibrillation that is not caused by a heart valve problem.

The tablets have also has been approved to treat deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have already been treated with a parenteral anti-clotting drug for five to 10 days.

“In patients with atrial fibrillation, anti-clotting drugs lower the risk of stroke by helping to prevent blood clots from forming in the heart,” said Norman Stockbridge, MD, PhD, the director of the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research. “It is important to have a variety of these types of drugs available as options for patients.”

ban with warfarin for treating patients with a DVT and/or PE to reduce the rate of recurrence of symptomatic venous thromboembolism (VTE) events (which includes DVT, PE and VTE- related death). In the trial, 3.2% of participants taking edoxaban tablets had a symptomatic recurrent VTE compared with 3.5% of those taking warfarin.

The most common side effects observed in the trial participants were bleeding and anemia. As with other FDA-approved anti-clotting drugs, bleeding, including life-threatening bleeding, is the most serious risk of edoxaban tablets.

Savaysa has a boxed warning indicating that edoxaban is less effective in atrial fibrillation patients with a creatinine clearance greater than 95 mL per minute. Kidney function should be assessed before initiating therapy with edoxaban. Patients with creatinine clearance greater than 95 mL per minute have an increased risk for stroke compared with similar patients given warfarin. Edoxaban tablets should not be used in non-valvular atrial fibrillation patients with a higher creatinine clearance.

As with other anticoagulants, the boxed warning states that premature discontinuation of edoxaban tablets increases the risk for stroke, and notes that spinal or epidural hematomas (collection of blood outside of a blood vessel) may occur in patients treated with edoxaban who are receiving anesthesia injected around the spine or undergoing spinal puncture.

Savaysa will be dispensed with a patient Medication Guide that provides instructions on its use and drug safety information. Health care professionals should counsel patients about the increased risk for bleeding when taking this product.

—Based on a press release from the FDA

The safety and efficacy of edoxaban in treating patients with atrial fibrillation not caused by cardiac valve disease was studied in a clinical trial of 21,105 participants. The trial compared two doses of edoxaban with the anticlotting drug warfarin on their effects on rates of stroke and systemic emboli.

The trial results showed the higher dose of edoxaban to be similar to warfarin for reduction in the risk for stroke.

Although warfarin is highly effective in reducing the risk for stroke in patients with atrial fibrillation, it increases the risk for bleeding. Edoxaban demonstrated significantly less major bleeding than warfarin.

Edoxaban for the treatment of patients with DVT and PE was studied in 8,292 participants. The study compared the safety and efficacy of edoxa-

Data On Painkiller Meds in Pregnancy Still Inconclusive

T

he FDA announced that current study results on the possible risks of pain medicine use in pregnancy are too limited to make any new recommendations. Health care providers should follow the recommendations in the drug labels and discuss medication risks and benefits with each pregnant patient before use, according to a safety alert from the agency. y The FDA analyzed data from seven observational studies and three retrospective case–control studies and stated that the “weight of evidence is inconclusive regarding a possible connection between NSAID use and

miscarriage.” The case–control studies included more than 100,000 subjects and reported a positive association between non-aspirin NSAID exposure and miscarriage (adjusted odds ratio [aOR], 7.0; 95% confidence interval [CI], 2.8-17.7; aOR, 3.4; 95% CI, 0.912.8; and aOR, 2.4; 95% CI, 2.1-2.8).

According to the researchers, limitations in the study designs included not identifying the reason for NSAID use, not determining if NSAID use occurred before or after the onset of a miscarriage, not including potential NSAID users whose pregnancies ended in induced abortion and not considering the timing of the subjects’ study entry (researchers cannot determine if a patient’s risk for miscarriage inherently differs with NSAID use).

The researchers reviewed two retrospective case-control studies that reported on opioid exposure in early pregnancy and risk for neural tube defects. They concluded that more research is needed and the current data represent a small increase in the absolute risk because of the low rate of neural tube defects in the United States: approximately four to six per 10,000 live births.

The studies, based on interviews from more than 28,000 women, found that mothers of infants with neural tube defects were more likely than mothers of infants without neural tube defects to report opioid use in early pregnancy (aOR, 2.2; 95% CI, 1.2-4.2; aOR=2.0; 95% CI, 1.3-3.2). The researchers said these studies were generally well designed, but the validity of the results may have been affected by the use of interviews and subject participation.

The reviewers then looked at a prospective cohort study that reported an association between acetaminophen use in pregnancy and ADHD in children, and found the evidence to be inconclusive.

The FDA plans to continue monitoring and evaluating the use of pain medicine in pregnancy, and will announce new safety information when it becomes available.

—Based on a press release from the FDA

Policy 23

Pharmacy Practice News • February 2015

FDA Watch

FDA Advisors Recommend Approval of First U.S. Biosimilar

T

he FDA Oncologic Drugs Advisory Committee (ODAC) in January unanimously recommended the approval of the first U.S. biosimilar, filgrastim (EP2006, Sandoz) for all five indications sought by the company.

Data show that “EP2006 is highly similar to U.S.-licensed Neupogen,” said Albert Deisseroth, MD, PhD, a medical officer team leader in the FDA’s Division of Hematology Products. EP2006 is

distributed under the name Zarzio outside the United States. No word is available yet on what its name will be if it is approved for use in the United States.

“Pharmacy directors are looking forward to the introduction of biosimilars as they will help mitigate the significant increases in the cost of existing and new biologic medicines,” said James G. Stevenson, PharmD, FASHP, a professor in the Department of Clinical, Social and Administrative Sciences at the University of Michigan College of Pharmacy, Ann Arbor.

This is the first U.S. biosimilar to be considered under the FDA’s new biosimilar approval pathway, and the advisory committee recommended that the FDA approve the product for the same indications as U.S.-licensed Neupogen (Amgen): • To decrease the incidence of infections as manifested by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever; • To reduce the time to neutrophil recovery and the duration of fever after induction or consolidation chemotherapy treatment of adults with acute myeloid leukemia; • To reduce the duration of neutropenia and neutropenia-related clinical sequelae, such as febrile neutropenia in patients with nonmyeloid malignancies undergoing myeloablative

chemotherapy followed by bone marrow transplantation • For the mobilization of hematopoietic progenitor cells in the peripheral blood for collection by leukapheresis; and • For chronic administration to reduce the incidence and duration of sequelae of neutropenia, such as fever, infections, oropharyngeal ulcers, in symptomatic patients with congenital

neutropenia, cyclic neutropenia or idiopathic neutropenia.

The recommendation was made after the presentation of a comprehensive package of nonclinical, clinical and postmarketing pharmacovigilance data, which demonstrated that the biosimilar filgrastim is highly similar to the reference product, Neupogen. The pivotal dataset included a pharmacokinetic and pharmacodynamics (PK/

PD) study in healthy volunteers, which established bioequivalence, and a clinical efficacy and safety study in breast cancer patients, which demonstrated the same clinical performance and safety as the reference product.

The dataset also is supported by a global program that includes five randomized, double-blind, single- and multiple-dose PK/PD studies in healthy

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24 Policy

Pharmacy Practice News â&#x20AC;˘ February 2015

FDA Watch

BIOSIMILARS continued from page 23

volunteers assessing the PK and PD equivalence of biosimilar filgrastim and Neupogen, as well as a European noncomparative clinical safety and efficacy study and postmarketing pharmacovigilance data from countries where the product is approved.

Committee members reported that they were impressed that Zarzio has generated nearly 7.5 million patientexposure days of experience outside

the United States.

Deborah K. Armstrong, MD, ODAC chairperson, called the data â&#x20AC;&#x153;more detailed analytic analysis than we are used to seeing at ODAC.â&#x20AC;?

â&#x20AC;&#x2DC;I believe that the FDA has taken a very conservative approach in approving biosimilars.â&#x20AC;&#x2122;

â&#x20AC;&#x2DC;Confidenceâ&#x20AC;&#x2122; in Safety And Efficacy For some time now, the U.S. health care sector has been debating whether biosimilars would be accepted by clinicians and patients. â&#x20AC;&#x153;I believe that the FDA has taken a very conservative approach in approving biosimilars,â&#x20AC;? Dr.

â&#x20AC;&#x201D;James G. Stevenson, PharmD Stevenson told Pharmacy Practice News. â&#x20AC;&#x153;That approach, along with the very positive experience with biosimilars in Europe over the next eight years, should

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provide clinicians with confidence in their safety and efficacy.â&#x20AC;?

Before the vote, the committee heard from many organizations and patients who overwhelmingly endorsed the recommendation, many citing the hope that biosimilars will lower the cost of biologic drug treatment for many Americans.

Although no one knows how much of a savings Americans are likely to see, Europeans have seen savings of up to 25% of the reference product, according to Dr. Stevenson.

If approved, hospitals will have to determine whether to include the product on their formularies. Dr. Stevenson said that most will follow the existing channels for evaluating a drug and use the pharmacy and therapeutics committee and formulary structure to evaluate the biosimilar products. They will likely be evaluated individually, he added, as they are approved. â&#x20AC;&#x153;There will be important considerations about how many â&#x20AC;&#x2DC;similarâ&#x20AC;&#x2122; products to have on the formulary, whether to extrapolate the use of biosimilars to broader indications, if they are not approved for the full scope of indications as the reference product, and how to handle patients at the transitions of care between outpatient and hospital,â&#x20AC;? he said.

Although the FDA does not have to follow the recommendations of its advisory panels, it usually does. â&#x20AC;&#x201D;Marie Rosenthal

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Policy 25

Pharmacy Practice News • February 2015

Supply Chain

FDA Forms Compounding Advisory Committee

T

he FDA has announced the membership of the Pharmacy Compounding Advisory Committee. The group, comprised of 12 voting and two nonvoting members, will provide advice on scientific, technical and medical issues concerning drug compounding under sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act. “Advisory committees are a very important source of knowledge and advice for drug regulation,” said Janet Woodcock, MD, the director of the FDA’s Center for Drug Evaluation and Research. “This is a key step toward implementing the compounding provisions of the Drug Quality and Security Act, and I expect we will

Committee Members • Chairperson: Jurgen Venitz, MD, PhD, associate professor, Virginia Commonwealth University School of Pharmacy, Richmond • Designated federal officer: Jayne E. Peterson, PharmD, JD, Division of Advisory Committee and Consultant Management, Office of Executive Programs, FDA Center for Drug Evaluation and Research, Silver Spring, Md.

benefit greatly from the advice and recommendations the members of the committee provide.”

The FDA solicited nominations for committee members, and more than 100 individuals were nominated. The agency also identified qualified candidates from its own pool of government employees.

The process yielded a final group that included experts in pharmaceutical compounding and manufacturing, pharmacy,

medicine and pharmaceutical regulation.

Voting members include the United States Pharmacopeia, which sets standards for the quality and purity of medicinal products, as well as the National Association of Boards of Pharmacy. Two nonvoting members represent the pharmacy compounding industry and the pharmaceutical manufacturing industry.

Candidates not representing a particular group were evaluated for conflicts of

interest and to determine whether their qualifications matched the required areas of expertise, according to the FDA. Allen Vaida, BSc, PharmD, FASHP, the executive vice president of the Institute for Safe Medication Practices, said he was honored to be included on the panel. His focus as an adviser, he told Pharmacy Practice News, will be on the safety aspects surrounding compounded products, both prepared internally and purchased from outsourcers.

—PPN Staff

H PA 11

th

ANNUAL CONFERENCE March 25–28, 2015 • JW Marriott Austin • Austin, TX

• Industry representative: Ned S. Braunstein, MD, vice president and head of regulatory affairs, Regeneron Pharmaceuticals, Tarrytown, N.Y. • Industry representative: William Mixon, RPh, MS, FIACP, owner, The Compounding Pharmacy, Hickory, N.C. • Consumer representative: Michael A. Carome, MD, FACP, director, Health Research Group, Public Citizen • Gigi S. Davidson, BSPh, DICVP, director, clinical pharmacy services, North Carolina State University College of Veterinary Medicine, Raleigh • Robert DeChristoforo, MS, FASHP, chief, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, Md. • John J. DiGiovanna, MD, staff clinician, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md.

Featuring the education and research findings you need to deliver the highest quality care to your patients

• Focus on subspecialty areas such as geriatrics, administration, and the new practitioner

• Stephen W. Hoag, PhD, professor, Department of Pharmaceutical Science, University of Maryland, Baltimore.

• Elizabeth Jungman, JD, director, drug safety and innovation, The Pew Charitable Trusts, Washington, D.C. • Katherine Pham, PharmD, BCPS, neonatal intensive care unit pharmacy specialist, Children’s National Medical Center, Washington, D.C. • Allen J. Vaida, BSc, PharmD, FASHP, executive vice president, Institute for Safe Medication Practices, Horsham, Pa. • Donna Wall, PharmD, clinical pharmacist, Indiana University Hospital, Indianapolis

• Sessions on immunotherapy, emerging therapies in chronic lymphocytic leukemia, antimicrobial/antifungal prophylaxis and treatment in cancer patients, and targeted therapies in gastroesophageal malignancies • How We Treat, How We Manage, Clinical Pearls, and Controversies in Care

• Padma Gulur, MD, professor, Department of Anesthesiology and Perioperative Care, University of California, Irvine

• William A. Humphrey, BSPharm, MBA, MS, director, pharmacy operations, St. Jude Children’s Research Hospital, Memphis, Tenn.

Educational Session Highlights

• Pro/con debates for two contemporary patient care scenarios

Optional Events In-depth and focused pre- and postconference educational sessions covering pediatrics, radiology, bone marrow transplantation, and hematologic malignancies also are being presented.

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26 Policy

Pharmacy Practice News • February 2015

Drug Safety

DQSA Making an Impact on Sterile Compounding Anaheim, Calif.—Although it is too early to fully gauge the effect of the 2013 Drug Quality and Security Act (DQSA), there are signs that the “needle may have moved a little” toward the positive end of the compounding quality scale, at least in terms of stepped-up regulatory oversight, according to Eric Kastango, MBA, BSPharm, FASHP, the president and chief executive of Clinical IQ LLC. A wave of federal and state inspections has helped drive home the message that poor adherence to compounding quality standards will risk serious governmental action, including loss of licensure for the worst violators. In the two years after the devastating 2012 fungal meningitis epidemic, the FDA alone carried out more than 150 compounding pharmacy inspections, according to Jane Axelrad, JD, the associate director for policy at the FDA’s Center for Drug Evaluation and Research, who spoke at the 2014 Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP).

Through September 30 2014, she reported, the FDA issued warning letters and FDA Form 483s to 27 compounding pharmacies and seven outsourcing facilities detailing quality-standard failures requiring correction.

“The FDA has put everybody on notice,” Mr. Kastango said, “that if they act like a manufacturer or do compounding for office use or any of the other provisions that make them qualify as 503B operations, they will be under the purview of the FDA and kept on a short leash.”

The 503B section of the DQSA framed the requirements for FDA-registered outsourcing facilities. The FDA has been issuing guidance documents detailing the more stringent and costly manufacturing and reporting standards used during inspections. These include adherence to current Good Manufacturing Practices (cGMPs) published specifically for 503B outsourcing facilities, twice-yearly reports on products compounded during the previous six months and labeling that provides much more detailed information about products supplied. Registered outsourcers must also pay annual registration fees and reinspection fees to bring their facilities into full compliance.

FDA registration provides additional benefits. It allows an outsourcing facility to make and distribute compounded sterile products in quantity for its health system and physician office customers, without the individual patient prescription requirement that traditional compounders must follow under the DQSA’s Section 503A. Despite such benefits, the fees and other regulatory requirements expected of 503B operators have limited registrations, which are voluntary under the law.

By early January, just 37 facilities registered as 503B outsourcers, including two multi-facility operators, PharMEDium with four locations and Central Admixture Pharmacy Services (CAPS) with two.

Unsafe Harbor?

Avoiding registration could shield some compounding outsourcers from federal scrutiny, although they would still be subject to state regulations. One unresolved issue of the new law is that “compounders may seek to hide out in the traditional compounding category and escape detection” as outsourcers, Ms. Axelrad said.

For that reason, experts say, choosing an FDA-registered outsourcer may be the safest option for hospitals that lack the resources to compound sterile preparations under the stringent standards defined in USP Chapter <797>, although due diligence is crucial.

ing questions about how the outsourcer is complying with sterility and other key quality requirements of the new law.

On the other hand, Rich Kruzynski, MBA, BSPharm, the president of PharMEDium, noted that visiting potential outsourcing facilities may not be an option for many hospitals because of budgetary or time restrictions. “Whether they visit a site or not,” he said, “they need to do due diligence.” He recommended several steps, including requesting reports on how the company addressed any issues raised by FDA inspectors or Joint Commission auditors. They should also check reference accounts, he said.

Even while urging pharmacy directors to be diligent, Mr. Kruzynski said FDA 503B registrants offer the best starting point for a sterile product supplier search. Many people who are purchasing outsourcing services, he said, “have rec-

Choosing an FDA-registered outsourcer may be the safest option for hospitals that lack the resources to compound sterile preparations under the stringent standards defined in USP Chapter <797>.

“While the FDA can have all the standards, it really comes down to the purchaser—whether it’s the pharmacist in the hospital or the physician in an office— to really evaluate what their options are and who they’re purchasing from,” said Christopher Topoleski, the director of federal regulatory affairs at ASHP. The society’s comprehensive guidelines for selecting a compounding outsourcer are being revised to reflect the new DQSA requirements, and are expected to be released by the end of March. The new guidance, Mr. Topoleski said, “will give our members, and anyone who has access to them, the opportunity to select vendors and look through a checklist of things to ensure quality and responsibility for the products that are coming into their doors.”

One way to evaluate potential outsourcers is to visit their sites. “First and foremost, you want to deal with a 503B entity,” Mr. Kastango said. But he added that hospital pharmacy directors “still need to go in and at least do a walk-through,” ask-

ognized that 503B registered outsourcers have raised the bar on themselves.

Many of them have made substantial investments and have responded to FDA inspections, whether they’ve received Form 483s or warning letters.

“The quality has gone way up,” he said.

ISMP’s Take Allen Vaida, PharmD, the executive vice president of the Institute for Safe Medication Practices, will be joining the February inaugural meeting of the FDA’s new Compounding Advisory Committee.

At the meeting, he plans to challenge the need for “some of these creams and ointments that contain multiple ingredients” and other questionable compounded products that result in numerous error and misuse reports.

Dr. Vaida said ISMP’s concern over sterile compounding actually predates the New England Compounding Center debacle, where the pharmacy’s criminally negligent safety oversight led to the release of contaminated injectable ste-

OIG Still Sees Safety Gaps in Hospitals

H

ospitals are falling short in ensuring the safety of their sterile compounding practices, according to a study by the Health and Human Services (HHS) Office of Inspector General. One potential fix, according to the OIG, is to boost the level of training that hospital surveyors receive on safe compounding practices. The OIG suggested that CMS should be responsible for ensuring that such training has taken place. The office also urged hospital surveyors to revamp their methods for reviewing the contracts that health systems sign with outsourcing compounders.

The full report can be accessed at http://goo.gl/RrVfcX.

roids, causing hundreds of infections and more than 60 deaths. “ISMP was always concerned about hospitals purchasing drugs from compounding pharmacies that might have been questionable,” he said. He cited, as a typical example, a surgeon who wants to use a drug that is in short supply, and who, instead of asking the pharmacy for an alternative, FDA-approved product, requests that the medication be obtained from a compounder that may not follow safe sterile compounding protocols.

Unresolved Issues Although the DQSA has existed for more than a year, several issues remain unresolved. For one, although the FDA has published its final rule governing compounding practices for 503A traditional compounders, the final rule for 503B outsourcing facilities is still pending. A proposed rule was issued in July, and the agency has also released five draft guidances, three final guidances and one final revised draft guidance—all available on the agency’s website, www.fda.gov. v “There are some major parts of 503B that have to be clarified so people understand what the rules of engagement are,” Mr. Kastango said. One gray area, he said, was how the new federal law applies to hospital pharmacies that compound sterile products for other hospitals within the same health system. “Some state boards of pharmacy allow what they call central fill,“ he said. “A lot of the health systems are doing that now. Resolution is required on whether this practice is safe under the DQSA.” Despite the gray areas in the new law, Mr. Kastango said it was “long overdue. It took until 2014 for those rules to be written. So, I’m cautiously optimistic that as there continues to be clarity as the FDA issues its legislatively mandated guidances, the quality of medications being prepared by these outsource facilities will continue to improve and patients will be safer.”

—Bruce and Joan Buckley Mr. Kastango disclosed that he has no relevant financial conflicts of interest, outside of his consulting business; the other sources disclosed no relevant financial conflicts of interest.

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Glycemic Control and the Hospitalized Patient: From Bedside to Beyond CURTIS TRIPLITT, PHARMD, CDE Clinical Assistant Professor of Pharmacy University of Texas Health Sciences Center San Antonio, Texas

CAROLINA SOLIS-HERRERA, MD Resident Physician, Internal Medicine Texas Tech University Health Science Center Odessa, Texas

H

igh glucose levels at hospital admission are common, and it is well documented that these

levels contribute to an increase in poor outcomes.1-3 The prevalence of hyperglycemia on admission to the hospital varies based on the setting and the population studied, with rates ranging up to 40% in community hospitals and critically ill patients, to 80% in cardiac patients after surgery.4

The odds ratio for mortality almost linearly increases with blood glucose levels greater than 110 mg/dL on admission.2 This trend holds true during hospitalization as well, with multiple studies reporting increasing morbidity and mortality as glucose levels rise. Those findings have been documented in patients with trauma, stroke, chronic obstructive pulmonary disease, and community-acquired pneumonia, and those undergoing cardiac bypass graft surgery, as well as other conditions.1-7 Multiple long-term outpatient trials also have documented that higher glucose imparts a greater risk for microvascular complications, although these adverse effects tend to appear after years of hyperglycemia.8,9 Hyperglycemia needs to be addressed, but it should be noted that the odds ratio for mortality also increases when the admission glucose is in the

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hypoglycemic range and when the patient has episodes of severe hypoglycemia in the inpatient or outpatient setting.10,11 Five distinct transition intervention areas should be addressed when considering hyperglycemia in a patient who has presented to the hospital: 1. On admission: Check glycemic status and determine whether the patient was admitted with a history of diabetes mellitus (DM), or has new-onset hyperglycemia, stress-induced hyperglycemia, or perhaps even hypoglycemia.

2. ICU: Determine which clinical issue related to glycemic status is most acute. (This is where most of the inpatient glycemic control literature is focused.)

3. General hospital medicine floor: Glycemic control is still necessary in many patients, and it can be

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Admission to Acute Care A patientâ&#x20AC;&#x2122;s glucose level at admission is correlated with the risk for increased morbidity and mortality across many different diagnoses, including acute myocardial infarction (MI), congestive heart failure (CHF), pneumonia, pulmonary embolism, and stroke.11-15 In a study of 4,102 patients hospitalized with CHF, for example, mortality risk was correlated with admission glucose levels; each 18-mg/dL (1-mmol/L) increase in glucose level was associated with a 31% increased risk for in-hospital mortality (adjusted odds ratio, 1.31; 95% confidence interval [CI], 1.10-1.57; P=0.003) and a 12% increase in 60-day mortality (adjusted hazard ratio, 1.12; 95% CI, 1.01-1.25; P=0.04).13 Similarly, in a group of more than 15,000 patients admitted to the hospital with an acute MI, an admission glucose of less than 110 mg/dL was associated with a risk for mortality of 4.93%, whereas a glucose level of at least 200 mg/dL was associated with a 12.95% risk for mortality (P<0.001 for the trend).10 This is not to say that admission glucose is the optimal predictor of survival during hospitalization. In the MI trial, the investigators determined that other glucometric outcomes, such as 24- or 48-hour post-admission mean glucose, were better predictors of in-hospital mortality. Additionally, it was found that hyperglycemia in patients without diabetes is associated with excess risk for mortality when compared with similar glucose levels in individuals with diabetes. For every 10 mg/dL above the 120-mg/dL threshold, there was a significant increase in the odds ratio for mortality10 (Figure 1).

Patients with high admission glucose can be stratified into 1 of 3 categories: DM previously diagnosed; newly discovered/onset, undiagnosed DM; and stress hyperglycemia. These categories will help drive therapeutic interventions because DM will need to be addressed after discharge, whereas most instances of stress hyperglycemia likely will resolve post-discharge, although continued screening for DM on an outpatient basis is warranted. A hemoglobin A1C (HbA1C) determination can be helpful in stratifying the patient in cases of newly discovered DM or stress hyperglycemia.16

Glycemic Control in the ICU The association with higher glucose levels and a higher risk for mortality in the ICU is clear. In a study

by Krinsley et al, mortality in medical ICU or surgical

2

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0.8 No diabetes All patients

Mortality rate

managed in multiple ways.

4. Discharge and transition: Discharge planning is crucial when patients are transitioned to the outpatient setting. This may involve transitions to a private residence, a rehabilitation facility, a skilled-nursing or longterm care facility, or hospice, among others.

5. Follow-up: During the early outpatient phase, the patient is at high risk for readmission.

These 5 glycemic control transition areas require different thought processes, interventions, and follow-up and will be discussed individually.

Diabetes

0.5

0.2

0.0

<70

90-110

200

250

300

Mean blood glucose (mg/dL)

Figure 1. Unadjusted risk for In-hospital mortality from diabetes.

Based on Reference 10

ICU patients increased from 9.6%, with a mean whole blood glucose value of 80 to 99 mg/dL, to 42.5% if the glucose value was greater than 300 mg/dL.17 This linear relationship also is true for hypoglycemia. In an analysis of 66,184 ICU admissions in Australia, hospital mortality, after multivariate adjustment, was 15.7%, 29.5%, and 57.4% for no hypoglycemia during admission, less than 73 mg/dL during admission, and greater than 40 mg/dL, respectively.18 This demonstrates the need to balance glycemic control with the need to avoid hypoglycemia.

Van den Berghe and colleagues were among the first investigators to show a strong association between ICU mortality and glucose levels, with their 2001 and 2006 Leuven trialsâ&#x20AC;&#x201D;so named because they took place in the Belgian cityâ&#x20AC;&#x201D;showing largely positive outcomes.19,20 The 2001 study randomized 1,548 surgical ICU patients to intensive glycemic control (goal glucose 80-110 mg/dL) or conventional glycemic control (180-200 mg/dL). Mortality was significantly decreased from 8% to 4.6% for the conventional and intensive groups, respectively. Additionally, sepsis, dialysis, blood transfusions, and critical illness polyneuropathy were decreased 30% to 50%. Many of these adverse outcomes were most pronounced among patients who were in the ICU for at least 5 days, the investigators reported.19 Five successive trials were unable to reproduce the Van den Berghe results,21-25 and a meta-analysis of the findings indicated that tight glycemic control imparted no benefits over less-intensive control.26 The reasons for these divergent results have been discussed extensively in the literature, and expertise of staff and resources dedicated to inpatient glycemic control are paramount.

Van den Berghe reported excellent outcomes from a single center, yet the broad implementation of similar practices did not find in similar results.

Table 1. Inpatient Guidelines for Glycemic Control Patient Population

Blood Glucose Treatment Threshold, mg/dL

Blood Glucose Target, mg/dL

Blood Glucose Hypoglycemia Definition, mg/dL

Updated Since NICE-SUGAR31 2009

Year

Organization

2009

AACE and ADA16

ICU

180

140-180

<70

Yes

2009

AACE and ADA16

General floor

<180

FBG <140 PPG <180

<70

Yes but N/A

2013

Surviving Sepsis Campaign29

ICU

180

<180

Not stated

Yes

2012

ACCM30

ICU

150

<150 (trauma) <180 (stroke+)

<70

Yes

2013

ACP31

ICU

Not stated

140-200

Not stated

Yes

2008

AHA32

ICU patients with ACS

180

90-140

Not stated

No

AACE, American Association of Clinical Endocrinologists; ACCM, American College of Critical Care Medicine; ACP, American College of Physicians; ACS, acute coronary syndrome; ADA, American Diabetes Association; AHA, American Heart Association; FBG, fasting blood glucose; NICESUGAR, No Normaloglycemia ormaloglycemia in In Intensive ntensive Care Evaluat Evaluation tion and Surviving Glucose e Algorithm Regulation Regulation; n; PPG, postprandial blood d glucose

Glycemic control is important in the critically ill patient, but the intervention must be implemented safely.27 Multiple organizations have recommended guidelines for glycemic control for inpatients, and if a broad overview of guidelines for glycemic control in ICU populations was taken, the glucose threshold for starting IV insulin administration would be 150 to 180 mg/dL (Table 1).28 The targeted blood glucose range is about 140 to 180 mg/dL, and the guidelines that define hypoglycemia usually set it at greater than 70 mg/dL. The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) recommend targeting the glucose level between 140 and 180 mg/dL for ICU patients. Lower glucose targets may be appropriate (110-140 mg/dL) in certain subpopulations of ICU patients. However, the management strategy only should be implemented in centers that have extensive experience and appropriate/extensive nursing support, to ensure a high level of safety.16 It should be noted that in both of the Van den Berghe studies, severe hypoglycemia, defined as greater than 40 mg/dL, was significantly higher in the intensive treatment arms. In the 2006 trial, severe hypoglycemia was reported, spontaneously or with insulin, in 18.7% of the intensively treated patients versus 3.1% in the control group.20 (Hypoglycemia also was documented in the studies that failed to reproduce Van den Berghe’s positive results.)

Severe hypoglycemia in the ICU has been associated with an increased mortality risk, but this also may be due, in part, to the severity of the patient’s underlying pathology. A higher Acute Physiology and Chronic Health Evaluation II score, for example, has been associated with a higher risk for hypoglycemia.33,34 Some

experts reported that short-duration severe hypoglycemia may not have significant long-term risks,35 but this may not be true for neurologic ICU patients. A post hoc analysis of the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Surviving Glucose Algorithm Regulation) trial documented a higher risk for death in critically ill patients, even with moderate to severe hypoglycemia.36 The first severe hypoglycemic reaction often happens early in the ICU stay, when insulin needs are dynamic. Thus, special caution in the first 24 hours of the IV insulin infusion is warranted.

Good glucose control in the ICU is almost exclusively accomplished via IV insulin infusion. Regular insulin, aspart, lispro, and glulisine have similar IV kinetics (differences are only present when administered subcutaneously), and regular insulin is almost exclusively used due to cost. Intensive (110-140 mg/dL) glycemic goals are not recommended for most patients because additional clinical benefit has not been documented, and the risk for severe hypoglycemia is elevated. New-onset hyperglycemia on admission has a higher mortality risk than established diabetes. In a recent meta-analysis of ICU patients with sepsis, the unadjusted mortality rate among patients with new-onset diabetes (25.3%) was double that in patients with established or known diabetes/hyperglycemia (12.8%). The hypothesis is that prior hyperglycemia may allow the body to adapt in some way to future hyperglycemia.37

Glycemic Control in the Noncritically Ill Inpatient The lack of large, prospective studies of glycemic control in noncritically ill inpatients is one likely explanation

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for why blood glucose often is not aggressively managed in these patients. Additionally, there are wide differences among noncritically ill inpatients that could affect the handling of their glucose control. For example, consider a man with diabetes who is admitted for rehabilitation.

He is taking only oral agents and will be in the hospital no more than 48 hours. Compare his care with a woman with stress hyperglycemia in the ICU, who has since normalized her glucose values on the general medicine service and now may not need medications to control it.

These widely different examples illustrate the need for individualized care for inpatients who are not critically ill. The ADA states that there are little data on the safety and efficacy of oral agents or noninsulin injectables in the hospital, and so they are not recommended.38

IV to Subcutaneous Insulin Transition Order sets for transition from IV to subcutaneous insulin are available widely. The transitional total daily dose (TDD) of insulin is given based conservatively on the recent needs of the patient on IV insulin. The TDD of insulin used for the transition usually is derived from the last 4 to 6 hours of the IV insulin infusion multiplied to equal a 24-hour amount of insulin. For safety, the TDD of insulin is reduced by 20% and then used to calculate a regimen, which can vary based on the patientâ&#x20AC;&#x2122;s needs. (A link to an algorithm detailing IV to subcutaneous transitions, developed by the Texas Diabetes Council, is provided in the Resource Box below.)

Basal insulin (insulin glargine or insulin detemir) is given to control hepatic glucose production and premeal glucose readings in the target range. Bolus/mealtime insulin (aspart, lispro, or glulisine) is given to address nutritional intake. There are instances where

Treatment Algorithms Transitioning patients from IV to subcutaneous insulin formulations is an important part of maintaining optimal glucose control in hospitalized patients.

Two algorithms developed by the Texas Department of State Health Services can be useful tools in implementing those transitions. To access PDfs of the algorithms, scan the 2D bar codes below or enter the provided URLs into your browser.

Transitioning from IV to Subcutaneous Insulin for Patients with Diabetes or Hyperglycemia http://goo.gl/azgXKn

Transitioning from I.V. to Subcutaneous Insulin Order Set: Eating Status NPO or PO http://goo.gl/1gtAI4

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Neutral Protamine Hagedorn (NPH) and/or regular insulin could be appropriate. The third component of the insulin regimen is correction insulin, which is given to normalize glucose when hyperglycemia is noted before a meal or potentially at bedtime. Correction insulin is given because, ideally, insulin given during mealtime will only cover the meal; thus, correction insulin increases the likelihood that the patient will have a blood glucose reading in the targeted range by the next reading.

Practices vary widely on giving correction insulin at bedtime. Many clinicians do not recommend it, but if it is given, about one-half of the normal correction insulin dose should be administered to decrease the risk for nocturnal hypoglycemia.39 (The Resource Box provides a link to order sets for IV to subcutaneous transitions, along with advice for common problems, such as total parenteral and enteral nutrition regimens.)

There are several reasons why the AACE/ADA guidelines do not recommend the use of sliding-scale insulin (SSI) in the inpatient setting.38 First, SSI treatment protocols promote action only when the glucose level is highâ&#x20AC;&#x201D;there are no provisions for treatment when glucose is in the targeted range. This places patients at risk for hyperglycemia. After the initial short-acting insulin dose is given in typical SSI treatment protocol, no further glucose testing or treatment is given for another 6 hours. In such a scenario, the short-acting insulin will be metabolized, and hyperglycemia ensues.

Insulin needs can be calculated, and the daily needs are at least 0.4 U/kg, even with type 1 diabetes. Starting near this range is unlikely to cause hypoglycemia, although lower doses are recommended for renal insufficiency, hepatic insufficiency, and older patients.

Despite the recommendations of national organizations, SSI use continues. If it is used, I recommend that after 24 hours of SSI use, one-half of the total daily insulin dose from the SSI over the previous day be given as basal insulin. This will help minimize the wide swings often seen with this suboptimal regimen.

Several studies have compared SSI with basal insulin dosing. RABBIT 2 Surgery (Randomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes Undergoing General Surgery) randomized 211 patients with type 2 diabetes to basal-bolus therapy with insulin glargine and glulisine started at 0.5 U/kg per day or sliding-scale regular insulin administered every 6 hours if blood glucose was greater than 140 mg/dL. A prespecified composite outcome of wound infection, pneumonia, bacteremia, respiratory failure, and acute renal failure were higher in the SSI group (24.3%) than in the basal-bolus group (8.6%; P=0.003).40 The open-label, randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients with Diabetes trial reported on NPH and regular insulin given twice daily versus insulin detemir given daily/ aspart given before meals in 130 inpatients. No significant differences in glycemic control, hypoglycemia, hospital length of stay, or mortality were reported.41 As data continue to be mixed, larger trials are

needed before health care providers can draw any conclusions. AACE/ADA recommends, based on clinical experience and judgment, that the glucose premeal goal generally be less than 140 mg/dL and the postprandial goal target less than 180 mg/dL. If glucose readings are less than 100 mg/dL, the regimen should be reassessed to avoid hypoglycemia and modified if readings below 70 mg/dL are identified.16 The Endocrine Society has issued similar recommendations for noncritically ill inpatients.42

Discharge Planning and Transition Preparation for transition to the outpatient setting is an important part of the inpatient stay. The reason for concern is a shift in responsibility from the hospital staff to self-management. Poorly handled transitions can lead to hospital readmissions and the substantial financial costs that go with them. Although the rate of 30-day readmissions has declined slightly in the past few years, it still hovers at approximately 18% and costs the health care system $12 billion to $44 billion per year.43,44 Affordable Care Act provisions incentivize positive and discourage negative outcomes. Hospitals can receive increases to their Medicare payments if they achieve or exceed performance targets for certain quality measures. Patient-centered education to increase knowledge of symptoms and/or problems post-discharge and understanding of what action to take and who to inform are just some of the measures included. Additionally, the Centers for Medicare & Medicaid Services continues to decrease payments to hospitals if their readmission rates for certain disease states remain high.

This problem is best approached using an interdisciplinary team, consisting of a physician, nurse, diabetes educator, dietitian, social worker, and pharmacist. A comprehensive team is essential because the reasons for poor transition to the outpatient setting are multifactorial. Common problems such as diet, restrictions and limitations, psychosocial stressors, costs of care and medications, lack of follow-up, lack of anticipation of home needs, and complexity of regimen can play a part in failure of the patient to transition smoothly back into the community. Several strategies can be used to improve the quality of care transitions, including a structured hospital discharge plan, reconciliation of medications from preadmission to postadmission, anticipation of follow-up needs and resources at home, primary care input into discharge planning, electronic discharge notifications, and summaries available at follow-up visits.45 Transitional care for patients with diabetes is similar.

Health care workers should assess physical and selfcare deficits (ie, mobility, decreased vision), socioeconomic issues (ie, ability to afford care and medications, insurance coverage of prescribed medications, and family support), access to follow-up care, and learning issues (ie, language, written competency, disabilities). As noted previously, HbA1c should be assessed in most patients, unless preexisting disease or hospital interventions are likely to severely skew the results (ie,

blood transfusions, severe anemia). For the approximately one-third of patients with stress hyperglycemia and a normal HbA1c, screening for diabetes on an outpatient basis may be all that is needed. For the remaining patientsâ&#x20AC;&#x201D;primarily those with previous diabetes or new-onset diabetesâ&#x20AC;&#x201D;a continuing glycemic control plan should be formulated.

The first step for managing established diabetes patients is to determine what their glycemic control plan was before admission. Assessments should include the appropriateness of the regimen on admission or whether substantial changes need to be implemented before or at discharge. If the current regimen is basal-bolus insulin therapy, assess the possibility of starting oral medications and teaching the patient how to transition from insulin. Many hospital providers will not focus on a transition back to oral agents and would prefer to let an outpatient provider restart orals, but this transitional care may help to limit hypoglycemia.

The outpatient ACCORD trial reported that the highest rates of severe hypoglycemia were found in patients who took insulin with or without other medications.46 The second step is to identify whether the admission or complications could be due to an elevated HbA1C. If so, these results will likely change the strategy for medications to continue or discontinue at discharge (ie, gastroparesis and use of glucagon-like peptide [GLP]-1 agonists or pramlintide, or renal insufficiency and metformin). The Society of Hospital Medicine has issued guidelines on which therapeutic strategy to consider in patients with new-onset or established diabetes based on the HbA1c (Tables 2 and 3).47 Education is another key component of the discharge process. Patients may or may not be in an ideal situation at discharge to understand and retain all the

Table 2. Discharge Planning: New Hyperglycemia HbA1C, %

General Guidelines

<5.7

Patient does not have diabetes or prediabetes

5.7-6.4

Patient has prediabetes (at risk); follow-up advisable; consider diabetes prevention strategies

6.5-7

Patient has diabetes; can be treated with lifestyle changes; consider metformin

7-9

Patient has diabetes; pharmacotherapy is indicated

>9

Most patients would likely benefit from basal-bolus insulin regimen at discharge

Based on reference 47.

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Table 3. Discharge Planning: Established Hyperglycemia HbA1C, %

General Guidelines

<7

Continue preadmission diabetes management therapy plan

7-8

Increase dose of preadmission diabetes medications and/or add a second or third oral agent or basal insulin at bedtime

9-10

Most patients should be on basalbolus insulin at discharge

Based ased o on reference e e e ce 47.

educational instructions necessary for successful selfmanagement of diabetes. This is why it is imperative to have family/friend involvement in discharge education. Dietary habits on the outpatient side need to be assessed by the dietitian and appropriate interventions and instructions given related to calories, carbohydrates, fat, and so on. If the patient has established diabetes, the health care provider should assess areas of misunderstanding or nonadherence, discuss these with the patient and family, and provide written instructions. In a patient with new-onset diabetes, it is best to provide survival skill education for diabetes, and then refer him or her to an outpatient diabetes education program for follow-up. The education may encompass how and when to take medications, as well as expected side effects, how and when to test blood glucose, what the glucose goals are, and what to do if glucose values are extremely high or low.

Hypoglycemia identification, treatment, and prevention should be given, as well as sick-day management, and a recommendation about following up with a health care professional when things do not go as planned.16 As an example, in the ACCORD trial, an analysis of the most common reasons for severe hypoglycemia was explored. The researchers found that almost half of all severe hypoglycemic episodes were preceded by a significant change in the patient’s diet.45 These interventions as a whole can decrease, but not eliminate, readmissions.

Early Outpatient Phase and Follow-Up As patients begin to manage their own diabetes, many unanticipated issues may arise. The hospital readmission rate for DM is approximately 20% at 30 days post-discharge.48 Post-discharge interventions can decrease readmissions. Response to these interventions appears to be highly individual based on the package of offered services. Timely telephone follow-up and medication reconciliation have proven effective in managing treatment issues that arise post-discharge.49 Glycemic goals should be individualized based on ADA or

6

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AACE guidelines.37,49 Factors to consider include duration of diabetes, life expectancy, important comorbidities including vascular complications, hypoglycemia risk, support system, attitude, and ability to perform self-care activities. HbA1c goals should be between 6.5% and 7% in otherwise healthy patients, and can even aim toward 6% if medications that do not cause hypoglycemia or weight gain are used. ADA and AACE guidelines mention that hypoglycemia and weight gain are important considerations for type 2 DM therapy.38,50 Metformin and α-glucosidase inhibitors have been on the market for some time and fit these criteria, but α-glucosidase inhibitors are not used widely in the United States due to gastrointestinal (GI) side effects. Metformin is used widely, and newer classes of medication such as GLP-1 receptor agonists (GLP1RAs), dipeptidyl-peptidase-4 (DPP4) inhibitors, and sodium-glucose cotransporter-2 (SGLT2) inhibitors also fit these criteria. All 4 classes have a low risk for hypoglycemia, with GLP1RAs and SGLT2 inhibitors often resulting in weight loss and DPP4 inhibitors and metformin being weight-neutral.

Treatment Options GLP1RAS There are 4 injectable GLP1RAs available in the United States. Exenatide (Beyetta, AstraZeneca) is available in an immediate-release form that is dosed twice daily and an extended-release form that is dosed weekly. Liraglutide (Victoza, Novo Nordisk) is dosed daily and albiglutide (Tanzeum, GlaxoSmithKline) is dosed weekly, as is dulaglutide (Trulicity, Eli Lilly), the newest FDA-approved product. Additionally, dulaglutide is the first weekly GLP1RA that does not require reconstitution before administration. All GLP1RAs result in pharmacologic levels of GLP-1 activity at the GLP1 receptor. This imparts increased insulin secretion, decreased glucagon secretion, slowed gastric emptying, and central nervous system appetite reduction. These actions, combined, improve glycemic control but also can cause side effects. Gastric slowing, for example, can result in nausea and/or vomiting in some patients. It is imperative to counsel patients that they must stop eating when satiated to limit nausea and stop any vomiting. GI side effects will lessen over time in most patients. Head-to-head trials have shown that liraglutide appears to decrease HbA1C 0.2% more compared with exenatide extended release or albiglutide, but liraglutide is associated with more GI side effects, and injection-site reactions are more common with the extended-release products.51,52

DDP4 INHIBITORS There are 4 DPP4 inhibitors, all of which are dosed daily. This product class generally decreases the endogenous degradation of GLP-1 and GIP, which results in normal physiologic levels of both hormones, suppressing inappropriate glucagon secretion and improving β-cell response to glucose.53 Physiologic levels of GLP-1

do not result in gastric slowing and satiety signals. This results in GI side-effect rates similar to placebo and weight neutrality, but they have less HbA1C reduction than GLP1RAs.54 The DDP4 inhibitors alogliptin (Nesina, Takeda), linagliptin (Tradjenta, Boehringer Ingelheim), saxagliptin (Onglyza, AstraZeneca), and sitagliptin (Januvia, Merck) are approved in the United States. All except linagliptin require dose reduction in renal insufficiency due to impaired renal clearance.55,56 There are limited clinical data comparing the DDP4 inhibitors head-tohead, but anecdotally agents in this class appear to have similar efficacy.

SGLT2 INHIBITORS SGLT2 inhibitors competitively block SGLT2 receptors, reducing renal reabsorption and increasing urinary glucose loss. Most agents in this drug class result in 50 to 80 g of glucose excretion per day, which accounts for only 40% to 50% of the potential glucose that could be excreted. Thus, compensatory mechanisms must play a role. SGLT2 inhibitors can result in weight reduction and blood pressure lowering due to their glucoretic effect. Approximately 200 to 300 calories per day may be lost in the urine, and there may be an associated blood pressure reduction from water that is excreted along with the glucose.57-59 Three SGLT2 inhibitors are approved in the United States: canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca), and empagliflozin (Jardiance, Boehringer Ingelheim). The side-effect profile of these medications is related to their mechanism of action and includes an increased risk for genital mycotic infections.

The largest risk is in patients with a previous history of the infections and in uncircumcised males.60,61 A small increase in uncomplicated urinary tract infections has been noted.

Additionally, the diuretic effect can result in dizziness, orthostatic hypotension, and, rarely, dehydration.62-64 Canagliflozin and empagliflozin are FDA-approved for use in individuals with an estimated glomerular filtration rate (eGFR) of at least 45 mL/min/1.73m2, whereas dapagliflozin is FDA approved to treat those with an eGFR of at least 60 mL/min/1.73m2.62-64 Efficacy wanes and the risk for side effects increases with all these agents as renal insufficiency worsens. No head-to-head trials have been conducted comparing the SGLT2 inhibitors.

Conclusion There are several opportunities for appropriate interventions for inpatient glycemic control. Efforts should begin at admission to ensure optimal outcomes. But those efforts should not stop once a patient’s hospital stay has concluded: Discharge planning is vital for the patient with diabetes. Pharmacists must fill in gaps in knowledge and/or provide survival skills education to the new-onset hyperglycemic patient until follow-up can be completed on the outpatient side. Frequent follow-up after discharge, along with appropriate medication reconciliation, not only improves clinical outcomes, but such

efforts also may decrease hospital readmissions.

Pharmacists can help improve outcomes and quality of life of inpatients who present with hyperglycemia as well as help such patients transition successfully to self-managed care.

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