November 2014

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M A ee S tin H se e g P us Iss at bo ue ot h

The Pharmacist’s News Source

pharmacypracticenews.com

Volume 41 • Number 11 • November 2014

#9

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EMERGING DISEASE UPDATE

in this issue UP FRONT

6

ASHP Literature Awards: the science behind the profession.

CLINICAL

14 25

In-hospital malnutrition linked to poor clinical outcomes.

Pertuzumab part of a practice-changing breast cancer regimen.

OPERATIONS & MGMT

42

Pharmacists save $1.2M treating at-risk rural patients post-discharge.

OPINION

44

Pharmacy graduate makes a case for taking risks when choosing practice site.

POLICY

46

Tips for not getting buried by new CMS payment rules.

TECHNOLOGY

50

Pharmacists, nurses use telemedicine to boost anticoagulation.

The Drug Quality and Security Act

A New Reality for the Practice Of Outsourcing Compounded Sterile Preparations See insert after page 28.

Pharmacists across the U.S. are responding to both outbreaks

Ebola + Enterovirus = Readiness Test T

wo emerging viruses—Ebola and enterovirus (EV) D68— 68— are testing the preparedness of the U.S. health ccare system. But as hospitals scramble to adopt the latest gu uidelines on protecting staffers at the bedside of Ebola patieents, EV-D68 has proven to be the far greater public health threat, according to infectious disease (ID) experts.

Unlike Ebola, EV-D68 has been causing virulent disease in the United States since at least August. And this year, this rare strain is far more potent than in the past, having caused more than 1,035 hospitalizations, eight deaths and possibly 51 cases of paralysis, all among children.

That’s not to say that the limited scope of Ebola—four confirmed U.S. cases at presstime—justifies complacency. Officials are urging ID teams to be on high alert for Ebola virus disease (EVD), and some hospital pharmacists have already responded by making sure plans are in place for obtaining investigational antivirals and providing other supportive care services.

Such efforts are clearly needed. “We had to rule out Ebola in Columbus last night at 10 p.m. The patient was negative, but we’re ready,” said Debra Goff, PharmD, an ID specialist at The Ohio State University College of Pharmacy.

For more details on how pharmacists are contributing to the preparedness effort, see pages 28 and 29.

Adverse Events From PGx Gap Still a Problem

Inclusion of three top chemotherapy drugs draws ire

Austin, Texas—Black patients experiencing “huge” warfarin overdoses.

Patients with autism showing clinically significant variations in drug metabolism. Researchers alleging bias in clopidogrel studies.

These were just a few top-line findings from nearly 20 pharmacogenetics (PGx) research papers presented at the American College of Clinical Pharmacy (ACCP) 2014 annual meeting.

G

enentech has moved all of its cancer infusion medications to the specialty distribution chain to ensure patient safety and better inventory control.

However, some hospitals are unhappy with this decision, citing several potential adverse consequences, including significantly higher drug purchasing costs, treatment delays, increased administrative burdens and a resultant strain on the manufacturer–oncology team relationship.

Charlotte Arnold, a spokesperson for Genentech in South San Francisco, Calif., said safety issues and other patient-focused concerns motivated the decision.

“We are committed to patient safety and protecting the integrity of our medicines as they move through the supply chain, and we believe the specialty distribution model best serves patients’ safety and access to our infused cancer medicines,” Ms. Arnold said.

Niesha Griffith, RPh, MS, FASHP, an administrator of Oncology Pharmacy and Infusion

see ADVERSE EVENTS, page 12

see CHEMO DRUGS, page 38

•

Genentech Doubles Down On Specialty Pharmacy Model

•

New Product AHP Launches New Unit-Dose Products.

See page 49

Get the App

40

Is IV Ibuprofen the Missing Piece to Your Surgical Pain Management Puzzle?

BRIEF SUMMARY OF PRESCRIBING INFORMATION CALDOLOR ® (ibuprofen) Injection WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.1)].

• Caldolor is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4.3) and Warnings and Precautions (5.1)].

Gastrointestinal Risk • NSAIDs increase the risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE: 1.1 Analgesia (Pain): Caldolor is indicated in adults for the management of mild to moderate pain and the management of moderate to severe pain as an adjunct to opioid analgesics.

1.2 Antipyretic (Fever): Caldolor is indicated for the reduction of fever in adults.

4 CONTRAINDICATIONS 4.1 HYPERSENSITIVITY: Caldolor is contraindicated in patients with known hypersensitivity (e.g., anaphylactoid reactions and serious skin reactions) to ibuprofen [see Warnings and Precautions (5.7, 5.8)].

4.2 ASTHMA AND ALLERGIC REACTIONS: Caldolor is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.12)].

4.3 CORONARY ARTERY BYPASS GRAFT (CABG): Caldolor is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS: 5.1 Cardiovascular Thrombotic Events: Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4.3)].

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. 5.2 Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation: NSAIDs, including ibuprofen, can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately

1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. These trends continue ysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the and symptoms of serious skin manifestations, and to discontinue Caldolor at the first appearance of skin rash course of therapy. However, even short-term therapy is not without risk. Prescribe NSAIDs, including Caldolor, or any other sign of hypersensitivity. 5.9 Pregnancy: Starting at 30 weeks gestation, Caldolor, and other NSAIDs, with extreme caution in those with a prior history of ulcer disease or GI bleeding. Patients with a prior history should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur [see of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for devel- Use in Specific Populations (8.1)]. 5.10 Masking Inflammation and Fever: The pharmacological activity of oping a GI bleed compared to treated patients with neither of these risk factors. Other factors that increase the ibuprofen in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoag- complications of presumed noninfectious, painful conditions. 5.11 Hematological Effects: Caldolor must be ulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most diluted prior to use. Infusion of the drug product without dilution can cause hemolysis [see Dosage and reports of spontaneous fatal GI events are in elderly or debilitated patients, and therefore special care should be Administration (2.3)]. Anemia may occur in patients receiving NSAIDs, including ibuprofen. This may be due to taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with fluid retention, occult or gross GI blood loss, or an incompletely described effect on erythropoiesis. In patients an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain on long-term treatment with NSAIDs, including ibuprofen, check hemoglobin or hematocrit if they exhibit any alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate addi- signs or symptoms of anemia or blood loss. NSAIDs inhibit platelet aggregation and have been shown to protional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the long bleeding time in some patients. Unlike aspirin, their effects on platelet function are less severe quantitatively, NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve of shorter duration, and reversible. Carefully monitor patients who may be adversely affected by alterations in NSAIDs should be considered. 5.3 Hepatic Effects: Borderline elevations of one or more liver tests may occur platelet function, such as those with coagulation disorders or patients receiving anticoagulants. 5.12 Pre-existing in up to 15% of patients taking NSAIDs, including ibuprofen. These laboratory abnormalities may progress, may Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirinremain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approxi- sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross-reactivity mately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clin- between aspirin and NSAIDs has been reported in such aspirin-sensitive patients, including bronchospasm, ical trials with NSAIDs. In addition, rare cases of severe hepatic reactions have been reported, including jaundice, Caldolor is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all fulminant hepatitis, liver necrosis and hepatic failure, some with fatal outcomes. A patient with symptoms and/or patients with pre-existing asthma. 5.13 Ophthalmological Effects: Blurred or diminished vision, scotomata, and signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the changes in color vision have been reported with oral ibuprofen. Discontinue ibuprofen if a patient develops such development of a more severe hepatic reaction while on therapy with ibuprofen. If clinical signs and symptoms con- complaints, and refer the patient for an ophthalmologic examination that includes central visual fields and color sistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ibuprofen vision testing. 5.14 Aseptic Meningitis: Aseptic meningitis with fever and coma has been observed in patients should be discontinued. 5.4 Hypertension: NSAIDs, including ibuprofen, can lead to onset of new hyper- on oral ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythetension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of matosus and related connective tissue diseases, it has been reported in patients who do not have underlying CV events. Use NSAIDs, including ibuprofen, with caution in patients with hypertension. Monitor blood pressure chronic disease. If signs or symptoms of meningitis develop in a patient on ibuprofen, give consideration to closely during the initiation of NSAID treatment and throughout the course of therapy. Patients taking ACE whether or not the signs or symptoms are related to ibuprofen therapy. 5.15 Monitoring: Because serious GI tract inhibitors, thiazides, or loop diuretics may have impaired response to these therapies when taking NSAIDs. ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms 5.5 Congestive Heart Failure and Edema: Fluid retention and edema have been observed in some patients tak- of GI bleeding. Patients on long-term treatment with NSAIDs should have CBC and chemistry profiles checked ing NSAIDs. Use Caldolor with caution in patients with fluid retention or heart failure. 5.6 Renal Effects: Use cau- periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestation when initiating treatment with Caldolor in patients with considerable dehydration. Long-term administration tions occur (e.g., eosinophilia, rash), or abnormal liver tests persist or worsen, discontinue Caldolor. of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in 6 ADVERSE REACTIONS: The following serious adverse reactions are discussed elsewhere in the labeling: patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these • Cardiovascular thrombotic events [see Boxed Warning and Warnings and Precautions (5.1)] patients, administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and, sec- • Gastrointestinal effects [see Boxed Warning and Warnings and Precautions (5.2)] ondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this • Hepatic effects [see Warnings and Precautions (5.3)] reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics or ACE • Hypertension [see Warnings and Precautions (5.4)] inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment • Congestive heart failure and edema [see Warnings and Precautions (5.5)] state. No information is available from controlled clinical studies regarding the use of Caldolor in patients with • Renal effects [see Warnings and Precautions (5.6)] advanced renal disease. If Caldolor therapy must be initiated in patients with advanced renal disease, closely mon- • Anaphylactoid reactions [see Warnings and Precautions (5.7)] itor the patient’s renal function. 5.7 Anaphylactoid Reactions: As with other NSAIDs, anaphylactoid reactions • Serious skin reactions [see Warnings and Precautions (5.8)] may occur in patients without known prior exposure to ibuprofen. Caldolor is contraindicated in patients with The most common adverse reactions reported in clinical studies are nausea, flatulence, vomiting, and headache. the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or The most common reason for discontinuation due to adverse events in controlled trials of Caldolor is pruritus (<1%). without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs 6.1 Clinical Studies Experience: Because clinical trials are conducted under widely varying conditions, adverse [see Contraindications (4.2)]. 5.8 Serious Skin Reactions: NSAIDs, including ibuprofen, can cause serious skin reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrol- another drug and may not reflect the rates observed in practice. During clinical development, 560 patients were

• Caldolor reduces surgical pain1,2,3 • Caldolor can be used prior to surgery1 • Caldolor reduces narcotic consumption1 • Caldolor offers an Anti-Inflammatory action3

> Caldolor offers New Price Assurance Program For more information, please contact Caldolor@CumberlandPharma.com

Caldolor is indicated in adults for the management of:3 • Mild to moderate pain • Moderate to severe pain as an adjunct to opioid analgesics • Reduction of fever • Caldolor must be diluted prior to use. Infusion of the drug product without dilution can cause hemolysis.3 • The most common adverse reactions are nausea, flatulence, vomiting, headache, hemorrhage, and dizziness (>5%).3 1. Singla N, Rock A, Pavliv L. Pain Med. 2010; 11: 1284-93.

2. Data on file, Cumberland Pharmaceuticals Inc. Nashville, TN. 3. Prescribing Information for Caldolor, 2014. Cumberland Pharmaceuticals Inc. Nashville, TN.

See full Prescribing Information including Boxed Warning at www.Caldolor.com exposed to Caldolor, 438 in pain and 122 with fever. In the pain studies, Caldolor was started intra-operatively and administered at a dose of 400 mg or 800 mg every six hours for up to three days. In the fever studies, Caldolor was administered at doses of 100 mg, 200 mg, or 400 mg every four or six hours for up to 3 days. The most frequent type of adverse reaction occurring with oral ibuprofen is gastrointestinal. Pain Studies: The incidence rates of adverse reactions listed in the following table were derived from multi-center, controlled clinical studies in post-operative patients comparing Caldolor to placebo in patients also receiving morphine as needed for post-operative pain.

Table 1: Post-operative Patients with Adverse Reactions Observed in ≥ 3% of Patients in any Caldolor Treatment Group in Pain Studies* Caldolor 400 mg 800 mg Placebo Event (N=134) (N=304) (N=287) Any Reaction 118 (88%) 260 (86%) 258 (90%) Nausea 77 (57%) 161 (53%) 179 (62%) Vomiting 30 (22%) 46 (15%) 50 (17%) Flatulence 10 (7%) 49 (16%) 44 (15%) Headache 12 (9%) 35 (12%) 31 (11%) Hemorrhage 13 (10%) 13 (4%) 16 (6%) Dizziness 8 (6%) 13 (4%) 5 (2%) Edema peripheral 1 (<1%) 9 (3%) 4 (1%) Urinary retention 7 (5%) 10 (3%) 10 (3%) Anemia 5 (4%) 7 (2%) 6 (2%) Decreased hemoglobin 4 (3%) 6 (2%) 3 (1%) Dyspepsia 6 (4%) 4 (1%) 2 (<1%) 4 (3%) 4 (1%) 4 (1%) Wound hemorrhage Abdominal discomfort 4 (3%) 2 (<1%) 0 Cough 4 (3%) 2 (<1%) 1 (<1%) Hypokalemia 5 (4%) 3 (<1%) 8 (3%) * All patients received concomitant morphine during these studies.

Fever Studies: Fever studies were conducted in febrile hospitalized patients with malaria and febrile hospitalized patients with varying causes of fever. In hospitalized febrile patients with malaria, the adverse reactions observed in at least two Caldolor-treated patients included abdominal pain and nasal congestion. In hospitalized febrile patients (all causes), adverse reactions observed in more than two patients in any given treatment group are presented in the table below.

Table 2: Patients with Adverse Reactions Observed in ≥ 3% of Patients in any Caldolor Treatment Group in All-Cause Fever Study Caldolor 100 mg 200 mg 400 mg Placebo Event N=30 N=30 N=31 N=28 Any Reaction 27 (87%) 25 (83%) 23 (74%) 25 (89%) Anemia 5 (17%) 6 (20%) 11 (36%) 4 (14%) Eosinophilia 7 (23%) 7 (23%) 8 (26%) 7 (25%) Hypokalemia 4 (13%) 4 (13%) 6 (19%) 5 (18%) Hypoproteinemia 3 (10%) 0 4 (13%) 2 (7%) Neutropenia 2 (7%) 2 (7%) 4 (13%) 2 (7%) Blood urea increased 0 0 3 (10%) 0 Hypernatremia 2 (7%) 0 3 (10%) 0 Hypertension 0 0 3 (10%) 0 Hypoalbuminemi 3 (10%) 1 (3%) 3 (10%) 1 (4%) Hypotension 0 2 (7%) 3 (10%) 1 (4%) Diarrhea 3 (10%) 3 (10%) 2 (7%) 2 (7%) Pneumonia bacterial 3 (10%) 1 (3%) 2 (7%) 0 Blood LDH increased 3 (10%) 2 (7%) 1 (3%) 1 (4%) Thrombocythemia 3 (10%) 2 (7%) 1 (3%) 0 Bacteremia 4 (13%) 0 0 0 7 DRUG INTERACTIONS: 7.1 Aspirin: When ibuprofen is administered with aspirin, ibuprofen’s protein binding is reduced, although the clearance of free ibuprofen is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of Caldolor and aspirin is not generally recommended because of the potential for increased adverse effects. 7.2 Anticoagulants: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a higher risk of serious GI bleeding than users of either drug alone [see Warnings and Precautions (5.2)]. 7.3 ACE Inhibitors: NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. 7.4 Diuretics: Clinical studies and postmarketing observations have shown that ibuprofen can reduce the natriuretic effects of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, observe patients closely for signs of renal failure, as well as to assure diuretic efficacy [see Warnings and Precautions (5.6)]. 7.5 Lithium: NSAIDs have produced elevations of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance of lithium decreased by 20%. This effect has been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity. 7.6 Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This indicates that NSAIDs may enhance the toxicity of methotrexate. Use caution when NSAIDs are administered concomitantly with methotrexate. 7.7 H-2 Antagonists: In studies of human volunteers, co-administration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations.

8 USE IN SPECIFIC POPULATIONS: 8.1 Pregnancy: Teratogenic effects - Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation. Starting at 30 weeks gestation, Caldolor, and other NSAIDs, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may

occur. Caldolor can cause fetal harm when administered to a pregnant woman starting at 30 weeks gestation.

There are no adequate, well-controlled studies in pregnant women. Prior to 30 weeks gestation, Caldolor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. 8.2 Labor and Delivery: The effects of Caldolor on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia and delayed parturition, and decreased pup survival. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Caldolor, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use: Safety and effectiveness of Caldolor for management of pain and reduction of fever has not been established in pediatric patients below the age of 17 years. 8.5 Geriatric Use: Clinical studies of Caldolor did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients are at increased risk for serious GI adverse events.

10 OVERDOSAGE: The following signs and symptoms have occurred in individuals following an overdose of oral ibuprofen: abdominal pain, nausea, vomiting, drowsiness, and dizziness. There are no specific measures to treat acute overdosage with Caldolor. There is no known antidote to ibuprofen. In case of an overdosage, discontinue Caldolor therapy and consider contacting a regional poison control center at 1-800-222-1222.

Manufactured for: Cumberland Pharmaceuticals Inc., Nashville, TN 37203 US Patent Number 6,727,286

PAD1470714

©2014 Cumberland Pharmaceuticals Inc. All rights reserved.

4 Up Front

Pharmacy Practice News • November 2014

Capsules

In Spain, Value of Pharmacy Shines Via Prevention of Chemotherapy Drug Errors

Web Exclusives Visit us online for Web-exclusive content.

Links to all the stories below can be found at: pharmacypracticenews.com/webex1114 or via your smart phone by scanning the adjacent 2D barcode.

T

Combination Therapy for COPD Yields Better Outcomes

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mong older adults with chronic obstructive pulmonary disease (COPD), newly prescribed long-acting β-agonist (LABAs) and inhaled corticosteroid (ICS) combination therapy, compared with newly prescribed LABAs alone, was associated with a lower risk for death or COPD hospitalization, according to a recent study out of Toronto, Canada. The combination therapy was particularly effective in COPD patients with comorbid conditions such as asthma.

Dosage of HIV Drug May Be Ineffective for 50% of Black Patients

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any black patients with HIV might not be receiving effective doses of the HIV drug maraviroc (Selzentry, ViiV Healthcare), suggested a study from Johns Hopkins University School of Medicine. Initial clinical trials included mostly Americans of European descent, who generally lack a protein that is key to clearing the medication. The Hopkins study results demonstrated that people with maximum levels of the protein, including nearly 50% of blacks, end up with less of maraviroc than those who lack the protein when given the same dose (Drug Metab Dispos 2014 Aug 12. [Epub ahead of print]).

High Frequency of Medication Errors In Children Reported

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very year, an average of 63,358 medication errors occur in children younger than age 6, and 25% of those errors are in infants, younger than 12 months old— that comes down to a child in the United States being given the wrong medicine or wrong dose every eight minutes, according to a new study in the journal Pediatrics (2014;134:867-876).

he push to get hospital pharmacists out of the basement and into patient care is not exclusive to the United States: The profession has also made great strides overseas in helping physician colleagues boost clinical outcomes.

A new study by pharmacists from the Hospital Costa del Sol, in Marbella, Málaga, Spain, shows just how effective that practice model can be. The investigators found that nearly half of patients undergoing chemotherapy were at risk for chemotherapy-related drug interactions (Int J Clin Pharm 2014 Oct 19. [Epub ahead of print]).

When pharmacists intervened, most of the physicians whose drug orders were being reviewed accepted the requested change in medication, potentially averting harm to patients.

The study was conducted in part to determine the prevalence of potential drug interactions in this at-risk patient population, according to lead author M. Carmen LopezMartin, MD, of the Pharmacy Department, Hospital Costa del Sol. “Cancer patients are especially vulnerable to drug interactions, which may alter the efficacy and toxicity of treatment, leading to severe clinical consequences,” Dr. Lopez-Martin said. Hence, the key clinical endpoints of the study were to determine the incidence of such interactions in patients receiving chemotherapy, as well as to identify the drugs most frequently involved, investigate the influence of the pharmacist’s interventions and verify the degree of acceptance of pharmacist’s recommendations by the medical team.

The study was conducted in the oncology department of a Spanish tertiary hospital, the researchers said. During the three-month period of observation, all the drug interactions were analyzed using two databases, and recommendations were made when clinically significant interactions (CSIs) were identified.

Of the 75 patients included, 31 (41%) presented with CSIs, Dr. Lopez-Martin reported. Most interactions were among drugs included in the patient’s usual treatment. The principal drug groups involved in CSIs were cytostatic agents, antiemetics and antidepressants.

The hospital pharmacist intervened on 20 occasions. These interventions mainly focused on recommendations to modify or discontinue drug prescriptions and were followed in 94% of cases.

The study results illustrate that “the incidence of drug interactions in cancer patients is high, and they most often involve medications to treat comorbid conditions,” Dr. Lopez-Martin and her colleagues reported. “The pharmacist, as a member of the multidisciplinary team, can contribute significantly by checking the treatment prescribed and detecting interactions.”

The goal of such efforts should be “to reduce medication-related problems and to optimize drug therapy” for these at-risk patients, the authors concluded.

—David Bronstein

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6 Up Front

Pharmacy Practice News • November 2014

Research ASHP Foundation Literature Awards:

A Strong Health Care Role for Pharmacists inners of this year’s Literature Awards, given out by the American Society of Health-System Pharmacists (ASHP) Research and Education Foundation, are being recognized for documenting how pharmacists improve outcomes in transplant medicine, the dangers of caffeinated energy drinks and other impressive feats of scholarship and investigation.

In advance of a ceremony to be held at the ASHP Midyear Clinical Meeting in Anaheim, Calif., honoring the awardees, Pharmacy Practice News spoke with the winners about their work.

Sustained Contributions Next time you pass Glen T. Schumock, PharmD, MBA, PhD, in a conference hall, you might want to thank him for the reimbursement you receive for your clinical services. That’s because Dr. Schumock has dedicated much of his still-thriving career to conducting some of the highest-quality research demonstrating that hospital and health-system pharmacists are financial assets to their employers.

“Glen’s seminal papers on the economic benefit of clinical pharmacy services are some of the most highly cited works in the pharmacy literature,” said Jerry Bauman, PharmD, who is the dean of the College of Pharmacy at the University of Illinois in Chicago, where Dr. Schumock is a professor and the head of the Department of Pharmacy Systems, Outcomes and Policy. “Nearly every institutional

land Journal of Medicine, which he coauthored, that identified the risk for red cell aplasia with epoetin therapy (2004;351:29-34); and a one-page commentary in which he and a colleague laid out criteria for determining whether an adverse event can be prevented ((Hosp Pharm 1992;27:547).

Reflecting on the widespread use of those criteria in adverse event reporting systems and software worldwide, Dr. Schumock said, “We just thought we were sharing some of our thoughts … we didn’t expect it to be of such interest.”

With his appointment as a department head, Dr. Schumock has expanded his focus beyond conducting his own research, but is sticking with his unstated mission of helping the field of pharmacy advance.

“I’m at a point now where I can use my own experience to help younger faculty and graduate students pursue their own ambitions,” he said.

Dr. Baumann added, “It’s faculty leaders like Glen that make our college program not only successful but enjoyable.”

Pharmacy Practice Research One could say that, with her many publications on the effect of pharmacist management of transplant recipients, Marie A. Chisholm-Burns, PharmD, MPH, MBA, has single-handedly carved out a prominent role for pharmacists in this area of care, but that would be only partially true.

“Marie is really successful not only at building strong research but at building

‘I’m at a point now where I can use my own experience to help younger faculty and graduate students pursue their own ambitions.’

—Glen T. Schumock, PharmD, MBA, PhD pharmacy leader, both in the United States and abroad, use them to justify their clinical pharmacy programs.”

Dr. Schumock is a West Coast transplant to Chicago with an admittedly “laid-back” personality. However, with more than 200 publications under his belt, Dr. Schumock has proven an easygoing spirit does not keep him away from the research bench.

Some of Dr. Schumock’s publications stand out in particular: a 1996 article in Pharmacotherapy (1996;16:11881208) that helped refine and cement the research methodology used to demonstrate pharmacists’ financial impact; a 2004 publication in The New Eng-

strong teams,” said Christina A. Spivey, PhD, an assistant professor in the Department of Clinical Pharmacy at the University of Tennessee Health Science Center (UTHS) College of Pharmacy, in Memphis, and who was part of the multidisciplinary group of investigators Dr. Chisholm-Burns assembled for the recognized study.

Indeed, through her academic and interpersonal skills, Dr. ChisholmBurns, who is the dean and a professor at the UTHS College of Pharmacy, has garnered the unwavering loyalty of colleagues like Dr. Spivey, who has worked with the awardee for several years at many institutions.

Contract

No Contract

100

Adherence, %

W

80 60 40 20 0

Baseline

3 mo

6 mo

9 mo

12 mo

Figure. Immunosuppressant drug adherence rates.

‘Having the study appear in such a highimpact journal will help get the word out to other providers that pharmacists can play an important part in managing transplant patients.’

—Marie A. Chisholm-Burns, PharmD, MPH, MBA The current study examined the effect of a one-year pharmacist-administered behavioral contract on tacrolimus and cyclosporine adherence and health care utilization in adult renal transplant patients.

As per the terms of the contract, patients met or spoke by phone with a specialty pharmacist for approximately 20 minutes every three months during a one-year period. At each meeting, they reviewed the patient’s drug adherence and improved medication use by reinforcing the patient’s motivation to follow the prescribed regimen; addressing barriers to adherence; identifying social supports that might help with adherence; implementing tools, such as text messaging–based dosing reminders; and discussing the consequences of nonadherence.

“The contracts carved out a time for patients and pharmacists to talk, which is really important in and of itself,” said Dr. Chisholm-Burns.

The findings showed that the 76 patients who committed to a contract had significantly higher adherence rates than a control group of 74 similar patients who had not been offered the contract intervention (Figure).

Additionally, 23.9% of the intervention patients were hospitalized over the oneyear period compared with 57.3% of the control group (risk ratio, 1.785; 95% confidence interval [CI], 1.314-2.425).

A projection based on an estimated hospitalization cost of $2,000 per day found the total savings in the interven-

tion group was approximately $27,852 per month. Importantly, the results were striking enough to secure the study a spot in the prestigious American Journal of Transplantation (2013;13:2364-2373).

“Having the study appear in such a high-impact journal will help get the word out to other providers that pharmacists can play an important part in managing transplant patients,” Dr. Chisholm-Burns said.

Innovation in Pharmacy Practice There is a noteworthy trend in this year’s ASHP Foundation awards: A subset unequivocally demonstrates the critical role pharmacists play in providing optimal, multidisciplinary care.

The study conducted by Joseph Cesarz, PharmD, MS, fits that trend. “As pharmacists, we tend to do a good job of bragging about ourselves to ourselves, so it’s important that positive findings are published in nonpharmacy journals,” said Dr. Cesarz, whose own study appeared in Annals of Emergency Medicine (2013;61:209-214).

As a first-year resident in the emergency department (ED) at the University of Wisconsin Hospital & Clinics in Madison, Dr. Cesarz and his colleagues saw that a substantial number of patients returned to the ED shortly after discharge, sometimes due to medication-related reasons.

To improve the accuracy of discharge prescription orders, Dr. Cesarz, who is now manager of ambulatory pharmacy services at the university, and his

•

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*Betamethasone 6 mg/mL as 3 mg/mL Betamethasone Sodium Phosphate and 3 mg/mL Betamethasone Acetate The intra-articular or soft tissue administration of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis.

Important Safety Information: Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use.

As with any potent corticosteroid, adverse events have been associated with Betamethasone Sodium Phosphate and Betamethasone Acetate, Injectable Suspension, USP including fluid and electrolyte disturbances, as well as adverse reactions involving the following systems: allergic reactions, cardiovascular, dermatologic, endocrine, gastrointestinal, metabolic, musculoskeletal, neurological/ psychiatric, ophthalmic and other. Corticosteroids may also affect immune response. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy.

Betamethasone Sodium Phosphate and Betamethasone Acetate, Injectable Suspension, USP should not be administered intravenously or used in systemic fungal infections. Vaccination administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.

Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infections. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles and to seek medical advice without delay if exposed.

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INDICATIONS AND USAGE When oral therapy is not feasible, the intramuscular use of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as follows: Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions.

Dermatologic Diseases Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome).

Endocrine Disorders Congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis.

Hydrocortisone or cortisone is the drug of choice in primary or secondary adrenocortical insufficiency. Synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance.

Gastrointestinal Diseases To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis.

Hematologic Disorders Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, selected cases of secondary thrombocytopenia.

Miscellaneous Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy.

Neoplastic Diseases For palliative management of leukemias and lymphomas.

Nervous System Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy.

Ophthalmic Diseases Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids.

Renal Diseases To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus.

Respiratory Diseases Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis.

Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus.

The intra-articular or soft tissue administration of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis.

The intralesional administration of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated for alopecia areata; discoid lupus erythematosus; keloids; localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; necrobiosis lipoidica diabeticorum.

Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, may also be useful in cystic tumors of an aponeurosis or tendon (ganglia).

CONTRAINDICATIONS Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is contraindicated in patients who are hypersensitive to any components of this product. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura.

WARNINGS Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension should not be administered intravenously.

Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use.

General Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy.

In patients on corticosteroid therapy subjected to any unusual stress, hydrocortisone or cortisone is the drug of choice as a supplement during and after the event.

Cardio-renal Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Endocrine Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Infections General Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection.

Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS, Drug Interactions, Amphotericin B Injection and Potassium-Depleting Agents section).

Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria.

Tuberculosis The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Vaccination Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted Viral Infections Chickenpox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. If exposed to chickenpox, prophylaxis with varicella zosterr immune globulin (VZIG) may be indicated.

If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered.

Neurologic Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS, Gastrointestinal and Neurologic/ Psychiatric sections).

High doses of corticosteroids, including Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, should not be used for the treatment of traumatic brain injury.

Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex.

PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial.

The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual.

Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Cardio-renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy. Therefore, in any situation of stress occurring during that period, naturally occurring glucocorticoids (hydrocortisone cortisone), which also have salt-retaining properties, rather than betamethasone, are the appropriate choices as replacement therapy in adrenocorticoal deficiency states.

Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation.

Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.

There is an enhanced effect of corticosteroids in patients with cirrhosis.

Intra-Articular and Soft Tissue Administration Intra-articular injected corticosteroids may be systematically absorbed.

Appropriate examination of any joint fluid present is necessary to exclude a septic process.

A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.

Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously injected joint is not usually recommended.

Corticosteroid injection into unstable joints is generally not recommended.

Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS, Musculoskeletal section).

Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (ie, decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (ie, postmenopausal women) before initiating corticosteroid therapy.

Neuro-psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect (see DOSAGE AND ADMINISTRATION). An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (eg, myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (eg, pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Ophthalmic Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Information for Patients Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection.

Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Drug Interactions Aminoglutethimide Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression.

Amphotericin B Injection and Potassium-Depleting Agents When corticosteroids are administered concomitantly with potassium-depleting agents (ie, amphotericin-B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Antibiotics Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance.

Anticholinesterases Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.

Anticoagulants, Oral Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.

Antidiabetics Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

Antitubercular Drugs Serum concentrations of isoniazid may be decreased.

Cholestyramine Cholestyramine may increase the clearance of corticosteroids.

Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.

Digitalis Glycosides Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.

Estrogens, Including Oral Contraceptives Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.

Hepatic Enzyme Inducers (eg, barbiturates, phenytoin, carbamazepine, rifampin) Drugs which induce hepatic microsomal drug-metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased.

Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased riskk of corticosteroid side effects.

Nonsteroidal Anti-inflammatory Agents (NSAIDS) Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids.

Skin Tests Corticosteroids may suppress reactions to skin tests.

Vaccines Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Route administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination section).

Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients.

Pregnancy Teratogenic Effects Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers Systematically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman.

Pediatric Use The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids, which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, eg, severe asthma and wheezing, are based on adequate and wellcontrolled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systematically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (ie, cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose.

Geriatric Use No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and young patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS (listed alphabetically, under each subsection) Allergic Reactions Anaphylactoid reaction, anaphylaxis, angioedema.

Cardiovascular Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine Decreased carbohydrate and glucose tolerance, development of cushingoid state, glucosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Fluid and Electrolyte Disturbances Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention.

Gastrointestinal Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis.

Metabolic Negative nitrogen balance due to protein catabolism.

Musculoskeletal Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures.

Neurologic/Psychiatric Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS, Neurologic section).

Ophthalmic Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections.

Other Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain.

OVERDOSAGE Treatment of acute overdose is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced.

DOSAGE AND ADMINISTRATION Benzyl alcohol as a preservative has been associated with a fatal “Gasping Syndrome” in premature infants and infants of low birth weight. Solutions used for further dilution of this product should be preservative-free when used in the neonate, especially the premature infant. The initial dosage of parenterally administered Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension may vary from 0.25 to 9.0 mg per day depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administrations in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.

It Should Be Emphasized That Dosage Requirements Are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient.

After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. ®

SEE FULL PRESCRIBING INFORMATION FOR FULL DOSAGE AND ADMINISTRATION DIRECTIONS. BS1019

Revised July 2014

Up Front 9

Pharmacy Practice News • November 2014

Research Student Research Award

LIT AWARDS continued from page 6

colleagues modified how orders were being processed. “Before our study, prescriptions were being printed in a number of locations in the ED, so we redirected them to a single printer in the ED pharmacy,” he explained.

Additionally, unlike the hospital’s inpatient discharge process, the ED did not have a hard-stop procedure in place ensuring pharmacists reviewed prescriptions; they changed that as well.

For a three-week period, ED pharmacists working during regular hours reviewed all discharge prescriptions

Jennifer K. Phan, PharmD, vividly remembers the high school assignment that sparked her interest in pharmacy.

“We were performing a lab experiment using a household herb to see if a zone of inhibition would form,” recalled Dr. Phan, who is now executive staff pharmacist for Target in Santa Rosa, Calif. “I had always been fascinated by science, but that simple exercise of discovering herbs that could prove successful in preventing infection led me to focus on health care and, ultimately, pharmacy.”

Following that turning point, Dr. Phan accelerated down her path to a career in health care: a stint volunteering at a

‘As pharmacists, we tend to do a good job of bragging about ourselves to ourselves, so it’s important that positive findings are published in nonpharmacy journals.’

—Joseph Cesarz, PharmD, MS

Table. Pharmacist interventions.

Intervention

Incidence

Examples/Comment

Medication error prevention

5.5% (37/674) of prescriptions

Quetiapine prescribed for patient on phenytoin. The interaction would decrease quetiapine levels fivefold. ED pharmacist worked with prescriber to identify alternative agent.

Medication optimization

4.6% (31/674) of prescriptions

Oxcarbazepine tablets prescribed for a patient unable to swallow pills. ED pharmacist discussed with prescriber and changed to oxcarbazepine solution.

Ann Emerg A e g Med. ed 2013;61:209-214 0 3;6 09

and documented errors and interventions. A look back at the data showed that 68 of the 674 prescriptions (10.1%) they reviewed required correction (Table). Strikingly, the intervention rate for prescriptions for pediatric patients was 23.6% (17 of 72).

“There was a belief that the computerized prescriber order entry system we had in place would catch errors in advance, but there were still significant mistakes,” Dr. Cesarz said, adding that the interventions were reviewed by ordering physicians.

The results compelled ED management to permanently adopt a policy of pharmacist discharge order review, noted study co-author Aaron Steffenhagen, PharmD, who is a pharmacy manager at the University of Wisconsin Hospital and Clinics, Madison.

“Dr. Cesarz put forth extraordinary efforts that resulted not only in a meaningful publication, but more importantly in an impactful service that lives on beyond the time he was involved in the research,” he said.

pediatric urgent care clinic; an internship at Merck & Co., Inc.; a pre-pharmacy degree at University of the Pacific, in Stockton, Calif.; and graduate studies at the university’s Thomas J. Long School of Pharmacy and Health Sciences.

During clinical rotations at Travis Air Force Base in Fairfield, Calif., during her last year as a graduate student, Dr. Phan and her preceptor, Sachin Shah, PharmD, an associate professor of pharmacy practice at University of the Pacific, collaborated on the study she is receiving this award for. “Jen can work for hours without getting tired,” Dr. Shah said. “She is so particular that if she was asked to take two blood pressure readings two minutes apart, they would actually be exactly 120 seconds apart.”

That may not be hyperbole. Dr. Phan had the chance to perfect her blood pressure (BP) measurements during the study, in which she and Dr. Shah documented the effects of caffeinated (215 mg caffeine) and noncaffeinated (6 mg caffeine) five-hour energy shots on peripheral and central hemody-

‘It’s concerning to postulate the effects energy drinks could have on older individuals or those with preexisting health conditions.’

—Jennifer K. Phan, PharmD namic parameters (Pharmacotherapy ( 2014;34:555-560). They enrolled 10 healthy individuals and administered each type of drink in a blinded manner and at least six days apart in each participant. Their results revealed dramatically greater increases in peripheral and central systolic BP from baseline after consumption of the caffeinated energy shots compared with the noncaffeinated versions. Peripheral and central pulse pressure was also consistently higher after consumption of the caffeinated energy shots.

The study participants were healthy and young (mean age 23 years), Dr. Phan noted, saying that “it’s concerning to postulate the effects energy drinks could have on older individuals or those with preexisting health conditions.”

Drug Therapy Research Award For every researcher that loses themselves in the details of a study, there are those like Katsiaryna Bykov, PharmD, MS, who examine masses of data trying to uncover critical patterns.

“In school, we learn that clinical trials are the gold standard of research, but they don’t always provide answers to clinically relevant questions—this is where observational studies could be of help,” said Dr. Bykov, who is a pharmacoepidemiologist in the Division of

in the immediate postoperative period was associated with a higher risk of nosocomial pneumonia in this population, compared with use of the older class of acid suppressors. At first glance, the numbers Dr. Bykov and her colleagues uncovered might not have seemed striking: 5% of PPI recipients and 4.3% of H2RA recipients developed nosocomial pneumonia in the immediate post-operative period. However, on a relative risk scale and after adjusting for potential confounders, these numbers represented a 19% increase in nosocomial pneumonia risk associated with PPI therapy, compared with H2RAs (relative risk, 1.19; 95% confidence interval, 1.03-1.38).

“Although the difference seems small, given the frequency with which CABG surgery is performed and the importance of nosocomial pneumonia in this population, it’s clinically meaningful and I think this is something clinicians should consider when making treatment decisions,” said Dr. Bykov, who is currently working toward a PhD in epidemiology at Harvard.

She said that clinical pharmacists need to develop a greater appreciation of the clinical value of pharmacoepidemiologic studies.

“To make evidence-based drug therapy decisions, pharmacists should be able to

‘In school, we learn that clinical trials are the gold standard of research, but they don’t always provide answers to clinically relevant questions—this is where observational studies could be of help.’

—Katsiaryna Bykov, PharmD, MS Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, Boston. She has declared it her dream “to bring clinical pharmacy and pharmacoepidemiology closer together.”

The retrospective cohort study Dr. Bykov is being awarded for boiled down data from 21,214 coronary artery bypass graft (CABG) surgery patients who received stress ulcer prophylaxis postoperatively, including 46.3% administered proton pump inhibitors (PPIs) and 53.7% given H2 receptor antagonists (H2RA) ( (BMJ 2013;347:f5416).

The data showed that use of PPIs

evaluate observational research, not just clinical trials,” she asserted.

That sense of conviction was welcomed by Brian Bateman, MD, MSc, who was the lead investigator of the awarded study and is an assistant professor of anesthesia in the Division of Pharmacoepidemiology and Pharmacoeconomics at Harvard Medical School, Boston.

“I loved working with Kate, as did everyone else,” Dr. Bateman said.

“She is very bright and hardworking.

She did everything with a smile, and balanced whatever she was working on with grace.”

—David Wild

12 Clinical

Pharmacy Practice News • November 2014

Pharmacogenomics

ADVERSE EVENTS continued from page 1

Given all of that research activity, has the genetic testing discipline finally come of age? Not quite, according to Kelly E. Caudle, PharmD, PhD, BCPS, the coordinator of the Clinical Pharmacogenetics Implementation Consortium (CPIC), Sciences Department at St. Jude Children’s Research Hospital in Memphis, Tenn. “Although there is good evidence to support the potential of genetic testing to improve medication response,” Dr. Caudle said, “uptake of pharmacogenetics into clinical practice has been slow due to the lack of guidance on how to use genetic test results to make informed prescribing decisions.”

Still, it is important for pharmacists to close that gap by being familiar with the latest research, she stressed.

Black Patients at Risk The addition of cytochrome (CYP) P450 2C9 polymorphisms that have been largely ignored in warfarin dosing algorithms could substantially boost dose-prediction accuracy for black patients who carry the variants, according to one of the studies presented at the ACCP meeting. Katarzyna Drozda, PharmD, MS, a postdoctorate research associate at the University of Illinois at Chicago (UIC), who led the warfarin study, said the research was prompted partly by two trials published last year that raised questions about the value of genotype-guided warfarin dosing (N ( Engl J Med d 2013;369:2283-2293; N Engl J Med 2013;369:2294-2303). Only one of the studies enrolled a racially diverse patient group, she said, and neither study included certain CYP2C9 variants found almost exclusively in blacks.

To test whether a more inclusive PGx approach would show different results for black individuals, the researchers enrolled 274 members of that population who were on stable warfarin doses.

They genotyped the subjects not only for the CYP2C9 alleles *2 and *3 and the vitamin K epoxide reductase complex 1 (VKORC1) enzyme that have been widely used in earlier warfarin pharmacogenetic studies, but also the CYP2C9 variants *5, *6, *8, *11 and rs12777823 that occur mostly in blacks.

The researchers found that adding the single-nucleotide single nucleotide polymorphisms *5 and *6 to the widely used warfarin algorithm developed by Brian F. Gage, MD, of Washington University in

St. Louis (www.warfarindosing.org), and reducing the doses for carriers of the *8, *11 and rs12777823 alleles significantly improved the modified algorithm’s predictive performance for black individuals compared with the original one. Dr. Drozda noted that the original algorithm’s estimated dose for blacks was 2.2 mg per day higher than that of the modified one. “This was not only statistically significant,” she said, “but also a huge overdose” for a patient who might only require 3 mg per day to achieve therapeutic stability.

The researchers also looked at the algorithm developed by the International Warfarin Pharmacogenetics Consortium (IWPC) and found a similarly significant overdose pattern; however, the prediction error was much lower at 0.7 mg of warfarin per day.

“There are lots of data showing that the risk for bleeding is highest at the beginning of therapy,” Dr. Drozda told Pharmacy Practice News. “By having better adjustments at the initiation of therapy—using clinical and genetic variants—we can better adjust the dose and potentially avoid those side effects.”

Samuel G. Johnson, PharmD, FCCP, BCPS (AQ-Cardiology), a clinical pharmacy specialist in applied pharmacogenomics at Kaiser Permanente Colorado, in Denver, said the study “showcases the importance of continuous applied translational research in pharmacogenomics—especially in light of the rapid improvements in genetic testing technology and applications.”

Although larger studies have cast doubt on the value of warfarin PGx test-

ing in routine clinical practice, “studies like this one reinforce the potential value of testing for specific ethnic or racial groups,” noted Dr. Johnson, who is also a clinical assistant professor at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Denver.

Web Exclusive

F

or details on study alleging clopidogrel research bias, visit pharmacy practicenews. com/clopidogrel.

PGx and Autism Another ACCP study looked at whether certain CYP2C19 polymorphisms were related to Autism Spectrum Disorders (ASD) symptoms and how those variants might affect the dosing of escitalopram (Lexapro, Forest Labs/Actavis) in patients with ASD. To carry out the investigation, a UIC research team led by Jeffrey R. Bishop, PharmD, MS, a board-certified psychiatric pharmacist who is now at the University of Minnesota College of Pharmacy, in Minneapolis, as an associate professor of experimental and clinical pharmacology, enrolled 97 participants, ages 5 to 50 years, with confirmed ASD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).

The participants were started on escitalopram 2.5 mg per day, with weekly increases of 5 mg for six weeks, unless intolerable side effects developed. The team studied the effect of the titrations on genotypes associated with ultrarapid/increased, extensive/normal and reduced/poor metabolizer categories.

Dr. Bishop said that although the group’s Aberrant Behavior Checklist irritability scores improved overall, one finding was “intriguing and frankly

‘Although there is good evidence to support the potential of genetic testing to improve medication response, [its] uptake into clinical practice has been slow due to the lack of guidance on how to use … test results to make informed prescribing decisions.’

—Kelly E. Caudle, PharmD, PhD, BCPS

unanticipated”: The more rapid metabolizers experienced a reduced tolerance of the titration schedule and a slower dose escalation rate over the course of treatment. “One would hypothesize,” he told Pharmacy Practice News, “that the poor metabolizers would be the ones with dose-related intolerance.”

Dr. Bishop speculated that certain escitalopram metabolites thought to be relatively inactive—“at least as far as how they interact with serotonin and serotonin receptors and transporters in the brain”—might have activity that influences “how the dose trajectory is received within an individual patient.

We really don’t have serum concentrations to evaluate this in depth, so it will have to await future investigations.”

Dr. Johnson said this paper, like the Drozda study, represented “important ongoing work to translate pharmacogenomic study findings into practice in a manner that improves quality, safety and affordability of care.

“Thus,” he said, “it has a high value— especially to inform larger studies. This is a unique perspective given its focus on ASD rather than depression/anxiety, the other indications for escitalopram.

Since many centers perform routine targeted CYP2C19 genotyping for clopidogrel, this study hints at the need to more fully understand the relationship between CYP2C19 and other frequently prescribed medications.”

—Bruce and Joan Buckley Dr. Johnson reported no relevant conflicts of interest. Dr. Drozda reported no conflicts, but noted that a co-researcher, Larisa Cavallari, PharmD, BCPS, was a co-investigator for U.S. Utility Patent Application No. 12/572,909 entitled “CyP2C9*8 alleles correlate with decreased warfarin metabolism and increased warfarin sensitivity.” Published May 27, 2010; Pub. No. US 1010/0180599. Dr. Bishop reported that he joined the Scientific Advisory Board of Physicians Choice Laboratory Services (PCLS), which is weighing entry into the market for PGx testing.

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14 Clinical

Pharmacy Practice News • November 2014

Nutrition

In-Hospital Malnutrition Linked to Poor Outcomes New progress report cites awareness gaps among caregivers

O

ne in three Americans enter a hospital malnourished, which increases their risk for adverse events, such as surgical site infections, postoperative pneumonia and the development of pressure ulcers. So with the Centers for Medicare & Medicaid Services (CMS) withholding payment to hospitals for 11 of these preventable conditions, hospitals and long-term care facilities should be looking at malnutrition as a contributing factor—or so one would think.

Recent research shows that many facilities are missing an opportunity to address malnutrition, which is associated with increased rates of complications and readmission, prolonged hospital length of stay (LOS) and greater mortality. In particular, malnourished patients are two to three times more likely to develop a surgical site infection or postoperative pneumonia ((Arch Surgg 2010;145:148-151) and twice as likely to develop a pressure ulcer ( (Nutrition 2010;26:896-901). Additionally, 45% of patients who fall in the hospital are malnourished ((J Hum Nutr Diet 2007;20:558-564).

“Of course, there is never one thing that influences a patient’s stay in the hospital, but malnutrition can be a significant factor,” said Melissa Parkhurst, MD, an associate professor in the Department of Internal Medicine at the University of Kansas Medical Cen-

ter in Kansas City, and the medical director of Nutrition Support Services at the University of Kansas Hospital. “The data we have over a number of years consistently show that one in three patients enter the hospital already meeting the criteria for malnourishment,” said Dr. Parkhurst, who is also the clinical representative in the Alliance to Advance Patient Nutrition, an interdisciplinary partnership dedicated to raising awareness about malnutrition in hospitals. “We know that if left unattended, about two-thirds will experience further decline while they are in the hospital.”

Also worrisome are the statistics that show that even well-nourished individuals will experience some type of nutritional decline when they enter the hospital because of their illness, poor appetite, dietary restrictions, gastrointestinal problems and other issues, according to Dr. Parkhurst.

“There are multiple reasons why malnutrition in the hospital is an issue,” she said. “The hospital care of a patient is a complex system with a lot of moving parts and a lot of things that are competing for the attention of the physician, nurses and administrators.

Then on top of that, you add a lack of general understanding of the cost of malnutrition and lack of awareness and inaction.”

‘Let’s catch these patients who are already at risk, who are showing signs of malnutrition when they hit the door, and make sure we have a plan in place quickly to intervene and track [their progress].’

—Melissa Parkhurst, MD

by the

numbers Fixing Malnutrition Studies have linked the effective treatment of malnutrition in the hospital with:

54% | reduction in the incidence of pressure ulcers (Curr Opin Clin Nutr Metab Care 2000;3:311-315)

4% | fewer overall complications (Cochrane Database Syst Rev v 2009:CD003288)

28% | decrease in avoidable hospital readmissions (Am J Med d 2006;119:693-699)

2-day | reduction in the average hospital length of stay (J Qual Improve 1999;25:191-206)

These factors make it easy for malnutrition to fall under the caregivers’ radar, she explained. Many patients are placed on NPO (nothing by mouth) orders for long periods or they are taken for radiographs or some other diagnostic test or procedure during mealtime and frequently miss meals.

Others stop eating because they do not like the food, feel nauseated, are experiencing medication-related changes in taste, are depressed or in pain, or have another issue.

Patients’ lack of adequate caloric intake may go unnoticed over time. Even if interventions are put into place, they are not always tracked to see if they are working. It happens every day in hospitals and long-term care facilities across the country, Dr. Parkhurst said.

The ‘Skeleton in the Closet’ Malnutrition in the hospital is not a new problem. In a landmark 1984 study, Charles E. Butterworth Jr., MD, referred to malnutrition as the “skeleton in the hospital closet” because it remains underrecognized and often goes untreated ((Nutr Today 1974;9:4-8).

Because one in three people enter the hospital already meeting the criteria for malnourishment ((Int J Environ Res Public Health 2011;8:514-527), and malnutrition has been linked to increased morbidity and mortality, the Joint Commission mandates that a nutrition assessment be done when a person enters the facility. However, the commission does not provide any guidance about the management of the patient once he or she is identified, which is how that patient falls through the cracks, Dr. Parkhurst pointed out.

If a patient is identified as being malnourished, often he or she is discharged before a full nutritional assessment is performed because the average time for

such an evaluation is five days after admission, which is also the average hospital LOS ((J Parenter Enteral Nutr 2011;35:209-216).

“Dietitians need to do an assessment within a timely fashion of the screening coming back at risk,” Dr. Parkhurst said.

“And the dietitian’s recommendations, which are only implemented about 40% of the time, need to be followed up by the physician-led team.”

The Alliance to Advance Patient Nutrition recently issued a progress report on alleviating hospital-based malnutrition (http://www.malnutrition. com/progressreport). t The report highlights some of the obstacles impeding progress in recognizing and treating malnutrition, as well as recommends a roadmap for institutions to follow.

To change the paradigm will require direct, system-wide and sustained intervention, according to the report. Among the recommendations are: • Hospital administrators and staff must view nutrition as a priority for improving care, quality and cost.

• Clinicians’ roles must be redefined to include nutrition, giving them the power to address a patient’s nutritional needs.

• The electronic health record (EHR) should be leveraged to standardize nutrition documentation and communicate nutrition care plans.

• Someone should take responsibility for the patient’s nutritional status.

The process begins with the screening, Dr. Parkhurst said. A simple, easyto-use tool tied to the EHR should be used. Once a patient is identified as malnourished, the dietitian must quickly perform a full assessment and make recommendations. Someone on the care team must act on these recommendations and periodically check the patient’s nutritional status. Finally, during the huddle, nutritional status should be one of the issues discussed by the health care team.

The ‘Skeleton in the Closet’ All members of the health care team should be part of the screening and the treatment of malnutrition, according to Carmen Roberts, MS, RD, LDN, a clinical dietician specialist at Johns Hopkins Bayview Medical Center in Baltimore. Nurses and physicians can screen patients on admission and during the physical and history taking to identify the need for nutritional intervention, as well as any educational requirements during the hospital stay.

“Dietitians are experts at assessing the patient’s nutritional needs and

Clinical 15

Pharmacy Practice News • November 2014

Nutrition providing appropriate nutritional interventions,” she said, which could include recommending therapeutic diets, providing education to the patient and caregivers, and making recommendations to the physician for supplemental nutrition if needed during the patient’s hospital stay.

Some malnutrition occurs because of nausea, vomiting, diarrhea and altered taste from medications. As such, pharmacists can conduct a medication reconciliation and side-effect profile and make recommendations that might foster calorie intake. They also can assist with IV nutritional support if needed, Ms. Roberts said.

Even physical therapists should help recognize if patients are not eating properly and report that to the health

care team. They also can recommend adaptive devices that might make eating easier for patients with handicaps.

Social workers can assist the patient in locating community resources if needed.

“Providing the patient with [such tools] is an essential part of treating nutritional problems and ... avoiding readmission for these conditions,” Ms. Roberts said. “The ultimate goal is to move the patient from the acute environment and to provide them with the resources in the community to ultimately treat any long-term nutritional problems.”

These efforts can pay off. Studies show a 25% reduction in the incidence of pressure ulcers ((Ageing Res Rev 2005;4:422-450), 14% reduction in overall complications (Cochrane Database Syst Rev 2009:CD003288) and a 28% reduction in avoidable hospital readmissions (Arch ( Intern Med 2001;161:1549-1554) when adequate nutrition is maintained in hospitalized patients. Additionally, well-nourished patients experience an average reduction in the hospital LOS of about two days ((Am J Med d 2006;317:495-501).

“Let’s catch these patients who are already at risk, who are showing signs of malnutrition when they hit the door, and make sure we have a plan in place quickly to intervene and track [their progress],” Dr. Parkhurst said.

—Marie Rosenthal The Alliance to Advance Patient Nutrition accepts major funding from Abbott Nutrition, which is a founding partner.

Ms Roberts reports no relevant financial conflicts of interest.

THE TRUTH HURTS The truth behind EXPAREL

®

Vasopressors and EN A Safe Combination AUSTIN, TEXAS—Despite earlier data to the contrary, enteral nutrition (EN) is well tolerated in most critical care patients receiving vasopressor therapy, according to a study presented at the 2014 annual meeting of the American College of Clinical Pharmacy.

In the retrospective study, electronic medical records were used to identify patients aged at least 19 years who received concomitant EN and an IV vasopressor (dopamine, epinephrine, norepinephrine, phenylephrine and/or vasopressin) in the medical/surgical or cardiovascular Intensive care units. The primary outcome was incidence of EN intolerance, defined as any gastric residual volume of at least 300 mL; abdominal distention; emesis; evidence of ileus or obstruction; bowel ischemia or perforation; or EN discontinuation with subsequent parenteral nutrition (PN) initiation.

Of the 53 patients in the study, 41 (77.4%) tolerated concomitant EN and vasopressor therapy, according to the researchers, from Harrison School of Pharmacy, Auburn University, in Alabama, and East Alabama Medical Center, in Opelika. No patients experienced ileus, obstruction or small bowel necrosis. EN intolerance occurred in seven patients, PN initiation in three patients, emesis in two patients, and abdominal distention in one patient.

The results run counter to previous studies citing concerns that vasopressors may alter blood flow through the stomach and intestines, leading to EN intolerance (Nutr Clin Practt 2012;27:521-526).

However, based on the current study, “the benefits of initiating EN may outweigh [these] theoretical risks,” the authors concluded.

—David Bronstein

(bupivacaine liposome injectable suspension)

EXPAREL® is promoted as the only single-dose local analgesic to reduce or eliminate opioids with pain control for up to three days with no need for catheters or pumps.1-2 Sound too good to be true? It is.

FICTION:

EXPAREL® provides patient-focused pain control for up to 72 hours.3

FACT:

The actual duration of action demonstrated in their pivotal studies was 24 hours or less of pain control.4,5 Exparel has not demonstrated superiority over traditional local anesthetics.6,7,8,9,10,11

FICTION:

The only single-dose local analgesic to reduce or eliminate opioids with pain control for up to three days.3

FACT:

The clinical benefit of the attendant decrease in opioid consumption was not demonstrated.2-3 Saline therapy (placebo) was favored between 12–72 hours.5

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Outpatient Surgery1 Nov. 2013:57-58. Print. 4. Golf M, Daniels SE, Onel E. A Phase III, randomized, placebo-controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. Sep 2011;28(9):776-788. 5. Gorfine SR, Onel E, Patou G, et al. Bupivacaine Extended-Release Liposome Injection for Prolonged Postsurgical Analgesia in Patients Undergoing Hemorrhoidectomy: A Multicenter, Randomized, Double-blind, Placebo-controlled trial. Dis Colon Rectum. Dec. 2011;54(12):1552-1559. 6. Langford RM, Chappell GM, Karrasch JA. A single administration of DepoBupivacaine intraoperatively results in prolonged detectable plasma bupivacaine and analgesia in patients undergoing inguinal hernia repair [Abstract P-9088]. Presented at the Annual Postgraduate Assembly in Anesthesiology of the New York State Society of Anesthesiologists, December 12–16, 2008, New York, NY. 7. White PF, Schooley GL, Ardeleanu M. Analgesia following a single administration of depobupivacaine intraoperatively in patients undergoing inguinal herniorrhaphy: preliminary dose-ranging studies [Abstract S-242].

Anesth Analg. 2009;108 Suppl 3S:S242. 8. Bramlett KW, Jones RK, Pink M, Pink T. A single administration of DepoBupivacaine intraoperative ly provides analgesia and reduction in use of rescue opiates compared to bupivacaine HCl in patients undergoing total knee arthroplasty [Abstract 0278]. Presented at the XXXVI Biennial World Congress of the International College of Surgeons, December 3–6, 2008, Vienna, Austria. 9. Smoot JD, Bergese SD, Onel E, Williams HT, Hedden W. The efficacy and safety of DepoFoam® bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammoplasty: a randomized,double-blind, active-control study. Aesthet Surg J. 2012;32(1):69–76. 10. SIMPLE Hemorrhoidectomy 312 A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Control Study to Evaluate the Safety and Efficacy of a Single Administration of SKY0402 for Prolonged Postoperative Analgesia in Subjects Undergoing Hemorrhoidectomy. Bupivacaine extended-release liposome Injection AMENDED CLINICAL REVIEW 022-496, Arthur Simone, MD, PhD October 7, 2011. 11. Bagsby DT, et al, Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty, J Arthroplasty (2014). 12. Data on File.

There are inherent risks in all medical devices. Please refer to the product labeling for Indications, Cautions, Warnings, and Contraindications. Failure to follow the product labeling could directly impact patient safety. Physician is responsible for prescribing and administering medications per instructions provided by the drug manufacturer. Refer to www.iflo.com for product safety Technical Bulletins.

EXPAREL® is a registered trademark of Pacira Pharmaceuticals Inc. *Registered Trademark or Trademark of Halyard Health, Inc. or its affiliates. © 2014 HYH. All rights reserved. RX Only. MK-00714

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

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

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

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

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

Pulmonary toxicity including pulmonary fibrosis is a well-recognized complication of long-term amiodarone use.

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

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

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

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

• Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation.

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

Please see Brief Summary of Full Prescribing Information on the following pages.

Baxter Healthcare Corporation Deerfield, IL 60015

nexterone.com

Avaailable in 150 mg/100 mL andd 360 mg/200 mL containers

Amid increasing costss and regulations, take another step towaard operational efficiency with a focuus on patient care. Call your Baxter saless representative to learn how NEXTERONE premixed injection can be a pivotal point on the path to pharmacy complian compliance. nce Visit www.nexterone.com for more information.

PRODUCT CODE

STRENGTH/VOLUME

CONCENTRATION

NDC #

PACK FACTOR (cartons/case)

2G3451 2G3450

150 mg/100 mL 360 mg/200 mL

1.5 mg/mL 1.8 mg/mL

43066-150-10 43066-360-20

12 10

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

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

Please see Important Risk Information and Brief Summary of Full Prescribing Information on adjacent pages.

Store in carton to protect from light until ready to use.

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

USMP/221/14-0013 08/14

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

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

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

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

• Cardiogenic shock.

• Marked sinus bradycardia.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thyroid: d thyroid nodules/thyroid cancer

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

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

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

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

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

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

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

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

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

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

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

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of amiodarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cardiovascular: r hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal:l myopathy, muscle weakness, rhabdomyolysis

Sourced from: 07-19-72-800 Rev. March 2014 USMP/221/14-0010(1) 10/14

20 Clinical

Pharmacy Practice News • November 2014

Oncology Briefs

ASCO Initiative Targets Link Between Obesity and Cancer

I

n its first policy statement on the connection between obesity and cancer, the American Society of Clinical Oncology (ASCO) called for increased education, research and advocacy to reduce the epidemic, both as a leading cause of cancer and as a hurdle in the care of patients with cancer.

The society outlined four priorities, including increased education and awareness about links between obesity and cancer, development of new clinician tools and resources, intensified and coordinated research, and policy changes to increase access to obesity screening, diagnosis and treatment.

“With nearly three in four Americans obese or overweight, obesity has become a tremendous public health challenge that also impacts cancer care and prevention today,” ASCO immediate past president Clifford A. Hudis, MD, FACP, said in a statement. “We can’t allow obesity to undo decades of progress in prevention, early diagnosis and treatment of cancer.”

Supporting ASCO’s stance, studies of breast and colorectal cancer have strengthened the association between obesity and cancer and

Colon Cancer Program Cuts Hospital Stays, Lowers Costs

A

program to help patients recover after colorectal cancer surgery reduced their hospital length of stay (LOS) by three days and saved $4,800 without increasing 30-day readmission rates, investigators in Oregon found.

The investigators examined practice patterns and patient outcomes for 244 patients undergoing elective colon and rectal resection at an Oregon community hospital before and after institution of the recovery program (JAMA Surg 2014 Jul 23. [Epub ahead of print]). The program focused on patient education, optimal management of fluids, minimal incision length, decreased use of tubes and drains, opioid-sparing analgesia, early mobilization and eating after surgery.

From 2009, before implementation of the program, to 2012, the use of laparoscopy increased by about 30%, from 57.4% to 88.8% of cases, and LOS decreased by three days, from 6.7 to 3.7 days, according to the researchers at Oregon Health & Science University (OHSU), in Portland.

Previous studies have found that although initial hospital LOS was reduced by so-called Early Recovery After

increased mortality.

In one recent study, researchers analyzed data from 70 clinical trials of breast cancer. Hormone status and breast cancer type varied in the patients included, but the steepest increase in mortality was seen in the 20,000 premenopausal women with estrogen receptor–positive breast cancer. Specifically, the 10-year mortality among those patients who were obese— defined as a body mass index (BMI) of 30 kg/m2 or greater— was 21.5%, which represented an absolute increase of 5% over the 16.6% mortality among those who were not obese.

This translated to a relative risk (RR) for death of 1.34 (95% confidence interval [CI], 1.22-1.47; P<0.00001). The RR for death rose steadily in a stepwise fashion for increasing BMIs stratified as less than 20, 20-25, 25-30, 30-35 and more than 35, according to investigator Hongchao Pan, PhD, who presented the study (abstract 503) at the 2014 annual meeting of the American Society of Clinical Oncology in Chicago.

—Paul Bufano

Surgery (ERAS) programs, this came at the cost of more patients requiring readmission, according to researcher Cristina Geltzeiler, MD, a surgeon at OHSU. “In our study, we did not find this to be the case,” she said. “In fact, with the ERAS program, our patient population had a decreased risk for requiring readmission, although this decrease did not reach statistical significance.”

Reductions in LOS resulted in estimated cost savings of $3,202 per patient in 2011 and $4,803 per patient in 2012, Dr. Geltzeiler and her colleagues reported.

—Paul Bufano

Early Palliative Care Shows Survival Benefit CHICAGO—Expanding the evidence that palliative care has measurable clinical benefits in cancer patients, a new randomized study has found that patients who receive palliative care starting soon after the cancer diagnosis have a reduced risk for death at one year compared with patients whose palliative care is delayed by three months.

Although palliative care has been shown to offer benefit, it “is often given weeks or even hours before death,” observed Marie Bakitas, DNSc, CRNP, the

associate director of the University of Alabama, Birmingham’s Center for Palliative and Supportive Care.

In the trial, newly diagnosed patients with advanced cancer were randomized to receive palliative care starting immediately or three months later (abstract 9512).

The palliative care protocol consisted of an initial inperson consult, followed by six structured telephone calls by specially trained advanced practice nurses, during which the nurses assisted with symptom management, problem solving and advanced care planning.

Median survival was substantially longer in the immediate palliative care group (18.3 vs. 11.8 months), although this difference did not reach statistical significance (P=0.17). There was, however, a highly significant difference in survival at one year, producing a hazard ratio (HR) of 0.72 in favor of immediate versus delayed palliative care (P=0.003).

“The potential explanations for this difference include enhanced medical care, reduced aggressive care, longer access to hospice care and the biological impact from an improvement in quality of life,” Dr. Bakitas reported.

She said that additional data analyses are trying to better define the mechanism(s) by which the survival advantage was achieved.

—Ted Bosworth

Plan for Preserving Fertility in Women With Breast Cancer CHICAGO—Adding goserelin to standard chemotherapy preserves fertility in women with early stage, hormone receptor–negative breast cancer, according to data from POEMS (Prevention of Early Menopause Study) presented at the 2014 annual meeting of the American Society of Clinical Oncology (abstract LBA505).

The Phase III POEMS enrolled women younger than age 50 with operable stage I, II and IIIA estrogen and progesterone receptor–negative breast cancers. Women who were going to receive an adjuvant or a neoadjuvant regimen containing cyclophosphamide were stratified by age and chemotherapy regimen and randomized to receive goserelin (Zoladex, AstraZeneca) (n=126) or not (n=131). Patients were ineligible if they were taking estrogen, progesterone, selective estrogen-receptor modulators or aromatase inhibitors. In the experimental arm, patients received goserelin 3.6 mg subcutaneously every four weeks, starting at least one week before the first chemotherapy dose. Hormone suppression was continued for the duration of chemotherapy, and the last dose was administered within two weeks of the final chemotherapy dose.

Compared with those not receiving goserelin, women

rece eiving it had less ovarian failure, as measured by elevated follicle-stimulating hormone and less amenorrhea at two years (8% vs. 22%; odds ratio [OR], 0.30; P=0.04). Women in the goserelin arm also had lower rates of ovarian dysfunction and high her rates of pregnancy.

Grrade II to IV endocrine toxicities, including hot flashes, mood changes, vaginal dryness and headache, were more common in patients receiving goserelin (48% vs. 24%; P=0.0006). There was no statistically significant difference in the number of grade III/IV endocrine toxicities, and there was only one grade IV toxicity, a thromboembolic event that occurred in a patient receiving goserelin. The two arms had a similar number of total miscarriages, elective terminations and delivery complications.

“For the 25% or so of women with breast cancer who are diagnosed under the age of 50, the induction of early menopause is a common and potentially devastating side effect of treatment,” said POEMS investigator Halle Moore, MD, a staff physsician at Cleveland Clinic’s Taussig Cancer Institute. “This is the first demonstration of improved fertility prospects and more succ cessful pregnancies when goserelin was used.”

—Kate O’Rourke

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22 Clinical

Pharmacy Practice News • November 2014

Oncology

PD-1 Blocker Class Shakes Up Melanoma Treatment I

n the past three years, six drugs have been approved for melanoma, including immunotherapies, BRAF inhibitors and a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor (Table 1). Programmed death receptor-1 (PD-1) inhibitors are the newest agents to jump into the mix, with the recent FDA approval of pembrolizumab, which was granted an indication for patients who do not respond to ipilimumab or a BRAF inhibitor. Approval of another PD-1 inhibitor, nivolumab, is thought to be just around the corner.

Stressing the efficacy of this new class of agents in an interview, Jeffrey Weber, MD, PhD, a melanoma expert at the Moffitt Cancer Center, in Tampa, Fla., said, “PD-1 blockers are great drugs.” Both nivolumab (Opdivo, Bristol-Myers Squibb [BMS]) and pembrolizumab, he said, have impressive antimelanoma activity, with low toxicity, high overall response rates and a long duration of response.

Pembrolizumab The FDA approved pembrolizumab (Keytruda, Merck) based on data from two trials. One trial included only patients who had failed prior treatment, but the other also included treatmentnaive patients.

In a study of 173 melanoma patients whose disease had progressed after prior therapy, 24% of individuals who received the recommended dose of the drug (2 mg/kg) experienced tumor shrinkage. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients, according to the FDA. A similar response rate was seen in patients who received a 10-mg/kg dose.

The second trial tested seven different pembrolizumab dosing strategies in 411 patients with advanced melanoma.

Antoni Ribas, MD, PhD, the director of

Table 1. Recently Approved Agents for Melanoma Drug Name

Drug Class

Year Approved

Peginterferon α-2b

Immunotherapy

2011

Ipilimumab

Immunotherapy (anti–CTLA-4)

2011

Vemurafenib

BRAF F inhibitor

2011

Dabrafenib

BRAF F inhibitor

2013

Trametinib

MEK inhibitor

2013

Pembrolizumab

Immunotherapy (PD-1 blocker)

2014

Table 2. Dose Cohorts in CA209-004, Nivolumab Plus Ipilimumab Cohort No.

N

Nivolumab Dose, mg/kg

Ipilimumab Dose, mg/kg

Nivolumab

Induction

Maintenance

Nivolumab q3wk × 8 doses + ipilimumab q3wk × 4 doses

Nivolumab + ipilimumab q12wk × 8 doses

Concurrent regimens 1

14

0.3

3

2

17

1

3

2a

16

3

1

3

6

3

3

8

41

1

3

Nivolumab 3 mg/kg q2wk (maximum 48 doses)

Sequenced regimens 6

17

1

Prior

7

16

3

Prior

the Tumor Immunology Program Area at the Jonsson Comprehensive Cancer Center, in Los Angeles, presented results from this trial at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA9000).

The overall response rate (ORR) was 34% in the entire study cohort, 44% in treatment-naive patients, 40% in ipilimumab (Yervoy, BMS)-naive patients and 28% in ipilimumab-treated patients.

ment-related deaths, according to the investigators, which included researchers from Merck.

Steven O’Day, MD, the director of clinical research at the Los Angeles Skin Cancer Institute at the Beverly Hills Cancer Center, in California, is also impressed with the anti–PD-1 data. “Pembrolizumab results in longlasting clinical responses in the majority of patients, and impressive overall survival with low toxicity. Importantly, it’s effective regardless of prior ipilimumab treatment. Anti–PD-1 as a single agent is a major breakthrough.”

Nivolumab q2wk (maximum 48 doses)

Responses were durable for both ipilimumab-naive and ipilimumab-treated patients, with 88% of responses persisting. The median progression-free survival (PFS) was 5.5 months, and the median overall survival (OS) at one year was 69%. Grade 3/4 events occurred in 12% of patients, with fatigue being the most common (2%). Treatment discontinuation due to adverse events (AEs) hovered around 5%, and there were no treat-

In another study presented at the ASCO meeting, investigators reviewed data on 107 patients with advanced melanoma who received different doses of the anti–PD-1 agent nivolumab (abstract 9002). The OS was 48% at two years and 41% at three years. With a median of 22 months of follow-up, the median duration of response was 22.9 months. Additional end points were ORR, 32%; median OS, 17.3 months; and median PFS, 3.7 months. Grade 3/4 events occurred in 5% of the patients.

The study was the first to assess threeyear OS in nivolumab-treated patients, according to the investigators, who included Mario Sznol, MD, a medical oncologist at Yale Cancer Center, in New Haven, Conn., as well as researchers from BMS.

Combination Therapy Researchers also are testing combining anti–PD-1 therapies with other drugs. At the ASCO meeting, Dr. Sznol presented data on several subsets of patients with advanced melanoma in the Phase I CA209-004 trial (abstract LBA9003).

Patients in subdivided cohorts received

•

see PD-1 BLOCKER, page 24

Studies Support MEK Inhibitor for BRAF-Positive Melanoma MADRID—Adding a MEK inhibitor to a BRAF inhibitor substantially improves outcome in patients with BRAF mutation–positive advanced melanoma, according to two large Phase III studies presented at the European Society for Medical Oncology (ESMO) 2014 Congress.

The results of the two studies, although using different types of BRAF and MEK inhibitors, were considered mutually reinforcing.

In both studies, patients with metastatic cutaneous melanoma with a BRAF F V600 mutation were randomized to receive a BRAF inhibitor alone or a BRAF inhibitor with a MEK inhibitor. One demonstrated—and the other strongly suggested—a significant improvement in overall survival (OS). In a trial called coBRIM, the combination of the BRAF inhibitor vemurafenib (Zelboraf, Genentech) plus the MEK inhibitor cobimetinib was compared with vemurafenib alone. In the other trial, called COMBI-V, the combination of the BRAF inhibitor dabrafenib (Tafinlar, GlaxoSmithKline) plus

the MEK inhibitor trametinib (Mekinist, GSK) was compared with vemurafenib alone (abstract LBA4-PR).

In coBRIM, the major finding was a 49% reduction in the risk for progression for the combination relative to the BRAF inhibitor alone, but the combination was also associated with a “promising” 35% reduction (P<0.05) in the risk for death, according to the presenting author, Grant McArthur, MD, PhD, the head of the Molecular Oncology Laboratory at Peter McCallum Cancer Centre, in Victoria, Australia. The survival benefit has not yet met the prespecified definition of significance.

The COMBI-V trial, which has more mature data, was stopped at an interim analysis when the primary survival end point was reached. At that time, the risk for death was reduced by 31% (HR, 0.69) for the combination relative to the BRAF inhibitor alone (P=0.005), according to the principal investigator, Caroline Robert, MD, the head of the Dermatology Unit at Institute Gustave Roussy, in Paris. She and

Dr. McArthur noted that the addition of a MEK inhibitor was generally well tolerated, leading to an increase in some side effects, such as pyrexia, but a reduction in others, particularly photosensitivity.

Both studies confirm that MEK inhibition slows resistance to BRAF inhibitors. According to the invited ESMO discussant, Christian Blank, MD, PhD, the group leader in immunology at the Netherlands Cancer Institute, in Amsterdam, a combination of BRAF and MEK inhibitors “is becoming the new standard of care” in melanoma with a BRAF F V600 mutation, based on the consistency of these data.

—Ted Bosworth Dr. McArthur reported financial relationships with Celgene, Millennium, Novartis and Pfizer. Dr. Robert reported financial relationships with Amgen, BMS, GSK, Merck, Novartis and Roche. Dr. Blank reported financial relationships with BMS, GSK, Merck, Novartis and Roche.

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24 Clinical

Pharmacy Practice News • November 2014

Oncology

PD-1 BLOCKER continued from page 22

either concurrent or sequential nivolu– mab plus ipilimumab (Table 2).

In cohorts 1, 2, 2a and 3, the ORR was 42%, the complete response rate (CRR) was 17%, and the two-year OS was 79%. In cohort 8, the ORR was 43% and the CRR was 10%. Most patients who responded to treatment had a reduction in tumor volume that exceeded 80%.

Most responses were ongoing and the median duration of response had not

been reached. Mutant BRAF F or low/ absent PD-L1 tumor expression did not substantially affect activity. Rapid and deep responses were observed in very aggressive and large bulky disease, and most patients who discontinued therapy continued to have ongoing responses, according to the investigative team, which included researchers from BMS. The rate of grade 3/4 AEs was roughly 60%. Dr. Sznol downplayed this high rate, pointing out that the most common grade 3/4 events were increased lipase and amylase, and laboratory abnormali-

ties, which were easily reversible. Onefourth of patients discontinued therapy due to treatment-related AEs, he noted. “The vast majority of adverse events were managed fairly easily with standard algorithms that were initially developed for ipilimumab-related adverse events,” Dr. Sznol said. There was one drug-related death from multiorgan failure in cohort 8.

Dr. Sznol pointed out that the KaplanMeier estimate of median survival was 40 months in the 53 patients in cohorts 1, 2, 2a and 3 (not calculated for cohort

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8). “This is the highest number that I have seen in any Phase I or Phase Ib trial of melanoma,” he said.

Future of PD-1 Treatment A l t h o u g h p e m b ro l i z u m a b wa s approved in the second-line setting, melanoma experts believe that the PD-1 blockers have a bright future in the first-line setting. “With pembrolizumab, patients have a 25% to 35% response rate,” Dr. Weber said. “If you are a BRAF F wild-type patient, the maximum [response rate] with ipilimumab is 15% to 20%.” He pointed out that the FDA and the European Medicines Agency will only approve a drug in a setting that is supported by data, and so far, Merck has only submitted second-line data.

This, however, will change.

“There is an ongoing pembrolizumab versus ipilimumab trial in treatmentnaive patients. There is a first-line nivolumab trial: ipilimumab versus nivolumab versus combo ipilimumab and nivolumab,” Dr. Weber said. “Each trial has an active-control arm (not placebo), so we are going to be waiting a little bit to see the results, but if those trials are positive, which I feel confident they both will be, the FDA will approve the anti–PD-1 drugs in the front-line [setting]. In the future, I would bet you good money that everybody is going to use PD-1 drugs first and ipilimumab later.”

Vananh Trinh, PharmD, BCOP, a clinical pharmacy specialist at the University of Texas MD Anderson Cancer Center, in Houston, also expects the Phase III front-line trials of anti–PD-1 therapies to be positive. She “absolutely” sees pembrolizumab and other anti–PD-1 therapies being used as first-line therapy in the future. The concurrent nivolumab and ipilimumab data presented at ASCO were “remarkable,” she said, and are being confirmed in the Checkmate 067 trial. “A Phase I/II trial of pembrolizumab in combination with peg-IFN [pegylated interferon] or with ipilimumab in patients with advanced melanoma has just started enrollment,” Dr. Trinh said.

“A Phase I/II trial of pembrolizumab with dabrafenib [Tafinlar, GlaxoSmithKline] and trametinib [Mekinist, GSK] is also enrolling patients.”

—Kate O’Rourke Dr. Ribas reported relationships with Amgen, Compugen, Daiichi-Sankyo, Genentech/Roche, GSK, Merck, Novartis and Pierre Fabre. Dr. Sznol reported relationships with Amphivena, Anaeropharma, BeiGene, BMS, Genentech/Roche, Immune Design, KyowaKirin, Lion Biotechnologies, MediImmune, Merus, NektasequentialeoStem, Seattle Genetics and Symphogen.

Dr. O’Day reported financial relationships with BMS, Delcath, Merck and Novartis.

Dr. Weber reported relationships with BMS, Genentech/Roche, GSK and Merck.

Dr. Trinh reported no relevant financial relationships.

Clinical 25

Pharmacy Practice News • November 2014

Oncology ‘Unprecedented’ overall survival gains when used in combo regimen

Pertuzumab a New Standard for Metastatic Breast Cancer Madrid—In patients with HER2-positive metastatic breast cancer (HER2+ mBC), the new standard of care is chemotherapy and trastuzumab plus pertuzumab, according to a substantial overall survival (OS) benefit found in a multinational Phase III trial. After a median follow-up of 50 months, median survival increased by more than a year compared with chemotherapy and trastuzumab alone.

When pertuzumab (Perjeta, Genentech) was added to treatment, “the median survival was 56.5 months, which is unprecedented and confirms this regimen as first-line therapy,” reported Sandra M. Swain, MD, the medical director of the Washington Cancer Institute at MedStar Washington Hospital Center, in Washington, D.C. Dr. Swain presented the final OS analysis of this trial, called CLEOPATRA, at the 2014 Congress of the European Society for Medical Oncology (ESMO; abstract 350O PR).

In this study, which included participants from 204 centers in 25 countries, 808 patients with HER2+ mBC were randomized to receive pertuzumab in an 840-mg loading dose followed by a 420-mg maintenance dose, or placebo. All patients received trastuzumab (Herceptin, Genentech), in an 8-mg/ kg loading dose followed by a 6-mg/ kg maintenance dose, plus at least six cycles of docetaxel (75 mg/m2 titrated up to 100 mg/m2 if tolerated). The advantage of pertuzumab over placebo for progression-free survival (PFS) was reported previously ((N Engl J Med 2012;366:109-119).

In the survival curves presented at ESMO, the benefit of pertuzumab emerged within the first year. After a median follow-up of 50 months, the median survival was 56.5 months in the arm that received pertuzumab versus 40.8 months in the placebo arm. The median 15.7-month increase in survival generated a hazard ratio of 0.68, or a 32% reduction in the risk for death ( =0.0002).

(P The extended safety analysis is consistent with safety data reported earlier.

The rates of diarrhea (68% vs. 48%), rash (37.5% vs. 24%), mucositis (27% vs.

19%) and headache (25% vs. 19%) were higher with the addition of pertuzumab, but most adverse events were grade 2 or lower. There was no sign of increased cardiovascular risk with combining the two HER2 dimerization inhibitors.

The trial was characterized as “an unquestionable therapeutic success” by Luca Gianni, MD, the director of medical oncology at the San Raffaele Scientific Institute, in Milan. Invited by

ESMO to put these results in perspective, Dr. Gianni called the more than one-year improvement in OS “dramatic,” and suggested that this provides a new paradigm for treating HER2+ mBC. The trial data confirm that “dual HER2 blockade is feasible and safe,” Dr. Gianni said, noting that HER2+ disease represents about 20% of breast cancers.

He said he believes that the next step in HER2+ mBC will be to individualize therapy by targeting mediators of resistance, such as mutations in the PIK3CA gene. However, he said he considers the CLEOPATRA data to be definitive. “The combination of pertuzumab, trastuzumab and docetaxel is not just an option for the first-line treatment of HER2+ meta-

static breast cancer,” Dr. Gianni said. “It is the new standard.”

—Ted Bosworth Dr. Swain is an uncompensated consultant for Genentech/Roche. Dr. Gianni has financial relationships with AstraZeneca, BioScience, Boehringer Ingelheim, Celgene, Genentech, GlaxoSmithKline, Pfizer, Roche and Tahio.

When MH strikes,

Keep cool in the crisis with administration in

LESS THAN 1 MINUTE

ADVANCING THE STANDARD IN MALIGNANT HYPERTHERMIA (MH) TREATMENT. RYANODEX® (dantrolene sodium) for injectable suspension is changing how MH is treated.

• Less time for reconstitution and administration – Less than 1 minute for a loading dose (2.5 mg/kg) of dantrolene sodium in an MH crisis1,2 • Less risk of complications with less fluid – Over 99% less sterile water for injection than other dantrolene sodium IV treatments3-5 • Less effort to stay cool in an MH crisis – 1 vial provides a loading dose for patients up to 100 kg and can be administered by 1 healthcare professional (eg, an anesthesia provider)1,3 To request that RYANODEX® be stocked in your institution or obtain ordering information, visit RYANODEX.com/ppn or call 855.318.2170.

References: 1. Data on file. Eagle Pharmaceuticals, Inc. 2. Managing an MH crisis. Malignant Hyperthermia Association of the United States website. http://www.mhaus.org/healthcareprofessionals/managing-a-crisis.

Accessed June 18, 2014. 3. RYANODEX [package insert]. Woodcliff Lake, NJ: Eagle Pharmaceuticals, Inc.; 2014. 4. Dantrium Intravenous [package insert]. Rochester, MI: JHP Pharmaceuticals, LLC; 2008. 5. Revonto [package insert]. Louisville, KY: US WorldMeds, LLC; 2011.

Please see Brief Summary of Prescribing Information on the following page. © 2014 Eagle Pharmaceuticals, Inc. All rights reserved.

50 Tice Blvd, Suite 315 Woodcliff Lake, NJ 07677 (201) 326-5300 RYN14-0027-01 8/2014

INDICATION RYANODEX® (dantrolene sodium) for injectable suspension is indicated for the treatment of malignant hyperthermia in conjunction with appropriate supportive measures, and for the prevention of malignant hyperthermia in patients at high risk.

IMPORTANT SAFETY INFORMATION RYANODEX® is not a substitute for appropriate supportive measures in the treatment of malignant hyperthermia (MH), including: • Discontinuing triggering • Instituting cooling when necessary anesthetic agents • Administering diuretics to prevent late kidney injury due to • Increasing oxygen myoglobinuria (the amount • Managing the of mannitol in RYANODEX® is metabolic acidosis insufficient to maintain diuresis)

26 Clinical

Pharmacy Practice News • November 2014

Transplant Pharmacy

Hydroxyethyl Starch Linked to AKI in Liver Transplant Patients Montreal—Patients undergoing orthotopic liver transplant who receive 6% hydroxyethyl starch (HES) have an increased risk for acute kidney injury (AKI) compared with those who receive 5% albumin. Researchers recommended that the starch derivative not be used in this patient population.

“Back in 2010, our Pharmacy and Therapeutics Committee recommended that we transition from albumin to hydroxy-

RYANODEX® (dantrolene sodium) for injectable suspension, for intravenous use.

Brief Summary of Prescribing Information. See Package Insert For Full Prescribing Information INDICATIONS AND USAGE RYANODEX® is indicated for the: • Treatment of malignant hyperthermia in conjunction with appropriate supportive measures (see Dosage and Administration) • Prevention of malignant hyperthermia in patients at high risk.

DOSAGE AND ADMINISTRATION (Selected Information) In addition to RYANODEX treatment, institute the following supportive measures: • Discontinue use of malignant hyperthermia (MH)-triggering anesthetic agents (i.e., volatile anesthetic gases and succinylcholine).

• Manage the metabolic acidosis • Institute cooling when necessary • Administer diuretics to prevent late kidney injury due to myoglobinuria (the amount of mannitol in RYANODEX is insufficient to maintain diuresis) Administer RYANODEX by intravenous push at a minimum dose of 1 mg/kg. If the physiologic and metabolic abnormalities of MH continue, administer additional intravenous boluses up to the maximum cumulative dosage of 10 mg/kg.

If the physiologic and metabolic abnormalities reappear, repeat RYANODEX dosing by intravenous push starting with 1 mg/kg.

Dosage for Prevention of Malignant Hyperthermia The recommended prophylactic dose of RYANODEX is 2.5 mg/kg administered intravenously over a period of at least 1 minute, starting approximately 75 minutes prior to surgery.

Avoid agents that trigger MH. If surgery is prolonged, administer additional individualized RYANODEX doses during anesthesia and surgery.

Dosage for Pediatric Patients The recommended weight-based dose of RYANODEX for pediatric patients in the treatment and prevention of MH is the same as for adults for these indications (see Dosage and Administration).

Reconstitution and Administration Instructions The supplied lyophilized powder must be reconstituted prior to administration: Reconstitute each vial of RYANODEX lyophilized powder by adding 5 mL of sterile water for injection (without a bacteriostatic agent).

Do not reconstitute with any other solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection).

Shake the vial to ensure an orange-colored uniform suspension. Visually inspect the vial for particulate matter and discoloration prior to administration.

Must use the contents of the vial within 6 hours after reconstitution. Store reconstituted suspensions at controlled room temperature (68°F to 77°F or 20°C to 25°C).

(For complete Dosage and Administration Section, see full Prescribing Information)

RYANODEX has been associated with dysphasia. Assess patients for difficulty swallowing and choking.

Somnolence and Dizziness Somnolence and dizziness can occur following administration of RYANODEX and may persist up to 48-hours post-dose. Patients should not be permitted to ambulate without assistance until they have normal strength and balance. Patients must not operate an automobile or engage in other hazardous activities for 48-hours post-dose.

The concomitant use of sedative agents with RYANODEX may increase the risk of somnolence and dizziness.

Potential for Tissue Necrosis with Extravasation Care must be taken to prevent extravasation of RYANODEX into the surrounding tissues due to the high pH of the reconstituted RYANODEX suspension and potential for tissue necrosis.

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

In a study designed to evaluate the safety and tolerability of RYANODEX, healthy volunteers were randomly assigned to receive treatment with RYANODEX or an active comparator at doses ranging from 1 mg/kg to 2.5 mg/kg.

• The RYANODEX dose was infused over the course of 1 minute for each of the doses evaluated.

• The active comparator was an injectable formulation of dantrolene sodium that differed from RYANODEX in that it contained dantrolene sodium and mannitol at concentrations of 0.33 mg/mL and 50 mg/mL, respectively, when reconstituted according to the product’s prescribing information. The active comparator was infused at a rate that administered 20 mg of dantrolene per minute for each of the doses evaluated.

Table 1 displays the most common adverse events in this study. These data are not an adequate basis for comparison of the types or frequencies of adverse event types between RYANODEX and the dantrolene sodium comparator.

Adverse events increased in frequency with increasing doses in the trial, but did not differ in frequency between the two treatment groups.

RYANODEX-treated subjects were more likely to report immediate adverse events of flushing, dystonia, and dysphagia than those receiving the active comparator.

In all dose groups, hand grip strength declined after dosing. In general, the decline in hand grip strength was more pronounced and occurred more rapidly in the RYANODEX-treated subjects in the 1.0, 1.75, 2.0 and 2.25 mg/kg treatment groups.

In the 2.5 mg/kg treatment group, the decline in hand grip strength both in amount and duration was similar between the two treatment groups.

Table 1: Adverse Events in Healthy Volunteers Number(%) of subjects RYANODEX [N=30]

DANTROLENE SODIUM COMPARATOR [N=31]

Flushing

8 (27)

1 (3)

Somnolence

5 (17)

4 (13)

Dysphonia

4 (13)

1 (3)

Dysphagia

3 (10)

4 (13)

Nausea

3 (10)

3 (10)

Feeling abnormal

3 (10)

3 (10)

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Muscle Weakness RYANODEX is associated with skeletal muscle weakness. The administration of RYANODEX in human volunteers has been associated with loss of grip strength and weakness in the legs.

Patients should not be permitted to ambulate without assistance until they have normal strength and balance.

RYANODEX has been associated with dyspnea, respiratory muscle weakness, and decreased inspiratory capacity. Monitor patients for the adequacy of ventilation.

ethyl starch for all surgical procedures,” said Joseph Whiteley, DO, an assistant professor of anesthesiology at the Medical University of South Carolina in Charleston. “However, a recent study [[N Engl J Med d 2012;367:1901-1911] found an association between the colloid and acute kidney injury. Given that kidney injury following liver transplantation is a very common complication, this retrospective study was our attempt to gauge whether

Headache

1 (3)

4 (13)

Vomiting

1 (3)

2 (6)

Vision blurred

1 (3)

1 (3)

Pain in extremity

1 (3)

1 (3)

Muscular Weakness/ Asthenia

1 (3)

1 (3)

Atrioventricular block

1 (3)

0

Tachycardia

1 (3)

0

Infusion site pain

1 (3)

0

Dizziness

1 (3)

0

hydroxyethyl starch does, indeed, lead to increased postoperative acute kidney injury in this patient population.”

Dr. Whiteley and his colleagues performed a retrospective, cross-sectional analysis of the institution’s electronic anesthesia records, surgical dictations and perioperative laboratory records.

Postoperative AKI was determined by the RIFLE criteria (i.e., risk, injury, failure, loss and end-stage renal disease).

Postmarketing Experience The following adverse reactions have been identified during postapproval use of another formulation of dantrolene sodium for injection.

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.

Pulmonaryy Edema There have been reports of pulmonary edema developing during the treatment of malignant hyperthermia crises with another dantrolene sodium dosage form. The contributory effect of the diluent volume and mannitol in these cases is not known.

Thrombophlebitis p and Tissue Necrosis There have been reports of thrombophlebitis following administration of intravenous dantrolene.

Tissue necrosis secondary to extravasation has been reported (see Warnings and Precautions).

Hypersensitivity/Anaphylactic yp y p y Reactions There have been reports of urticaria and erythema possibly associated with the administration of dantrolene sodium for injection. Anaphylaxis has been reported.

Injection j Site Reactions Injection site reactions including pain, erythema, and swelling, commonly due to extravasation, have been reported.

DRUG INTERACTIONS Calcium Channel Blockers Cardiovascular collapse in association with marked hyperkalemia has been reported in patients receiving dantrolene in combination with calcium channel blockers. The concomitant use of RYANODEX and calcium channel blockers is not recommended during the treatment of malignant hyperthermia.

Muscle Relaxants The concomitant administration of RYANODEX with muscle relaxants may potentiate the neuromuscular block.

Antipsychotics and Antianxiety Agents The concomitant administration of RYANODEX with antipsychotic and antianxiety agents may potentiate their effects on the central nervous system (see Warnings and Precautions).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy g y Category g yC Adequate and well controlled studies have not been conducted with RYANODEX in pregnant women. However, animal reproduction studies have been conducted with dantrolene sodium. In these studies, dantrolene sodium administered to rats and rabbits produced embryolethality (rabbits) and decreased pup survival (rats) at doses seven times the human oral dose. RYANODEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery In one uncontrolled study, 100 mg per day of prophylactic oral dantrolene sodium was administered to term pregnant patients awaiting labor and delivery. Dantrolene readily crossed the placenta, with maternal and fetal whole blood levels approximately equal at delivery; neonatal levels then fell approximately 50% per day for 2 days before declining sharply. No neonatal respiratory and neuromuscular side effects were observed in this study.

Nursing Mothers Dantrolene is present in human milk. In one case report, low dantrolene concentrations (less than 2 micrograms per milliliter) were measured in the breast milk of a lactating woman during repeat intravenous dantrolene administration over 3 days. Because of the potential for serious adverse reactions of respiratory depression and muscle weakness in nursing infants from dantrolene, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and efficacy of RYANODEX in the treatment and prevention of malignant hyperthermia in pediatric patients is based on clinical experience with other intravenous dantrolene sodium products, which suggests adult weight-based doses are appropriate for pediatric patients.

Geriatric Use Clinical studies of RYANODEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

OVERDOSAGE Overdosage Symptoms Overdosage symptoms include, but are not limited to, muscular weakness and alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea, and crystalluria.

Management of Overdosage Employ general supportive measures for acute overdosage of RYANODEX. PATIENT COUNSELING INFORMATION Inform patients, their families, or their caregivers of the following: Muscle Weakness Muscle weakness (i.e. decrease in grip strength and weakness of leg muscles, especially walking down stairs) is likely to occur with the use of RYANODEX. Patients should be provided assistance with standing and walking until their strength has returned to normal (see Warnings and Precautions).

Difficultyy Swallowingg Caution is indicated at meals on the day of administration because difficulty swallowing and choking have occurred with the use of dantrolene sodium products in general; dysphagia has been reported with the use of RYANODEX (see Warnings and Precautions).

Dizziness and Somnolence The use of RYANODEX has been associated with dizziness and somnolence. (see Warnings and Precautions).

Drivingg or Operating p g Machineryy Symptoms such as “lightheadedness” may occur.

Since some of these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in other hazardous activity during this time (see Warnings and Precautions).

Revised: 7/2014 Marketed by: Eagle Pharmaceuticals, Inc. Woodcliff Lake, NJ 07677

© 2014 Eagle Pharmaceuticals, Inc. All rights reserved.

50 Tice Blvd, Suite 315 Woodcliff Lake, NJ 07677 (201) 326-5300 8/2014

AKI was classified one of three ways— risk, injury or failure—based on change in serum creatinine from preoperative baseline to peak level by postoperative day 7.

As Dr. Whiteley reported at the 2014 annual meeting of the International Anesthesia Research Society (abstract S-132), the records of 174 orthotopic liver transplant patients were reviewed. Of these, 50 received only 5% albumin, 25 received both albumin and HES, and 99 received only HES. There was a statistically significant association between the type of colloid administered and AKI. Indeed, patients who received HES were three times more likely to develop AKI within seven days of surgery than their counterparts who received albumin (adjusted odds ratio, 2.94; 95% confidence interval, 1.13-7.7; P=0.027). The linear association between any colloid use and the development of AKI was statistically significant ((P=0.048).

No difference was found in 30-day mortality between the three groups.

“The way we administer colloids at our institution is largely protocol-driven,” he explained. “We use arterial waveform analysis to determine fluid responsiveness to hypotension. We all keep central venous pressure at around 10. We try to keep hematocrit levels between 24 and 30. So we are all pretty uniform how we treat these patients.”

James Findlay, MBChB, director of liver transplant anesthesia at Mayo Clinic, in Rochester, Minn., was not surprised by these findings given recently published trials and meta-analyses that demonstrate an association between the use of HES for resuscitation in ICU patients and renal injury. “The ICU studies also suggest an increased mortality with the use of hydroxyethyl starch; although this was not a finding in Dr. Whiteley’s study, I would be concerned that the renal injury reported could translate into worse outcomes in larger series of patients,” he said. “With the available evidence, I don’t think the continued use of hydroxyethyl starch is justified in liver transplantation. If colloids are required, I’d favor using 5% albumin.”

Another Vote Against HES “After the ICU studies suggesting increased mortality with the use of hydroxyethyl starch were published, most hospitals completely removed hetastarch products from their formularies,” said Eric Tichy, PharmD, a senior clinical specialist in solid organ transplantation at Yale-New Haven Hospital, in Connecticut. “I know we did. At this point in time, with overall reliable supplies of albumin and alternatives such as crystalloids, I don’t see much of any role for [HES] in the hospital setting.”

—Michael Vlessides

Clinical 27

Pharmacy Practice News • November 2014

Transplant Pharmacy

Transplant Rejection Decreases Tacrolimus Absorption Austin, Texas—Patients who undergo small bowel transplantation often experience acute cellular rejection, triggering absorption abnormalities that can lead to the buildup of potentially toxic blood levels of immunosuppressants and other medications, a new study has found.

Researchers at the University of Pittsburgh Medical Center (UPMC) examined the effect of acute rejections on the immunosuppressant tacrolimus in 118 adult patients who underwent small bowel transplantation at UPMC’s Presbyterian Hospital over a 15-year period.

A total of 285 rejections occurred, according to the researchers, who presented the study (abstract 198) at the 2014 annual meeting of the American College of Clinical Pharmacy. A significant elevation in median dose-normalized tacrolimus concentrations in the blood was observed during rejection episodes, along with higher levels of serum creatinine (SCr) and blood urea nitrogen (BUN)—results that suggest kidney dysfunction.

Lead author Alicia Beth Lichvar, PharmD, a solid organ transplant pharmacy resident at UPMC, said although the study focused on tacrolimus, the “bigger clinical impact” might be on “the many other medications that these patients rely on,” including other immunosuppressants and antibiotics. The bioavailability of these drugs, she explained, is altered by cytokine-induced mucosal damage and increased intestinal permeability that occur during rejection. The affected drugs are oral agents, such as tacrolimus, that are metabolized in the gut through the cytochrome P450 3A (CYP3A) system, or effluxed by P-glycoprotein in the intestinal plasma membrane.

“A lot has yet to come to light about the pharmacokinetic changes that intestinal transplant recipients encounter throughout their care—acute cellular rejection being one example,” said Dr. Lichvar, adding that “this is an area for future research into drug pharmacokinetics and dynamics and their clinical implications for transplant care.”

Median dose-normalized tacrolimus concentrations rose from 1.74 to 4.03 ng/mL during episodes of acute cellular rejection, the researchers noted. There were significant correlations between tacrolimus concentrations and severity of rejections, time post-transplant and initial versus recurrent acute rejection episode.

Raman Venkataramanan, PhD, the director of the Clinical Pharmacokinetics Laboratory at the University of Pittsburgh, and a study co-author, said it was “fortunate” that the intestinal transplant patients were routinely monitored for levels of tacrolimus as well as SCr and BUN, which indicated to researchers the potential damage that transplant patients

might incur during acute rejections. Dr. Venkataramanan said it was “important to look for signs and symptoms of overdose in those patients whenever there is an acute rejection of the transplanted organ.”

Transplant Pharmacist’s Take Eric Tichy, PharmD, a senior clinical specialist in solid organ transplantation at Yale-New Haven Hospital, in Connecticut, agreed. “In patients having rejection,

you are potentially doubling exposure to a drug [tacrolimus] that has a narrow therapeutic window,” he said. “So, you have this paradox: The patient is having rejection and you probably want to increase their drug exposure, but you don’t want them to have toxicities. You may have to reduce the dose, and as the rejection resolves, increase it again. There is no real substitute for following the levels very closely.”

Yale-New Haven Hospital is not among

the small number of U.S. centers that perform intestinal transplants, but Dr. Tichy said clinicians at the hospital have seen similar increases in drug absorption in other solid organ transplant patients when they have diarrhea. “That is something that we have to account for,” he said.

—Bruce Buckley Drs. Lichvar, Venkataramanan and Tichy reported no relevant conflicts of interest.

28 Clinical

Pharmacy Practice News • November 2014

Emerging Diseases

Anatomy of an Enterovirus Outbreak

EV-D68 at a Glance

What happens when a ‘common cold’ becomes something more?

E

E

Activity of Enterovirus D68-like Illness in States

Symptoms

For the week of Oct. 5-11, 2014, 44 states and the District of Columbia have submitted assessments to CDC of activity of EV-D68–like illness; 32 states and the District of Columbia reported low or declining activity; 12 states reported increasing or elevated activity.

Mild symptoms may include fever, runny nose, sneezing, cough and body and muscle aches. Severe symptoms may include wheezing and respiratory distress.

nteroviruses are as ubiquitous as the common cold, circulating in the United States in late summer and early fall, causing mild symptoms like nasal congestion, rhinitis and cough.

This year, however, one strain took everyone by surprise. Enterovirus D68 (EV-D68) has been confirmed in 1,035 hospitalized patients in 47 states and the District of Columbia, but it probably affected millions of Americans who had mild symptoms that did not require medical care.

All of the hospitalized cases were children, many were admitted to the pediatric intensive care unit (PICU) and so far, eight who tested positive for EV-D68 have died, according to the Centers for Disease Control and Prevention (CDC).

In addition, there have been 51 reports of neurologic illnesses, although whether they were caused by EV-D68 has yet to be confirmed, the CDC said.

“What we were seeing is different,” said Aaron Milstone, MD, an assistant professor of infectious diseases at Johns Hopkins University Children’s Center in Baltimore and chair of the Society for Healthcare Epidemiology of America (SHEA) Pediatric Leadership Council.

“We’ve [encountered] enterovirus D68 in the past. So, this was not a new virus, but it was presenting with increased disease,” he noted, adding that it also resulted in far greater numbers of pediatric hospitalizations.

Spread EV-D68 can be found in an infected person’s respiratory secretions. EV-D68 is spread person to person by touching a contaminated surface and then touching one’s nose, mouth or eyes.

Who is at risk?

Infants, children and teenagers are most likely to become infected.

Diagnosis District of Columbia

Low

Decreasing

Elevated

Increasing

No Report

Consider EV-D68 as a possible cause of acute, unexplained severe respiratory illness, even if the patient does not have fever. The specific testing can only be done at the CDC and some state health departments.

Although it is not a reportable disease, the CDC is asking that hospitals report clusters to local and state health departments.

Testing

‘At best, [drug shortages] are a daily nuisance and an inconvenience, but when you have an outbreak like this, [they] can lead to significant adverse outcomes.’

—Brian O’Neal, PharmD, MS

Wrong Time of Year Every hospital worker knows that high numbers of children with wheezing or asthma exacerbations coming through the emergency department (ED) is common in the winter, but it is unusual in the summer, said Brian O’Neal, PharmD, MS, the director of pharmacy at Children’s Mercy in Kansas City, Mo. “In pediatrics, there is a lot of seasonality to the daily census,” Dr. O’Neal said. “You get a lot of viruses in the winter, such as colds, flu and respiratory syncytial virus, and we are usually pretty full [during that time]. So it was unusual for us to see these volumes in late summer.”

That pattern was not limited to the Midwest: EDs throughout the country saw an unusual number of children with wheezing who presented during the warmer months, some of whom were eventually diagnosed with EV-D68 infections. Many of the children had a history of asthma or wheezing, which is probably why their symptoms did not raise immediate red flags in many institutions.

“You can imagine the front-line staff; they would have a patient who came in with respiratory distress. They were

nterovirus was first identified in California in 1962; EV-D68 is one of more than 100 non-polio enteroviruses.

wheezing, had no fever, and in a children’s hospital or a children’s urgent care clinic, you are not thinking infection,” said Jason G. Newland, MD, MEd, the medical director of patient safety and systems reliability at Children’s Mercy. “Instead, you are thinking: This is the summer, this is asthma.” One astute ED physician, however, realized that something more was going on. Not all of the children coming through her department had a history of asthma or wheezing; they were taking a lot longer to stabilize; and several had to be admitted to the PICU. On Aug. 15, Irene “Renie” Walsh, MD, the ED attending at Children’s Mercy, sent an email to her infectious disease (ID) colleagues explaining that she had just seen six children with severe respiratory distress primarily with wheezing.

She asked: “Is there a ferocious lower respiratory virus in the community?”

Mary Anne Jackson, MD, FPIDS, chief of ID at Children’s Mercy, said she would investigate. She reviewed microbiologic records and found “essentially five times” the number of

rhino-enterovirus tests being ordered.

These tests are done solely on children admitted to the hospital with serious respiratory problems. The Biofire Respiratory Panel polymerase chain reaction (PCR) tests for 20 different pathogens. Nineteen are very specific; one gives a class of viruses: enterovirus, according to Dr. Jackson, so the tests were coming back as rhinovirus/ enterovirus-positive. It would still be some time before she discovered the culprit was enterovirus D68, which has occurred in the United States before, but is rare ((MMWR 2011;60:1301-1304).

Filled to Capacity The hospital was experiencing a surge in the number of positive tests and children admitted with unusual bronchospasm, and Dr. Jackson alerted the CDC, sent samples for further testing and then notified pediatric and adult ID specialists around the country. “They [the children] were going to our ICU after spending hours in our emergency room being stabilized. By Aug. 22, we were beyond our bed capacity,” she said.

The CDC Picornavirus Laboratory developed and evaluated the EV-D68–specific rRT-PCR assay, which is primarily focused on evaluating respiratory disease due to EV-D68. For protocols about using the new assay: http://tinyurl.com/ k4zqs4m.

Source: CDC

The average daily census is around 230 beds at Children’s Mercy, which comprises two hospitals, two EDs, three urgent care centers and two primary care clinics, according to Dr. Newland.

Dr. Jackson compared admissions for children with asthma for the months of August and September in 2012, 2013 and 2014 and found three times the number of children in the PICU. About 100 children were sent to the PICU. About two-thirds had asthma or a history of wheezing, but one-third had no such history, she said.

On Aug. 23, the University of Chicago Medicine Comer Children’s Hospital in Illinois reported an increase in patients similar to those seen in Kansas City ((MMWR 2014;63:798-799). As the summer progressed, more states reported cases.

There are no antivirals or other drugs indicated for the treatment of EV-D68, so treatment is supportive. “We treated most of these children as we would an

Clinical 29

Pharmacy Practice News • November 2014

Emerging Diseases

Ebola Preparedness, Screening and Treatment Pharmacists ready to provide supportive care expertise

B

ringing pharmacists directly to the bedside has become a core element of pharmacy practice in many U.S. hospitals. But when it comes to caring for patients who have been exposed to the Ebola virus, the consensus is clear: The risk for infection vastly outweighs the benefit of having pharmacists directly involved in face-to-face patient care.

“If any patient coming into one of our hospitals has a positive screen as a possible Ebola case based on the Centers for Disease Control and Prevention [CDC] triage questions, they will be immediately moved to one of the isolation rooms identified for this use at each of our hospitals,” said Ronda Akins, PharmD, an infectious diseases (ID) clinical specialist at Methodist Health System, which includes four hospitals in the Dallas area. “Those rooms would then be restricted to select patient care providers—nurses and physicians who have volunteered for these cases. Pharmacists will be present to assist, but will not be directly going into the room.”

That policy is mirrored in hospitals across the country, according to ID and emergency medicine pharmacists from

asthma exacerbation due to their significant wheezing,” Dr. Newland said.

The children required IV fluids, oxygen, albuterol inhalation, corticosteroids, magnesium, aminophylline, as well as therapies that are used for chronic obstructive pulmonary disease, such as bilevel positive airway pressure, which is a type of noninvasive ventilation used to help open the airways, in addition to mechanical and high-frequency oscillatory ventilation.

“Albuterol was a huge factor in [managing] these patients,” Dr. Newland said. “They were on continuous albuterol for four or five hours, which was longer than normal.”

Hospital Resources Stretched The outbreak taxed about every aspect of the hospital. Every day, staffing and supplies had to be assessed.

Subspecialist physicians helped with general pediatric admissions and ID specialists volunteered to help the hospitalists, Dr. Newland explained. At one point, there were not enough respiratory therapists to provide the numbers of inhalation therapy to all the children, and nurses used metered dose inhalers to help with the workload.

“No one predicted that this was coming,” Dr. O’Neal said. “We were one of the first hospitals to experience it. We

several areas who have spoken with Pharmacy Practice News. “I’m a huge advocate of pharmacists at the bedside, but this is one bedside I don’t think we’ll provide a lot of benefit by being physically right there,” said Kyle Weant, PharmD, BCPS, a clinical pharmacy manager and an emergency medicine pharmacist at KentuckyOne Health in Louisville.

New Case in New York In late October, a new confirmed case of Ebola infection was reported in New York City: Craig Spencer, MD, an emergency medicine physician who had been treating Ebola patients in Guinea, Africa, on behalf of Doctors Without Borders.

Dr. Spencer tested positive for the virus Oct. 23 and was placed in isolation at Bellevue Hospital Center. At presstime, he remained in serious but stable condition, according to hospital officials.

Dr. Spencer is the fourth person to contract Ebola virus disease (EVD) in the United States. His case follows that of Texas Health Presbyterian Hospital nurse Amber Vinson, RN, who reported a fever on Oct. 14 and was transferred to the special biocontainment unit at Emory University Hospital in Atlanta the next day.

were ‘flying through’ all of our respiratory medications. We had to reorder albuterol, IV fluids, corticosteroids and other respiratory medications at a rate far beyond our norm.”

Where products were usually ordered once a week, they were ordering new supplies every other day, but the hospital was fortunate that it never suffered any shortages, according to Dr. O’Neal. “An outbreak like this magnified the potential impact of drug shortages,” he said. “At best, they are a daily nuisance and an inconvenience, but when you have an outbreak like this, drug shortages can lead to significant adverse outcomes.”

Just when hospitals thought the outbreak was winding down, children started turning up with weakness and flaccid paralysis. Some have tested positive for EV-D68 and some have not. Children’s Mercy is investigating three such cases.

“None of these children presented for unusually severe respiratory care either to the ED or the hospital,” Dr. Jackson said, “but they all had an antecedent illness that sounded like the common cold.”

Colorado reported a cluster of nine children with acute neurologic disease characterized by extremity weakness and/or cranial nerve dysfunction ( (MMWR 2014;63:901-902). There also was a report of acute flaccid paralysis in

Nina Pham, RN, who cared for the sole Ebola patient to die in the United States, Thomas Edward Duncan, also contracted EVD. In late October, both nurses were declared free of the Ebola virus.

“Fortunately there have only been four cases in the United States, but we always want to prepare for all possible scenarios,” Dr. Akins said. She reported that the state of Texas, local health departments and the CDC have identified a biocontainment facility where any future patients can be treated without placing the public and other hospitalized patients within the region at risk. The facility, Methodist Campus for Continuing Care, which is part of the Methodist Health System, contains a recently vacated ICU and emergency department providing an easily adaptable environment for specialized central care. The response plan is in collaboration with UT Southwestern and Parkland Hospital, which will be providing specially trained staff and

a California man aged 29 years, whose physician requested poliovirus testing because the man was unvaccinated ( (MMWR 2014;63:903-906). (Poliovirus is an enterovirus; EV-D68 is classified as a non-polio enterovirus.)

The CDC said it has received reports of 51 neurologic cases, which it is investigating, but said it was too soon to tell whether the cause is EV-D68.

Limb Weakness a Key Finding Dr. Jackson said the case definition is an acute onset of limb weakness, as well as a very specific finding in the brain or the spine on magnetic resonance imaging (MRI). “This MRI finding is distinctly different from other types of neurologic findings. They are specific to gray matter and involve the ventral horns,” she explained.

Findings from the radiologic scans are similar to those seen in true polio cases.

Moreover, “it is known that enteroviruses can cause paralysis and similar presentations, but EV-D68 is a non-polio enterovirus,” Dr. Milstone explained, adding that no one knows whether EV-D68 has changed or whether the virus is causing such broad disease that it increases the probability of neurologic manifestations. Millions of Americans have probably had EV-D68 this year.

“There have been many, many people

supplies, along with other Methodist health care workers.

Nationwide, similar plans for transferring patients to central locations with expertise in handling virulent outbreaks are in place. Ms. Vinson, for example, was moved to Emory, and Ms. Pham to the National Institutes of Health (NIH) Clinical Center in Bethesda, Md. Biocontainment units are also available at the University of Nebraska Medical

•

see EBOLA, page 30

out there in the community who have had this enterovirus and who have not presented for medical attention,” he said.

Because the country is moving into influenza season, Dr. Milstone reiterated the importance of getting an influenza vaccination, frequent hand washing, and covering the mouth and nose when sneezing or coughing. Additionally, Dr. Jackson said it was critical for parents and children with asthma to renew their asthma action plan and seek medical attention if the child is suffering an exacerbation. “If the child is sitting down and breathing so rapidly he or she cannot say a sentence, that is a signal to seek attention,” she warned. “But most parents know when to come in.”

Being on the front lines, Dr. O’Neal experienced the outbreak uniquely from his colleagues. “For us, it was initially a supply issue,” he said. “It reinforced the need to keep an eye on inventory and make sure you are not just dismissing an outage as being a random event. There might be something behind it that you need to further investigate. That was really one of the first triggers for us that something unusual was going on.”

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

30 Clinical

Pharmacy Practice News • November 2014

Emerging Diseases

EBOLA continued from page 29

Center in Omaha and St. Patrick Hospital in Missoula, Mont.

Such a central treatment strategy makes all the more sense, given the many missteps that occurred at Texas Health Presbyterian Hospital in Dallas, where Mr. Duncan was treated.

“With the screen-and-transfer setup that the CDC has been employing, patients with confirmed cases will probably be moved to one of these [central] sites very quickly,” Dr. Akins said. Still, “you have to prepare well, with our efforts focused on making sure that the patients are identified immediately when they come in the door, and on how to isolate them and prevent exposure to unnecessary individuals, and use appropriate personal protective equipment [PPE] to protect our health care workers.”

Even if Ebola patients are likely to be quickly transferred, ID and emergency medicine pharmacists are preparing to provide their expertise in caring for them should any present to their hospitals.

“Although we won’t be directly at the bedside, there are many things that we add to patient care,” Dr. Weant said.

He cited, as an example, “making sure patients are being resuscitated appropriately with IV fluids and electrolytes, maintaining their blood pressure with vasopressors, if necessary, and managing any concomitant infections.”

Dr. Weant added that his team has been reviewing its process for investigational new drug (IND) applications in emergent situations. “Hospitals have to be prepared to submit these applications in many situations, such as with experimental drugs for malaria,” he said. “We’re making sure that everyone is more familiar with that process, and that they have the necessary tools and contact information for submitting such requests.”

OSU Acts Quickly At The Ohio State University Medical Center in Columbus, preparations for a possible Ebola case have taken on more urgency given the institution’s proximity to Cleveland, where Ms. Vinson visited while possibly symptomatic with Ebola. “We had to rule out Ebola in Columbus last night at 10 p.m. The patient was negative, but we’re ready,” said Debra Goff, PharmD, FCCP, an ID specialist and associate professor at The Ohio State’s College of Pharmacy, in Columbus. “There’s a dedicated room with its own lab right outside so no blood will be transported elsewhere in the institution. Our volunteers are all in place and have extensively practiced the donning and doffing of their protective gear. We feel like we’re prepared.”

In 2009, ID pharmacists at Ohio State played a key role in the IND applica-

tion to use the experimental drug peramivir (BioCryst) for the treatment of two patients with H1N1, Dr. Goff noted.

“We’ve gotten the paperwork in order for brincidofovir [Chimerix], an antiviral that has in vitro activity against Ebola. We can’t send in an application ahead of time, but we’re ready to do it if we have a case.”

In addition to brincidofovir, several other experimental medications have been used to treat Ebola (see Web exclusive at pharmacypracticenews.com/ebola). But perhaps just as critical in the management of an Ebola patient are supportive medications. Because it is dehydration from the intense vomiting and diarrhea that often can lead to the catastrophic cascade of hemorrhaging and organ failure that often marks the later stages of Ebola, the first line of supportive medications includes fluids and electrolytes.

“Patients with Ebola need intensive hydration; they’re losing copious amounts of fluids,” Dr. Akins said. Electrolyte shortages have been plaguing hospitals and home-infusion suppliers nationwide for several years. “Those are slowly resolving, but we still have some weeks when we may not get as much as initially ordered. Right now we have a sufficient supply on hand, but if there were a more significant outbreak situation with multiple cases anywhere in the country, that could certainly make the shortage worse.”

Drug Monitoring Problematic Another common concern for Ebola patients is secondary bacterial infections. Because Ebola’s primary form of transmission is through contact with an infected person’s bodily fluids, routine care for such secondary infections—such as a sputum, urine, or blood sample for culture—would be too risky. Taking such samples to a hospital laboratory, beyond the carefully controlled confines of an isolation unit, would add to the risk of spreading the virus, Dr. Goff noted.

But there are helpful measures a pharmacist can take, she stressed. For example, “if the patient has developed pneumonia, normally vancomycin would be an option but you’d need to monitor those drug levels, so that would be off the table here,” she acknowledged.

“In these pneumonia cases, your [better] option might be one of the new anti-MRSA antibiotics plus piperacillin-tazobactam. To select the right one, each hospital needs to be very familiar with the IV antibiogram of its ICU.” Dr. Goff said ID pharmacists also can play an important role in simplifying the medication process for front-line clinicians treating Ebola patients. “We need to do everything we can to help limit their contact with blood.” In some cases, such as the Texas nurses who were conscious and communicative, she would recommend switching IV

medications for oral medications wherever possible. “Generally, in the ICU, most medications are given parenterally, but if you have a conscious patient, you would want to minimize the utilization of IV lines to help protect nurses [against infection].”

Whether the medications are oral or IV, pharmacists also can help minimize the number of steps involved in administering them while actually in the room and exposed to the patient. “When you’re wearing a hazmat suit with double gloves, the simplest thing, such as getting a unit dose out of a blister pack, becomes complicated,” Dr. Goff said. “Another example is spiking the IV bag; we could have a pharmacist or another nurse outside the room spiking the bag, so that it’s ready to be put together and administered without a nurse in the room having to do that step. It will all be about trying to simplify and evaluate the drug therapy going in and out of the rooms so the nurse doesn’t have to deal with that type of issue.”

In late October, the CDC issued updated guidelines on PPE that may be worn by health care workers treating Ebola patients (http://goo.gl/TkbldI).

Although the agency fell short of requiring hazmat suits, it did outline several upgraded protections that hospitals may consider, including powered air-purifying respirators or an N95 or higher respirator. If such equipment is used, the CDC stressed, the hospital must train health care workers to ensure that the donning and doffing procedures used with conventional PPE “are adjusted and practiced accordingly.”

Pain management and narcotics will also be more challenging. “The law requires that if there is wastage, it has to be witnessed,” Dr. Goff pointed out.

“That’s not simple to do, because nothing can leave the room. In our case, the dedicated room has a glass window and the nurse can hold up the morphine drip to let those outside the room witness the wastage. Those are just some of the logistics we’re talking through.”

Protocol Establishment Overall, the most important role of pharmacy in managing any Ebola cases should be the establishment of protocols, according to Andrew Roecker, PharmD, BCPS, the chair of pharmacy practice at Ohio Northern University,

in Ada. “If you can do things in a more regimented, controlled fashion, you can increase safety both for the patients and the caregivers. That means standardizing supportive therapy for these highly communicable hemorrhagic fevers. The pharmacist should also be the hospital’s go-to education source for the latest information on potential therapies as well as supportive care.”

Outpatient/retail pharmacists could also play a role during these times of high concern and even fear over a potentially more widespread Ebola outbreak, according to David Bearden, PharmD, president of the Society of Infectious Diseases Pharmacists. “From a community pharmacy standpoint, the risks are very low, but it’s useful to have pharmacists aware of when they should refer people back to the health care system, without overwhelming it for things that are not likely to be Ebola,” Dr. Bearden said.

The national outcry over Ebola should be channeled into a more productive focus on general readiness for new (or “renewed”) biologic threats, suggested Dr. Weant, who previously worked in disaster preparedness, helping state and local governments develop response plans from a pharmacotherapy perspective.

“Ebola has been around since 1976 and has been a Category A agent since 1999, and yet opportunities still remain for us to be better prepared,” he stressed.

“This is a wake-up call that pharmacy needs to get more involved in developing plans for responding to a threat from any of the many agents that are out there—be it anthrax, smallpox, Ebola or something else.”

—Gina Shaw

Web Exclusive

T

here is no treatment approved for Ebola virus disease; therapy remains symptomatic. There are several experimental treatments that have been tried during this outbreak. For more details, visit pharmacypracticenews.com/ Ebola or scan the adjacent 2D barcode.

Enoxaparin Sodium Injection, USP

WARNING: SPINAL/EPIDURAL / HEMATOMAS

See full prescribing information for complete boxed warning.

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal antiinflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery.

• Optimal timing between the administration of enoxaparin sodium injection and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. [see Warnings and Precautions (5.1) and Drug Interactions (7)].

Please see brief summary of full prescribing information including boxed warning on following page.

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. www.us.sandoz.com © 2014 Sandoz Inc., a Novartis company. All rights reserved.

SDZ0434 02/2014

Available in 7 strengths in pre-filled syringes.

• 30 mg/0.3 mL pre-filled syringe 40 mg/0.4 mL pre-filled syringe 60 mg/0.6 mL pre-filled syringe 80 mg/0.8 mL pre-filled syringe 100 mg/1.0 mL pre-filled syringe 120 mg/0.8 mL pre-filled syringe 150 mg/1.0 mL pre-filled syringe • Sandoz is a member of the Novartis family of companies — a name you can trust for quality and reliability

Choose the full potential of generics.

Enoxaparin Sodium Injection, USP WARNING: SPINAL/EPIDURAL HEMATOMAS See full prescribing information for complete boxed warning.

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal antiinflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery.

• Optimal timing between the administration of enoxaparin sodium injection and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary. [see Warnings and Precautions (5.1) and Drug Interactions (7)].

- - - - - - INDICATIONS AND USAGE - - - - - Enoxaparin sodium injection, USP is a low molecular weight heparin [LMWH] indicated for: • Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness • Inpatient treatment of acute DVT with or without pulmonary embolism • Outpatient treatment of acute DVT without pulmonary embolism • Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction [MI] • Treatment of acute ST-segment elevation myocardial infarction [STEMI] managed medically or with subsequent percutaneous coronary intervention [PCI] - - - - - - DOSAGE AND ADMINISTRATION - - - - - Indication

Dose

DVT prophylaxis in abdominal surgery

40 mg SC once daily

DVT prophylaxis in knee replacement surgery

30 mg SC every 12 hours

DVT prophylaxis in hip replacement surgery

30 mg SC every 12 hours or 40 mg SC once daily

DVT prophylaxis in medical patients

40 mg SC once daily

Inpatient treatment of acute DVT with or without pulmonary embolism

1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily*

Outpatient treatment of acute DVT without pulmonary embolism

1 mg/kg SC every 12 hours *

Unstable angina and non-Q-wave MI

1 mg/kg SC every 12 hours (with aspirin)

Acute STEMI in patients <75 years of age [For dosing in subsequent PCI, see Dosage and Administration]

30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC every 12 hours (with aspirin)

Acute STEMI in patients ≥75 years of age

0.75 mg/kg SC every 12 hours (no bolus) (with aspirin)

• See recommended durations for enoxaparin sodium injection therapy • *See recommendations regarding transitioning to warfarin therapy • Adjust the dose for patients with severe renal impairment

- - - - - - DOSAGE FORMS AND STRENGTHS - - - - - 100 mg/mL concentration: Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL 150 mg/mL concentration: Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/mL - - - - - - CONTRAINDICATIONS - - - - - Active major bleeding Thrombocytopenia with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium Hypersensitivity to enoxaparin sodium Hypersensitivity to heparin or pork products Hypersensitivity to benzyl alcohol [for multi-dose formulation only] - - - - - - WARNINGS AND PRECAUTIONS - - - - - Increased risk of hemorrhage: Use with caution in patients at risk Percutaneous coronary revascularization: Obtain hemostasis at the puncture site before sheath removal Concomitant medical conditions: Use with caution in patients with bleeding diathesis, uncontrolled arterial hypertension or history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage History of heparin-induced thrombocytopenia: Use with caution Thrombocytopenia: Monitor thrombocytopenia closely Interchangeability with other heparins: Do not exchange with heparin or other LMWHs Pregnant women with mechanical prosthetic heart valves and their fetuses may be at increased risk and may need more frequent monitoring and dosage adjustment

- - - - - - ADVERSE REACTIONS - - - - - Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea and nausea To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

- - - - - - DRUG INTERACTIONS - - - - - Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium injection or conduct close clinical and laboratory monitoring - - - - - - USE IN SPECIFIC POPULATIONS - - - - - Severe Renal Impairment: Adjust dose for patients with creatinine clearance <30 mL/min Geriatric patients: Monitor for increased risk of bleeding Patients with mechanical heart valves: Not adequately studied Hepatic Impairment: Use with caution Low Weight Patients: Observe for signs of bleeding • Obese Patients: Not adequately studied. Observe for thromboembolism

Manufactured by Baxter Pharmaceutical Solutions LLC for Sandoz Inc., Princeton, NJ 08540 Rev. November 2013

Clinical 33

Pharmacy Practice News • November 2014

Pain Medicine

Opioid-Induced Constipation Identifiers Vary W

hen the Joint Commission (JC) issued its Sentinel Event Alert on opioid-induced oversedation (OIOS) in 2012, the group included an extensive list of patient characteristics to help hospitals identify patients at risk for this complication (box). However, recent research suggests the JC’s risk factors are not necessarily universally applicable, and hospitals and health systems should conduct their own OIOS risk factor analyses.

One recent set of findings indicating the need for institution-specific analyses comes from Kent Hospital, a 350bed acute care community hospital in Warwick, R.I., where researchers used a naloxone trigger tool to single out a handful of significant OIOS risk factors ((Am J Health Syst Pharm 2014;71:746-750).

Benjamin Stevens, PharmD, who was a pharmacy student in the Department of Pharmacy at the time of the study, said that some of the risk variables were not on the JC’s list, and others were on the list but were not correlated with the risk for OIOS at Kent Hospital. “For example, the JC identified opioid naiveté as a risk factor, but we actually found that use of opioids prior to hospital admission was a risk factor for OIOS,” said Dr. Stevens, who is now a staff pharmacist at Liberty Drug & Surgical in Chatham, N.J. The researchers used a naloxone trigger in their electronic medical record (EMR) system to retrospectively compare 65 inpatients who received opioids at Kent Hospital between October 2011 and 2012 and required naloxone for OIOS with the same number of inpatients administered similar doses of opioids (average dosage, 88.57 mg) but who did not require naloxone. Because they set out to specifically identify OIOS associated with inpatient opioid prescribing, Dr. Stevens’ team excluded patients who received naloxone intraoperatively and those given the antidote within 24 hours of admission, due to the fact that they could not control the effect of immediate preadmission opioid use in those patients.

The most significant predictor of naloxone use—and by implication, OIOS— was renal disease, which had an odds ratio (OR) of 6.034 (95% confidence interval [CI], 2.565-14.195). Rounding out the top six factors were cardiac disease (OR, 5.829; 95% CI, 2.687-12.642), central nervous system depressant use (OR, 4.750; 95% CI, 1.949-11.578), a history of smoking (OR, 4.7421; 95% CI, 2.114-9.245), and respiratory disease (OR, 3.600; 95% CI, 1.742-7.441). Although cardiac dysfunction is on the JC’s list, renal, respiratory and hepatic diseases are not.

“I can’t really speculate on why there are differences between our study and the JC’s list [of risk factors],” Dr. Stevens said.

“There is always room for more studies

7%

Added order comments for multiple short-acting opioid orders

29%

Discontinued duplicate short-acting opioid orders

50% 29%

Discontinued continuous opioid infusion in presence of another long-acting opioid Added order comments for oral short-acting opioid orders when PCA also ordered

Total interventions = 14 Chronic pain patients, N=10

Figure. Pain management plan interventions.

to be done in order to clarify these questions, and this topic could benefit from examination of a larger population, possibly including multiple health systems.”

Dr. Stevens added that his team is basing its OIOS prevention initiatives on the risk factors found at Kent Hospital and are developing an OIOS risk assessment tool that incorporates these variables.

Clues From Pyxis Pharmacists at Munson Medical Center in Traverse City, Mich., are also developing interventions based on OIOS risk factors, which they recently isolated by tracking naloxone use. Along with several colleagues, Jason Williamson, PharmD, who was a resident at Munson during the study period and is currently a clini-

cal staff pharmacist at Genesys Regional Medical Center in Grand Blanc, Mich., tracked Pyxis-dispensed naloxone over a two-month period.

Dr. Williamson and his team analyzed patients by age, weight, demographic information, medical history, number of opioid orders, perioperative administration of opioids, opioid doses administered in the emergency department and risk factors included in the JC’s Sentinel Event Alert. During the study, four patients received naloxone for hospitaladministered opioid overdose.

“Upon data analysis, we found that individuals admitted with chronic pain and those with three or more opioid orders were at significant risk of OIOS,” he said.

After identifying these risk factors,

Patient Risk for Opioid Oversedation And Respiratory Depression • • • • • • • • •

Sleep apnea or sleep disorder diagnosis Morbid obesity with high risk for sleep apnea Snoring Older age No recent opioid use Postsurgery, particularly if upper abdominal or thoracic surgery Increased opioid dose requirement or opioid habituation Longer period receiving general anesthesia during surgery Receiving other sedating drugs, such as benzodiazepines, antihistamines, diphenhydramine, sedatives or other central nervous system depressants • Preexisting pulmonary or cardiac disease or dysfunction, or major organ failure • Thoracic or other surgical incisions that may impair breathing • Smoker Source: The Joint Commission Sentinel Event Alert. August 8, 2012; issue 49.

Dr. Williamson examined charts of 12 patients admitted in a single day who met the two criteria, and conducted a range of interventions to reduce unnecessary prescribing of opioids (Figure).

He compared opioid prescribing in 260 inpatients admitted to the hospital with chronic pain during a two-week period before his interventions, and found that he could reduce the number of opioid orders per patient from an average of 2.57 in the pre-intervention group to 1.33 with his interventions. Notably, he reduced the number of orders for short-acting opioids from an average of 2.35 to 1.25 per patient, and orders for long-acting opioids from 0.22 per patient before the initiative to 0.08 afterward. The brief study period precluded analyses of the effect of his interventions on the use of naloxone or incidence of OIOS. Terry Baumann, PharmD, who is a clinical pharmacy manager at Munson and was Dr. Williamson’s research supervisor at the time of the study, said the hospital’s opioid safety committee is developing additional opioid safety initiatives using Dr. Williamson’s naloxone use analysis, as well as the JC’s risk factors. “For example, we are putting together a program that will allow clinicians to screen patients for potentially undiagnosed sleep apnea, which is a risk factor on the JC’s list,” he said.

Kudos to Both Institutions Examining population-specific risk factors is something for which John Devlin, PharmD, an expert on OIOS who was not involved in the studies, applauded both institutions. “These researchers have helped overcome a potential barrier to the use of the JC’s list of risk factors for opioid-induced oversedation in clinical practice by identifying and prioritizing those risk factors that are most commonly seen in clinical practice,” said Dr. Devlin, who is a professor in the Department of Pharmacy Practice at Northeastern University’s Bouvé College of Health Sciences School of Pharmacy, in Boston.

“This will help hospitals to streamline OIOS prevention and education efforts.”

He emphasized that institution-specific risk factors need to be included in EMR systems to be most effective, so that clinicians are alerted to patients who are more likely to develop OIOS. “This information can help prescribers decide whether to modify the opioid dose before an adverse event develops and naloxone administration is required,” Dr. Devlin said.

—David Wild Drs. Devlin, Williamson, Stevenson and Baumann reported no relevant financial conflicts of interest.

34 Clinical

Pharmacy Practice News • November 2014

Medication Safety

‘Silent Epidemic’ From Herbal and Dietary Supplements?

A

10-year study by investigators tasked with tracking the primary causes of liver injury has found that although conventional medications continue to be a major contributing factor, the proportion of cases tied to herbal and dietary supplements (HDS) is growing at a nearly threefold faster pace.

Products marketed for bodybuilding were a common type of HDS causing liver abnormalities, the investigators reported ( (Hepatology 2014;60:1399-1408). But the most severe outcomes—liver transplantation and death—were seen in patients who ingested non-bodybuilding formulations. Middle-aged women were among the most at risk for such outcomes.

“Contrary to widespread belief, this study demonstrates that HDS products are not always safe,” reported Victor J. Navarro, MD, the first author of the study and a contributor to the DrugInduced Liver Injury Network (DILIN), which helped coordinate the decadelong investigation. Part of the blame, he noted, goes to government regulations such as the Dietary Supplement Health and Education Act of 1994 that “require less safety evidence to market products than what is required for conventional pharmaceuticals.”

Cathy Rosenbaum, PharmD, MBA, a holistic clinical pharmacist and CEO of Rx Integrative Solutions, who was not involved in the study, praised the researchers for using the DILIN databank to measure the extent of HDS-induced liver injury. The research tool, Dr. Rosenbaum noted, “is a much-needed resource to rigorously quantify clinical patterns in this suspected ‘silent epidemic.’”

The prospective study, conducted between 2004 and 2013, included patients with signs of having developed DILI within the preceding six months.

Inclusion criteria included common markers for DILI, such as jaundice (total bilirubin >2.5 mg/dL) and coagulopathy (international normalized ratio >1.5).

In all, 839 patients with liver injury were included in the final analysis; 709 (85%) of the cases were attributed to medications and 130 (15.5%) to HDS. Of the latter group, 45 (35%) had taken bodybuilding HDS and 85 (65%) had ingested non-bodybuilding supplements.

During the first two years of the study, 7% of DILIN cases were attributed to the supplements. Ten years later, that number nearly tripled, to 20% ((P=0.0007), when all types of HDS products were combined.

Although bodybuilding supplements caused prolonged jaundice (median, 91 days) in the men included in the study, no fatalities or liver transplants (LTs) occurred in that group. Those severe outcomes were only observed in patients

taking non-bodybuilding products, and they occurred far more frequently in patients taking those supplements versus conventional medications (13% vs.

3%, respectively; P<0.05). All 13 of the patients who underwent LTs or died were middle-aged women.

Weighing the Evidence Given the fact that the study was based on data from only eight DILIN centers,

Dr. Navarro and his colleagues fell short of concluding that the observed rise in liver injury from HDS is truly a nationwide problem. But they came close, noting that the potentially severe adverse event “not only occurs, but also may be increasing in frequency over time in the populations surrounding the DILIN

centers and, probably, in the United States as a whole.”

Dr. Rosenbaum also feels that “it’s too soon to tell from these regional results” whether HDS-induced liver injury is a nationwide problem. Outside of this study, she added, there are many other challenges in quantifying the extent of the risks posed

by HDS. For one, “we lack an accurate

Si FDA approved

Kabiven® and Perikabiven® Fresenius Kabi’s three-chamber bags for parenteral nutrition contain: • Amino Acids and Electrolytes • Dextrose • Lipids (Intralipid® 20% IV Fat Emulsion) www.KabivenUSA.com. To order, call 1-888-386-1300.

Kabiven and Perikabiven three-chamber bags must be mixed prior to infusio on. For admixing insstructions see DIRECTIONS FOR ACTIVATING THE BAG in the presc cribing information n available at www.K KabivenUSA.com.

INDICATIONS AND LIMITATIONS OF USE calories, protein n, electrolytes and essential fatty • Kabiven and Perikabiven are each indicated as a sourcee of calories acids for adult patients requiring parenteral nutrition when oral or enteral nutrition is not posssible, insufficient, or contraindicated. Kabiven and Perikabiven may be ussed to prevent essen ntial fatty acid deficciency or treat negative nitrogen balance in adult patients.

• Kabiven is indicated for intravenous infusion into a central vein.

• Perikabiven is indicated for intravenous infusion into a peripheral or central vein.

• Neither Kabiven nor Perikabiven is recommended for usse in pediatric patiennts < 2 years, includinng preterm infants because the fixed content of the formulations do not me eet the nutritional requirements in this age group.

Clinical 35

Pharmacy Practice News • November 2014

Medication Safety tally of the number of Americans who consume dietary supplements, of which there are an estimated 60,000 on the worldwide market,” she said. Moreover, “adverse reactions and causality related to supplements are difficult to quantify.”

But the adverse events are likely far more common than currently appreciated, she stressed, in part because “these reactions are underreported to the FDA, to supplement manufacturers and to health care professionals.”

Dr. Rosenbaum stressed that it is also important to remember a key cause of

liver injury not covered by the current Hepatologyy study: accidental overdoses of acetaminophen.

Dr. Navarro agreed that clinicians should heed the painkiller’s potential to cause liver injury. As for why it was excluded from his study, he explained in an email that hepatic damage caused by acetaminophen far outstrips cases attributed to other drugs and thus would have skewed the results. He added that the National Institutes of Health, which supports DILIN, “needed to focus its resources on the less understood (and studied)

agents” contributing to liver disease.

Study methods aside, Dr. Navarro stressed the central challenge raised by his team’s research. “All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers and consumers, must take note of these findings if a culture of safety for HDS use is to be established.”

—David Bronstein None of the sources had any relevant financial conflicts of interest to disclose.

plify IM MPORTANT SAFET TY INFORMATION

• •

Deaths in preterm m infants have been reported in literature.

•

Preterm and low b birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels follo owing lipid emulsion infusion.

Autopsy findings included intravascular fat accumulation in the lungs.

CO ONTRAINDICATIONS • Known hypersensiitivity to egg, soybean proteins, peanut proteins, corn or ccorn products, or to any of the active substances or excipients.

•

Severe hyperlipide emia or severe disorders of lipid metabolism with serum triglyce erides >1000 mg/dL.

• • •

Inborn errors of am mino acid metabolism.

Cardiopulmonary p y iinstability.

WARNINGS AND PRECAUTIONS Kabiven is hypertonic and may cause vein irritation, vein damage and even thrombosis if infused in a peripheral vein.

Only infuse Kabiven into a central vein.

• •

Monitor for signs or symptoms of hypersensitivity reactions and discontinue infusion if reactions occur.

•

Monitor patient closely for signs and symptoms of infection, hypertriglyceridemia, hyperglycemia and refeeding complications.

•

Monitor laboratory parameters for alterations in electrolytes, liver and renal impairment, fluid status and coagulation parameters. Adjust rate and dose of Kabiven and Perikabiven according to clinical status.

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, Vigilance & Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Hemophagocytic ssyndrome.

Ple ease see Brief Summ mary of Prescribing Information, including Boxed Warning, for Kabiven and Perikabiven on the following page.

Fre esenius Kabi ©2014.

Alll rights reserved. 060 05-KAB-09-11/13

Web Exclusive

T

here are several steps that pharmacists can follow to ensure the safe use of herbs and dietary supplements. To access, visit pharmacypracticenews. com/herbs or scan the adjacent 2D barcode with your smartphone.

36 Operations & Management

Pharmacy Practice News • November 2014

Leadership in Action

Our Boundaries and Self-Leadership

I

n the previous articles of this series based, in part, on Henry Cloud’s “Boundaries for Leaders” (HarperCollins 2013), we looked at the relationship between our thinking—that is, our actual brain function—and the effect that it has on our creativity, productivity and leadership. We looked at the importance of paying attention and focusing on the relevant issues of the day to make decisions. We also explored the impor-

tance of cultivating a positive emotional climate in ourselves, and how that can help us to make strong, productive connections with others.

But there’s a catch to that last element of personal growth: It’s difficult to foster any lasting change in ourselves if we don’t have a strong foundation of selfawareness. The ability to look inward truthfully and see what character traits are working both for and against us is a

critical component of what Cloud terms “self-leadership.”

Knowing Oneself To that end, how well do you know you? This question of introspection is often a difficult one. We tend to think that we have the right ideas, skills and experience. After all, we are the leader.

So let me ask you a few questions: • How open are you to feedback? In

DOSAGE AND ADMINISTRATION

WARNINGS AND PRECAUTIONS

• Kabiven is for intravenous infusion only into a central vein • Perikabiven is for intravenous infusion into a central or peripheral vein • Recommended dosage depends on clinical status, body weight and nutritional requirements • Kabiven adult dosage: 19 to 38 mL/kg/day (0.63 to 1.26 g/kg/day of amino acids, 1.85 to 3.71 g/kg/day of dextrose, 0.74 to 1.48 g/kg/day of lipid) • The maximum infusion rate for Kabiven is 2.6 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.1 g/kg/hour of lipid) • Perikabiven adult dosage: 27 to 40 mL/kg/day (0.64 to 0.94 g/kg/day of amino acids, 1.83 to 2.71 g/kg/day of dextrose, 0.95 to 1.4 g/kg/day of lipid) • The maximum infusion rate for Perikabiven is 3.7 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.13 g/kg/hour lipid) • The recommended infusion period is 12 to 24 hours

• Hypersensitivity yp y reactions: Monitor for signs or symptoms and discontinue infusion if reactions occur • Infection,, fat overload,, hyperglycemia yp g y and refeedingg complications: p Monitor for signs and symptoms; monitor laboratory parameters

INDICATIONS AND USAGE

DOSAGE FORMS AND STRENGTHS

USE IN SPECIFIC POPULATIONS

Kabiven and Perikabiven are each indicated as a source of calories, protein, electrolytes and essential fatty acids for adult patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated.

Kabiven and Perikabiven may be used to prevent essential fatty acid deficiency or treat negative nitrogen balance in adult patients.

• Kabiven and Perikabiven are sterile, hypertonic emulsions in a three-chamber container. The individual chambers contain one of the following: amino acids and electrolytes, dextrose, or lipid injectable emulsion, respectively

Renal Impairment: p Patients on hemodialysis or continuous renal replacement therapy may require additional supplementation to meet nutritional requirements. If required, adjust the volume of Kabiven or Perikabiven administered based on serum electrolyte levels and fluid balance.

BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Kabiven and Perikabiven safely and effectively. See full prescribing information, including Boxed Warning, for Kabiven and Perikabiven available at www.KabivenUSA.com.

KABIVEN® (Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion), for intravenous use Initial U.S. Approval: 2014 PERIKABIVEN® (Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion), for intravenous use Initial U.S. Approval: 2014 WARNING: DEATH IN PRETERM INFANTS See full prescribing information for complete boxed warning • Deaths in preterm infants have been reported in literature.

• Autopsy findings included intravascular fat accumulation in the lungs.

• Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion.

Limitation of Use: Not recommended for use in pediatric patients < 2 years, including preterm infants, because the fixed content of the formulation does not meet nutritional requirements in this age group

• Kabiven is available in four sizes 2566 mL, 2053 mL, 1540 mL and 1026 mL • Perikabiven is available in three sizes 2400 mL, 1920 mL and 1440 mL CONTRAINDICATIONS • Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products, or to any of the active substances or excipients • Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1000 mg/dL • Inborn errors of amino acid metabolism • Cardiopulmonary instability • Hemophagocytic syndrome

ADVERSE REACTIONS The most common adverse reactions to Kabiven (>3%) are nausea, pyrexia, hypertension, vomiting, decreased hemoglobin, decreased total protein, hypokalemia, decreased potassium and increased gamma glutamyltransferase.

The most common adverse reactions to Perikabiven (> 3%) are hyperglycemia, hypokalemia, pyrexia and increased blood triglycerides.

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, Vigilance & Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS Coumarin and coumarin derivatives,, includingg warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, of Brockton, Mass.

Mr. Anderson welcomes your input on leadership issues, at ernestanderson1130 @gmail.com

Ernest R. Anderson Jr., MS, RPh

fact, do you ask for it?

• Do you ask those in and out of the workplace for input? How about your spouse?

• Do you read leadership books and articles in order to grow and improve? Or have you “arrived” and have nothing new to learn?

• Are you defensive if someone tries to give you feedback?

• Do you play the blame game, always pointing to someone else or your circumstances and not taking real ownership of your thoughts and actions?

• How would you respond if told you need an executive coach?

Often, many people may have a mentor at their workplace, but what about outside of that setting? In our pharmacy profession, we are often great networkers, but do you formally have your “goto” person to seek feedback and guidance—someone who doesn’t have a bias other than an interest in your growth and development?

I recommend that you have both a professional and a personal mentor outside of the pharmacy profession. Perhaps the personal mentor is someone who observes your leadership in a social setting, such as a society, club or church.

My wife is someone from whom I seek feedback regularly. I know she won’t sugarcoat things and is constructive with her comments and criticisms. I also know she possesses insights that I do not have; she experiences situations from a different perspective. Thus, I value her input tremendously. After more than 40 years together, she knows me well, for better and for worse.

As I have asked in past articles, do you have your “truth-tellers”? And more importantly, how do you respond to their feedback? Remember that if you become defensive, you likely are shifting into the “fight or flight” mode, and the resulting surge of adrenalin and aggressiveness surely is not conducive to an open, frank exchange about your behaviors and attitudes. We must be hungry for such feedback and view it positively, as part of our growth plan. As Cloud states, “Good character welcomes feedback and foolish character fights it off.”

If you’re already open to your mentors, team or spouse for their feedback and receive it graciously, then you’re ahead of the game! But do you always remember to thank them for their com-

Operations & Management 37

Pharmacy Practice News â&#x20AC;˘ November 2014

Leadership in Action â&#x20AC;&#x2DC;Bringing someone into your hospital for advice and assistance is not a sign of weakness; rather, it is a sign of strength that comes through knowing yourself.â&#x20AC;&#x2122;

ments? That type of acknowledgment is always appreciated and can make good relationships even stronger.

5DWLRQDOH 5HYHUVDO DQG 5HFRYHU\ RI 1HXURPXVFXODU %ORFNDGH

Youâ&#x20AC;&#x2122;ve Got Mail Before you hit the â&#x20AC;&#x153;sendâ&#x20AC;? button on that email, think about whether its tone and content will help you accomplish your goal or instead create unintended consequences, such as anger and resentment. Particularly if you are facing an emotional issue, I would suggest writing the email but not sending it. If you donâ&#x20AC;&#x2122;t have someone to review it, sit on it for a day or a weekend. Letting it â&#x20AC;&#x153;marinateâ&#x20AC;? for a time will get you out of your limbic system of emotional response, and give you the opportunity to move into the precortex center of rational thinking.

Get Fresh Thinking If you are having difficulty in any one of the areas above, it may be perfectly appropriate to consult with someone outside of your personal or professional sphere, such as a consultant. As a consultant, I often tell the client that our job is to help you be successful. Bringing someone into your hospital for advice and assistance is not a sign of weakness; rather, it is a sign of strength that comes through knowing yourself.

The first element in emotional intelligenceâ&#x20AC;&#x201D;a concept weâ&#x20AC;&#x2122;ve covered in past articles, based on Daniel Golemanâ&#x20AC;&#x2122;s workâ&#x20AC;&#x201D;is honest self-analysis.

Great leaders are always hungry for feedback. Ken Blanchard of â&#x20AC;&#x153;One Minute Managerâ&#x20AC;? fame says, â&#x20AC;&#x153;Feedback is the breakfast of champions.â&#x20AC;?

Boundaries and Fears Letâ&#x20AC;&#x2122;s face it: We do not think rationally all the time; we all have our insecurities. Setting our boundaries through knowing ourselves is essential. So here are some recommendations: â&#x20AC;˘ Donâ&#x20AC;&#x2122;t let one bad outcome define who you are. Think big picture! â&#x20AC;˘ Donâ&#x20AC;&#x2122;t personalize and question yourself detrimentally. â&#x20AC;˘ Donâ&#x20AC;&#x2122;t allow fear to control you. Be bold, not fearful. â&#x20AC;˘ Commit to change. â&#x20AC;˘ Above all, remember you are ridiculously in charge! â&#x2013;

Part 2: Ongoing Challenges and Opportunities Case Study Dennis is a 68-year-old man undergoing open abdominal surgery (colectomy).

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38 Operations & Management

Pharmacy Practice News • November 2014

Specialty Pharmacy

CHEMO DRUGS continued from page 1

Services at the Arthur G. James Cancer Hospital at The Ohio State University in Columbus, questioned that explanation.

“We’ve never had an issue with the supply chain for Genentech drugs—never a shortage issue and never any product integrity concerns,” she stressed.

Although Ms. Arnold said no specific issue led to the decision, she pointed to a 2012 incident when counterfeit Avastin (bevacizumab) was found in the United States as a reason for concern. “Avastin has been targeted by people acting outside the legitimate supply chain, and while this did not necessarily impact [hospitals], we have been focusing on enhancing our overall supply chain security since that occurred,” she told Pharmacy Practice News.

The FDA found that the counterfeit product had been ordered online from an overseas distributor. In a warning letter to health care professionals, the FDA stressed that agency-approved versions of Avastin were not in short supply and could be obtained from legitimate U.S.based drug wholesalers (http://goo.gl/ EXhHmC).

High Usage Equals High Concern Two of the three products moved to specialty distribution, bevacizumab and rituximab (Rituxan), are essential cancer therapies because they are indicated for multiple cancer types, according to Ms. Griffith. Combined with the third product, trastuzumab (Herceptin), which is used primarily for breast cancer, the medications are among the top five cancer treatments used globally.

As a result, there will be a significant financial impact from this change in distribution, according to Matt Farber, MA, the director of Provider Economics and Public Policy at the Association of Community Cancer Centers (ACCC) in Rockville, Md. By moving these drugs to the specialty distribution chain, Mr. Farber noted, hospitals will spend considerably more for them than if they purchased the products through their normal wholesaler.

Ernest R. Anderson Jr., RPh, MS, a pharmacy consultant in Brockton, Mass., explained why a move to specialty pharmacy distribution can increase costs. When hospitals order drugs through the normal distribution chain, he noted, they are privy to various discounts and rebates, such as cost-minus, which are exempt to specialty distributors. Hospitals also tend to purchase as many products as possible from the same distributor to receive a volume discount. Hospitals estimate that they will spend an additional $200,000 to

‘Even if [physicians] cannot [stop using Genentech products], the sheer fact that they are thinking about it ... should make Genentech stop and think about this.’

—Matt Farber $4 million, depending on the size of the cancer center, to purchase these three products because they are so widely used for cancer treatment. These added expenditures could increase the cost for treating cancer by more than $300 million annually, several hospital pharmacists estimated.

“I was talking with a colleague, and he [projected] that for his hospital, this will result in about $400,000 in added costs,” Mr. Anderson said. “For a busy cancer center, this is not something they can afford.”

However, these estimates are near impossible to confirm because they involve confidential contracting terms among manufacturer, distributor, hospital and payor, according to Jason Rucker, the director of Copay Offset Monitor at Zitter Health Insights, a health care research firm that assists companies with issues related to product access, reimbursement and managed markets.

Even without factoring in such contracting variables, Mr. Anderson pointed out, the added costs to the system are clear. “Any way you look at it, these medications are going to be very expen-

for these cancer drugs also means additional ordering, invoicing, mailing costs and staff time, as well as waste disposal costs, pharmacy stakeholders point out.

According to a letter sent to Genentech by the Hematology/Oncology Pharmacy Association (HOPA), which was signed by several groups, including ACCC, the packaging issue is a real burden. When products are shipped by courier services—the preferred method used for most specialty pharmaceuticals—the packaging is more extensive than that used by conventional distributors, and is not returned.

“Sites that have limited space will experience challenges when they receive a larger volume of inefficiently packed items,” HOPA wrote. “Disposal of the packaging materials will add to our cost of waste management. Further, delivery method and location will need to be altered because cardboard and similar packaging materials cannot be received in the vicinity of our clean rooms.”

Ms. Arnold said that “while we don’t believe there has been an appreciable increase in shipping materials, we are working closely with our authorized dis-

‘The majority of hospitals already have accounts set up and purchase our other three medicines [via the specialty pharmacy] … model with minimal concern from customers.’

—Charlotte Arnold sive for pharmacies to buy through the specialty pharmacy [supply] chain,” he said. “The whole idea for using a wholesaler is that you can go to one place and buy all your drugs. Thirty to 40 years ago, pharmacies bought their drugs directly from the manufacturers; as a result, they needed an account with every manufacturer, and it was very labor-intensive. Then wholesalers consolidated the process, and that move enabled better efficiencies and resultant savings.”

Mr. Farber said ACCC members are also indicating that the loss in rebates and other discounts will be in the six figures for individual hospitals and cancer centers or higher, depending on the facility, so the financial piece is “definitely an issue.”

Using a separate specialty distributor

tributors to ensure any potential additional packaging is kept to a minimum.”

Because of the sheer volume of these products being used in the United States today, hospital pharmacists and providers say they are concerned about supply delays and patient access to the medications. “Cancer hospital pharmacy directors and others with large cancer programs have been communicating with each other almost daily by email with updates on this issue,” Ms. Griffith said, and several have already reported shipment delays.

Distributors who are not used to this type of volume might not be able to deliver the products on time, she added. “Additional risk of not receiving the medication in a timely manner is introduced because we are no longer able to use our reliable wholesaler delivery.”

Mr. Farber said his members are also

concerned about access to these medications. “We want to make sure that the drug that they need and want will be available,” he stressed, adding that there has never been a supply problem with these three products when they went through the wholesalers.

Ms. Arnold agreed that access is an important issue. “Patients are our primary concern, and we believe patients are getting their medicines when they need them,” she stressed.

In fact, ensuring prompt access to these medications is another reason why Genentech decided to switch to specialty pharmacy. The products “require tighter inventory management than our other medicines,” she explained. “While we are not reducing the numbers of distributors, using the specialty pharmacy chain does reduce the number of distribution centers from 80 to five, and this helps us better manage and track our supply, particularly if the supply was to become constrained.”

As an example, Ms. Arnold said when pertuzumab (Perjeta) was launched in 2012, the FDA only approved a limited supply due to manufacturing challenges. “We were able to launch with a limited supply because the specialty distribution enabled us to better manage our inventory, and we were able to do that with no customer outages or patient impact,” she said.

Absorbing the Costs With most hospitals still facing financial constraints, there is a question as to whether they can absorb the added costs that may result from specialty distribution. Whether providers, patients or third-party payors will ultimately pay these costs “is too soon to tell,” Mr. Farber said. “Hospitals are looking at all the data now to see the best way they can move forward on this.”

Asked to comment on the potential for cost shifting, Ms. Arnold said, “There is no change to the list price or wholesale acquisition cost that Genentech charges for these medicines, so we don’t anticipate any change in patients’ insurance or out-of-pocket ability to pay.” As for the other players in this scenario, “we are not privy to and do not influence the terms between hospitals and distributors.”

One of those other players is the government. As the largest third-party payor through the Centers for Medicare & Medicaid Services, the Department of Veterans Affairs, and federal and state worker insurance plans, the government certainly has a stake in any drug distribution changes that might affect cost.

However, there does not seem to be a legal means for the government to get involved in the dispute.

Other than a large facility getting its local representative to draft a letter to

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40 Operations & Management

Pharmacy Practice News • November 2014

Specialty Pharmacy

CHEMO DRUGS continued from page 38

Genentech, “I don’t see any official action on the part of the government,” Mr. Farber said. “They might not be very happy, but I’m not sure [they have] recourse [unless patient] access is impinged.”

Ms. Arnold reminded pharmacists that they use the specialty channel for many cancer drugs and that this was “not a new model.” Many medications, including several other cancer therapies that Genentech manufactures (pertuzumab, ado-trastuzumab emtansine [Kadcyla] and obinutuzumab [Gazyva]), are distributed through the specialty supply chain, she pointed out. “The majority of hospitals already have accounts set up and purchase our other three medicines this way.

Starting with Perjeta in 2012, we launched cancer medicines into this model with minimal concern from customers.”

Still, “we recognize that some hospitals may need to make some adjustments to working with this slightly different delivery system for these medications,” Ms. Arnold said.

“This is in fact a very different situation,” Ms. Griffith countered. “The other drugs that are [purchased] through the specialty channel are not nearly as widely used as these three medications.” Those other agents, she noted, “are niche products that are used for a specific type of cancer. We are not talking about niche products [with the new distribution announcement]; we are talking about widely used, essential cancer treatments.”

Whether they verbalize a complaint to the manufacturer or not, Ms. Griffith added, “we are never happy when drugs

go through the specialty channel.”

Genentech’s current move to specialty distribution carried an additional sting: The company did not give pharmacy stakeholders an opportunity to express their concerns before the decision was made, and they had less than three weeks’ notice to prepare for the change, according to Mr. Farber.

Several stakeholders are trying to meet with Genentech to address some of these concerns and are considering various options for voicing their displeasure with the company. Sources said several facili-

cannot do that, the sheer fact that they are thinking about it, however, should make Genentech stop and think about this.”

Following Genentech’s Lead Hospitals and cancer centers are also concerned that other companies will follow Genentech’s lead. “Unless you get a loud enough and forceful enough pushback from the provider community, I do see this expanding,” Mr. Farber said.

“This is coming at a time when all of us are doing everything we can to control costs,” Ms. Griffith said. That makes

‘We are not talking about niche products [with the new distribution announcement]; we are talking about widely used, essential cancer treatments.’

—Niesha Griffith, RPh, MS, FASHP ties are talking about banning Genentech sales representatives from the hospital and denying them access to leading cancer doctors. The facilities are also reevaluating their participation in Genentech-sponsored clinical trials. A knee-jerk reaction was to stop using Genentech products, but that option is less likely than the other two, Mr. Farber admitted.

In some cases, there are other clinical treatment pathways that providers can take, but in many cases, the three drugs are the clear choice for a given patient.

“The last one would be hard to [accomplish], given that doctors will always do what is clinically warranted and best for the patient,” Mr. Farber said. “Even if they

it all the more worrisome, she noted, to have to suddenly deal with the budget impact of increased costs associated with Genentech’s expanded specialty distribution model.

Ms. Arnold stressed that the company values its partnership with the pharmacy and provider community. “Our relationship to our customers is extremely important to us, and we will work with them on this change,” she said. “We believe doctors have the right to prescribe the medication that they think is best for their patient, and they will continue to do so.”

Based on a letter Genentech wrote in response to HOPA’s letter, which had little in it to indicate any compromise on the

company’s part, Mr. Anderson predicted that the dispute will not go away. In fact, “I think this will be an extended battle.”

Mr. Farber concurred. Providers, he noted, want to make sure that they have access to the therapies that they want to give, when they want to give them and where they want to give them. “My job is to try to stop anything that is going to get in the way of that,” he said. “If this new policy is going to [be such an obstacle], then we are going to try and push back as best we can against it.”

Ms. Arnold said Genentech has no plans to reverse its decision. But in late October, some movement came in the form of a conference call between the company, the ACCC and other stakeholders. “We wanted to make Genentech aware of the operational and financial difficulties getting drugs to patients,” said Mr. Farber, adding that the meeting had positives and negatives.

During the discussion, Genentech said it would look into packaging and delivery issues. As for financial losses that may result from the initiative, the company reminded callers that it had a robust patient financial assistance program.

—Marie Rosenthal

NASP, SPAARx Merger Boosts Representation

O

rlando, Fla.—The merger of the National Association of Specialty Pharmacy (NASP) and the Specialty Pharmacy Association of America (SPAARx) comes at a time when the industry is experiencing double-digit growth and facing many complex challenges, experts noted during the NASP 2014 annual meeting and exposition.

“There is no more exciting time to not only be in specialty pharmacy, but to be in health care,” said Mike Ellis, BSPharm, RPh, the president of NASP. The merger “brought two competing forces into a single voice to represent the industry,” added Mr. Ellis, who is also corporate vice president of Specialty Pharmacy & Infusion at Walgreens.

The newly merged group now represents all stakeholders in the industry— the specialty pharmacy provider, manufacturer, distributor, health systems and home infusion, according to Robert Fulcher, CAE, chief operating officer of

NASP. Given that new breadth of representation, the group is well positioned to address many of the challenges facing the profession, he noted.

Mr. Ellis noted. In fact, “many of the key services [we] provide have nothing to do with the route of the drug” or other clinical considerations, he said. Rather, “it is about [providing] the right counseling and [ensuring] the right access to these drugs—affordable access.”

The high cost of specialty pharmaceuticals is one such challenge. Thirdparty payors are particularly concerned about the cost of sofosbuvir (Sovaldi, Gilead), which at $84,000 carries a hefty price tag. All of the specialty pharmacy experts said that the concern over the immediate costs ignores the long-term savings, because sofosbuvir cures HCV and prevents the need for a $400,000 liver transplant and lifetime suppressive medications.

Helping patients navigate the complexities of those high up-front costs is one of the most important skills that specialty pharmacy brings to the table,

A Focus on Education Education has always been important to the two groups and they plan to continue that focus as a merged association, Mr. Fulcher said. Those efforts will be front and center during NASP’s two meetings a year, as well as webinars and other educational opportunities. “We are looking to expand our education program,” he said. “That has been a hallmark of the organization.”

Moving forward, NASP also will be working on the local, state and federal levels to represent specialty pharmacy and help legislators and others understand the critical impact that specialty

pharmacy has on health care.

As a “new” organization, there is plenty of room for members to participate and a number of committees still need volunteers, Mr. Fulcher noted. In addition, NASP will continue to look for new members and plans a membership drive for the end of the year.

“We want to hear from you about what you expect and what you need,” he said. “In the end, NASP is about you, and we represent all stakeholders in specialty pharmacy. We want this to be the place where people come together and get the support that they need.”

“It is a wonderful thing to be part of an industry where we make a difference every day,” said Burt Zweigenhaft, the CEO of Onco360 Oncology Pharmacy Solutions, who sits on the board of directors of NASP and was instrumental in fostering the merger.

—Marie Rosenthal

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42 Operations & Management

Pharmacy Practice News • November 2014

Ambulatory Care

Pharmacists Show $1.2M in Post-Discharge Savings Austin, Texas—A federally funded Virginia program, which deployed pharmacists to better assist chronically ill patients after leaving the hospital, reaped an estimated cost savings of $1.2 million during the first 14 months, according to a study presented at the 2014 annual meeting of the American College of Clinical Pharmacy (abstract 88E).

The estimated savings, based on reduced medication costs and treatment services, was among the preliminary outcomes involving the program, Improving Health for At-Risk Rural Patients (IHARP). Other research abstracts detailed outcomes related to pharmacist interventions, including early trends in blood pressure control and other health indicators.

The medication therapy management program, funded through a three-year $4.2 million grant from the Centers for Medicare & Medicaid Services, was designed to reduce medication-related challenges in the rural and medically underserved region of southwestern Virginia, which includes 23 counties. The grant, awarded to Carilion New River Valley Medical Center in partnership with Virginia Commonwealth University (VCU) School of Pharmacy and selected community pharmacies, is part of the federal agency’s Health Care Innovation Awards, which fund projects targeted at improving care and reducing costs.

Before the program’s implementation, relatively few connections were forged between hospital and outpatient clinicians, making it difficult to pass along medication-related concerns to the patient’s primary care provider to follow up after discharge, said Mike Czar, RPh, PhD, the director of pharmacy at the Carilion and one of the IHARP leaders. “The inpatient pharmacist really had no relationship with the outpatient docs,” he said. “It would essentially be a random email from somebody you didn’t know, saying that this patient needs a [medication] change. By having pharmacists embedded in the clinics, and having developed good working relationships with the doctors, the recommendations coming from a pharmacist whom they know and trust, it makes a huge difference.”

The ongoing program shows promise in its commitment to measure not only outcomes, but also cost savings related to reduced need for medical services, said Toni Fera, PharmD, a Pittsburgh independent consultant who has been involved with other community initiatives, including the Diabetes Ten City Challenge. “Being able to measure outcomes and demonstrate the value of these programs is essential to their scalability and sustainability,” she said. “It

plexity of the patients’ medication needs soon resulted in a change in plans. “We knew they were complex,” said Leticia Moczygemba, PharmD, PhD, an assistant professor in the School of Pharmacy at VCU, in Richmond, who leads data analysis and evaluation for IHARP. “But they are even more than we had anticipated, when we were trying to plan for the pharmacists’ patient loads and panels.”

Follow-up Often Needed

A pharmacist at one of 22 primary care clinics run by Carilion New River Valley Medical Center helps a patient understand her blood pressure readings and medications.

‘Pharmacy and drug therapy touch [on] a lot of different quality issues, and quality is increasingly being tied to reimbursement.’

—Mike Czar, RPh, PhD will be exciting to see more details about their results on the financial and clinical outcomes.”

Juggling Complex Patients The program, which is now operating in 22 of Carilion’s primary care clinics and five of its hospitals, focuses on patients who have at least two chronic diseases and are taking four medications

at minimum, Dr. Czar said. “We see many more diseases and medications in our patients,” he noted. The seven primary disease conditions are hypertension, hyperlipidemia, diabetes, asthma, chronic obstructive pulmonary disease, heart failure and depression.

When the program first began enrolling patients in January 2013, its goal was to reach 4,000 people, but the com-

IVIG: Follow the (Grant) Money

T

he ambitious ambulatory care outreach program launched by Carilion New River Valley Medical Center was helped along by a grant from the Centers for Medicare & Medicaid Services (CMS). If your hospital is interested in obtaining such funding, the first step is to become familiar with CMS’s Innovation Center, which is the source of a wide range of quality improvement projects supported by significant grant money (htttp://innovation.cms.gov/index.html).

One of the more recent programs to go live is the Medicare Intravenous Immune Globulin (IVIG) Demonstration project, which is aimed at measuring the benefits of providing IVIG in a home-care setting for patients with primary immune deficiency disease (PIDD). The goal for participating hospitals is to enroll up to 4,000 Medicare beneficiaries during a three-year period of observation. Under the demonstration, Medicare will provide a bundled payment under Part B for items and services that are needed to administer IVIG at home. CMS is calculating the payments based on certain national benchmarks, under the provisions of the Outpatient Prospective Payment System. Eligible patients include those who are not otherwise homebound and who are receiving home health care benefits.

Applications are now being accepted on a rolling basis, according to a Sept.

18 post on the CMS website. For more information on the IVIG demonstration project, including eligibility criteria for hospitals interested in participating, and how to subscribe to a listserv containing frequent updates, visit http://innovation.cms.gov/initiatives/IVIG. —David Bronstein

When the pharmacists’ time was recorded for one week, they learned that a significant chunk was spent on follow-up, Dr. Moczygemba said. The cost savings estimate, for the first 14 months, reflected that complexity. In all, 4,008 medication-related problems were identified in 1,049 patients, for a mean of 2.63 per patient. In four out of 10 of those problems (39%), follow-up was needed to determine if the problem had been resolved.

After the time analysis, the number of patients each pharmacist was asked to manage was reduced from about 800 to about 450, for the five pharmacists hired through the CMS grant, Dr. Moczygemba said. (Along with the five IHARP pharmacists, two other existing Carilion pharmacists follow the medication management approach, although they are responsible for fewer patients.) As of mid-September, the IHARP program had enrolled about 2,400 patients. The total enrollment goal is about 3,000, with enrollment continuing through year’s end.

It’s not uncommon for reevaluation of patient panels to occur in such circumstances, Dr. Fera said. “People tend to underestimate the magnitude of the problem and the intensity of the care required for some of these patients with complex issues,” she explained.

In southwestern Virginia, noncompliance was the biggest medication-related issue, representing 36%, followed by the need for additional drug therapy (13%), adverse drug reaction (13%) and unnecessary drug therapy (11%), among the problems most frequently identified.

Further analysis determined that cost was a big factor in noncompliance, with one-third of patients unable to afford their prescription, according to Dr. Moczygemba. In some instances, a more costeffective drug was available, Dr. Czar said, adding that in others, sometimes a drug assistance program could be identified with help from other Carilion staffers. “It’s not a cookie-cutter sort of thing,” he stressed. “Every drug company has its own set of financial criteria.”

Hospitalized patients enrolled in the program typically get a call from an outpatient pharmacist within 72 hours after discharge to schedule a meet-

Operations & Management 43

Pharmacy Practice News • November 2014

Ambulatory Care ing at a Carilion primary care clinic, said Karen Williams, PharmD, BCPS, IHARP’s lead primary care clinical pharmacist. The program also started accepting outpatient referrals as well.

“Physicians were [indicating] that they had some patients who weren’t in the hospital yet, but who they were afraid were going to wind up in the hospital if they didn’t do something soon.”

Depending on the complexity of the medication issues, a pharmacist consult can range from a 15-minute phone call to as long as two hours for an inperson medication review, Dr. Williams said. In separate research (abstract 432), IHARP clinicians tracked several key clinical indicators, with only blood pressure data showing significant improvement. After six months, blood pressure readings in 482 patients declined from 141/76 at baseline to 134/74 mm Hg ((P<0.0001 for systolic, P<0.007 for diastolic). Patients with diabetes (n=123) experienced a decline in hemoglobin A1c from 7.9% to 7.6% at 180 days ((P=0.13). Among 73 patients with hyperlipidemia, low-density lipoprotein (LDL) levels were similar at baseline and at follow-up: 99.8 versus 100.2 mg/dL ((P=0.91). Those findings are based on a smaller sample size than the IHARP leaders would prefer, in part because obtaining follow-up lab results was difficult, Dr. Czar said.

The cost savings of $1.2 million also is an estimate only, IHARP leaders stressed, as exact figures won’t be available until insurance reimbursement is finalized. The program initially projected three-year savings of $4.3 million, according to the CMS grant. But that figure was based on an anticipated enrollment closer to 4,000 patients, said Gary Matzke, PharmD, FCCP, an IHARP leader, and a professor and director of practice transformation initiatives at VCU School of Pharmacy.

The most common reason cited for the $1.2 million estimated cost savings was a reduction in the cost of the medications used. Other savings involved reductions in physician, emergency department or hospital visits.

VCU oversaw related education efforts, including for the pharmacists, as well as data analysis. Given the design of electronic health records, one of the challenges has been to pull out the sort of pharmacy-related outcomes data needed, Dr. Matzke said. It required “almost a herculean effort” by pharmacy information technology specialists and others to customize the existing system to generate some of the data needed, he said.

One of the key next steps is to provide pharmacists with some prescriptive autonomy now that they’ve built up some trust with the primary care physicians, Dr. Czar said. The physicians “feel like they are getting sound

‘People tend to underestimate the magnitude of the problem and the intensity of the care required for some of these [discharged] patients with complex issues.’

—Toni Fera, PharmD suggestions for modifications of therapy,” he noted. “So, I think the time is approaching when collaborative practice agreements are possible.”

Carilion benefited from a $4.2 million grant to jump-start the program, but Dr.

Czar believes that the cost savings that have already been tracked indicate an opportunity for health systems searching for patient care investments that can pay off. “Pharmacy and drug therapy touch [on] a lot of different quality

issues,” he said, “and quality is increasingly being tied to reimbursement.

“As the payment system shifts from fee-for-service toward shared savings, the more you lower your costs, the more financial reward there is for the system,” Dr. Czar said. “So it’s an investment up front. But I think that’s the direction we are moving in as far as a health care payment system.”

—Charlotte Huff None of the sources reported any relevant financial conflicts of interest.

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*Infusion time calculations are based on recommended dosage of 60 mg/kg body weight and infusion rate of 0.2 mL/kg/min, as determined by the response and comfort of patient.

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INDICATION FOR GLASSIA GLASSIA is an Alpha1-Proteinase Inhibitor (Human) (Alpha1-PI) indicated for chronic augmentation and maintenance therapy in adults with clinically evident emphysema due to severe congenital deficiency of Alpha1-PI (alpha1-antitrypsin deficiency). GLASSIA increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining fluid levels of Alpha1-PI. The effect of augmentation therapy with any Alpha1-PI, including GLASSIA, on pulmonary exacerbations and on the progression of emphysema in alpha1-antitrypsin deficiency has not been conclusively demonstrated in randomized, controlled clinical trials.

Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy of individuals with GLASSIA are not available.

GLASSIA is not indicated as therapy for lung disease in patients in whom severe Alpha1-PI deficiency has not been established.

DETAILED IMPORTANT RISK INFORMATION FOR GLASSIA HYPERSENSITIVITY • GLASSIA is contraindicated in immunoglobulin A (IgA) deficient patients with antibodies against IgA or individuals with a history of severe immediate hypersensitivity reactions, including anaphylaxis, to Alpha1-PI products.

• Hypersensitivity reactions have been reported in patients following administration. Patients should be closely followed and vital signs monitored continuously. Discontinue the infusion if hypersensitivity symptoms occur and administer appropriate emergency treatment.

TRANSMISSION OF INFECTIOUS AGENTS • GLASSIA is derived from pooled human plasma and may carry a risk of transmitting infectious agents such as viruses, the variant Creutzfeldt-Jakob disease (vCJD) and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. Despite manufacturing steps designed to minimize the risk of viral transmission, such products may still potentially transmit human pathogenic agents.

USE DURING PREGNANCY • GLASSIA should not be given to pregnant women unless clearly needed, as reproduction studies have not been done in animals or humans.

ADVERSE REACTIONS • The serious adverse reaction observed during clinical trials was exacerbation of chronic obstructive pulmonary disease (COPD). The most common adverse reactions occurring in >0.5% of infusions in clinical trials were headache and upper respiratory infection Please see GLASSIA Brief Summary of Full Prescribing Information on the adjacent page.

References: 1. GLASSIA [Alpha1-Proteinase Inhibitor (Human)] Prescribing Information. Westlake Village, CA: Baxter Healthcare Corporation. 2. ASHP guidelines on preventing medication errors in hospitals. American Society of Health System Pharmacists website. http://www.ashp.org/s_ashp/docs/files/MedMis_Gdl_Hosp.pdf. Accessed June 18, 2013.

Baxter is a registered trademark of Baxter International Inc. Glassia is a registered trademark of Kamada Ltd. March 2014 USBS/341/14-0009

44 Opinion

Pharmacy Practice News â&#x20AC;˘ November 2014

New Practitioners

The Risk That Paid Off An urban pharmacy graduate discovers the rewards of rural practice Steven Nguyen, PharmD Clinical Staff Pharmacist Mee Memorial Hospital King City, California

A

recent article in the New Republic1 stated that new and future pharmacists would struggle to find employ-

ment for two reasons. First, experts who predicted an increased need for pharmacistsâ&#x20AC;&#x201D;presumably due to the aging population and a resulting boom in prescriptionsâ&#x20AC;&#x201D;were far off the mark: Although there has been some growth, it has slowed considerably.2 Second, because of the earlier erroneous estimates, there has been a big spike in the

Adverse Reactions1 Occurring in > 5% of Subjects During the First 12 Weeks of Treatment

GLASSIA [Alpha1-Proteinase Inhibitor (Human)] Injection Solution - For Intravenous Use Only Brief Summary of Prescribing Information. Please see package insert for full prescribing information.

GLASSIA No. of subjects: 33

Prolastin No. of subjects: 17

No. of subjects with adverse reactions1 (AR) (percentage of all subjects)

No. of subjects with adverse reactions1 (AR) (percentage of all subjects)

Cough

3 (9%)

4 (24%)

Upper respiratory tract infection

3 (9%)

0 (0%)

Headache

3 (9%)

3 (18%)

Sinusitis

2 (6%)

1 (6%)

Adverse Event (AE)

INDICATIONS AND USAGE GLASSIA is an Alpha1-Proteinase Inhibitor (Human) (Alpha1-PI) indicated for chronic augmentation and maintenance therapy in adults with clinically eWident emphysema due to seWere congenital demciency of Alpha1-PI (alpha1-antitrypsin demciency) GLASSIA increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining nuid levels of Alpha1-PI â&#x20AC;˘ The effect of augmentation therapy with any Alpha1-PI product, including GLASSIA, on pulmonary exacerbations and on the progression of emphysema in Alpha1-PI demciency has not been conclusively demonstrated in randomi[ed, controlled clinical trials â&#x20AC;˘ Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy of individuals with GLASSIA are not available â&#x20AC;˘ GLASSIA is not indicated as therapy for lung disease in patients in whom severe Alpha1-PI demciency has not been conclusively established

DOSAGE AND ADMINISTRATION

number of new pharmacy schools, with an attendant increase in newly minted pharmacists looking for work.

As a result, new pharmacy graduates are indeed finding it difficult to land full- or even part-time employment that helps to pay off their big student loans.

But itâ&#x20AC;&#x2122;s not all doom and gloom. In fact, Iâ&#x20AC;&#x2122;ve found that a successful entry

Chest discomfort

2 (6%)

0 (0%)

Dizziness

2 (6%)

0 (0%)

Hepatic enzyme increased

2 (6%)

0 (0%)

For Intravenous Use Only.

6se aseptic techniRue for all preparation and administration steps %ose mg Lg body weight intravenously once weeLly Administer at a rate not to exceed mL Lg body weight per minute, depending on patient response and comfort â&#x20AC;˘ %ose ranging studies using efmcacy endpoints have not been performed

Postmarketing Experience The following adverse reactions have been identimed during post-approval use of GLASSIA Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their freRuency or establish a causal relationship to drug exposure â&#x20AC;˘ 3espiratory, Thoracic and .ediastinal Disorders: Dyspnea â&#x20AC;˘ Gastrointestinal Disorders: Nausea â&#x20AC;˘ General Disorders and Administration Site Conditions: 'atigue

CONTRAINDICATIONS

USE IN SPECIFIC POPULATIONS

GLASSIA is contraindicated in immunoglobulin A (IgA) demcient patients with antibodies against IgA or in individuals with a history of severe immediate hypersensitivity reactions, including anaphylaxis, to Alpha1-PI products

Pregnancy Pregnancy Category C

â&#x20AC;˘ â&#x20AC;˘ â&#x20AC;˘ â&#x20AC;˘

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions GLASSIA may contain trace amounts of IgA Patients with selective or severe IgA demciency and with Lnown antibodies to IgA, have a greater risL of developing severe hypersensitivity and anaphylactic reactions .onitor vital signs continuously and observe the patient carefully throughout the infusion Discontinue the infusion if hypersensitivity symptoms occur and administer appropriate emergency treatment Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction

Animal reproduction studies have not been conducted with GLASSIA It is also not known whether GLASSIA can cause fetal harm when administered to pregnant women or can affect reproductive capacity GLASSIA should be given to a pregnant woman only if clearly needed Nursing Mothers It is not known whether Alpha1-PI is excreted in human milk Because many drugs are excreted in human milk, caution should be exercised when GLASSIA is administered to a nursing woman Pediatric Use Safety and effectiveness in pediatric patients have not been established

Transmissible Infectious Agents Geriatric Use Because this product is made from human plasma, it may carry a risk of Clinical trials of GLASSIA included 11 subKects of years of age or transmitting infectious agents, such as viruses, the variant Creutzfeldtolder This number of subKects was not sufmcient to determine whether they Jakob disease (vCJD), and theoretically, the Creutzfeldt-Jakob disease respond differently from younger subKects As for all patients, dosing for (CJD) agent This also applies to unknown or emerging viruses and other geriatric patients should be appropriate to their overall situation Safety and pathogens The risk of transmitting an infectious agent has been minimized effectiveness in patients over years of age have not been established by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections and by inactivating and PATIENT COUNSELING INFORMATION removing certain viruses during the manufacturing process (see Description â&#x20AC;˘ Inform patients of the early signs of hypersensitivity reactions, including <11> in full prescribing information for viral reduction measures) Despite these hives, generalized urticaria, chest tightness, dyspnea, wheezing, faintness, measures, such products may still potentially transmit human pathogenic hypotension, and anaphylaxis Advise patients to discontinue use of the agents product and contact their physician and/or seek immediate emergency care, All infections thought by a physician possibly to have been transmitted by this depending on the severity of the reaction, if these symptoms occur product should be reported by the physician or other healthcare provider to â&#x20AC;˘ Inform patients that GLASSIA is made from human plasma and may contain ,amada Ltd at 1- -GLASSIA or 'DA at 1- -'DA-1 or www fda gov infectious agents that can cause disease (e g , viruses and, theoretically, medwatch the CJD agent) Explain that the risk of GLASSIA transmitting an infectious agent has been reduced by screening the plasma donors, by testing the No seroconversions for hepatitis B or C (HBV or HCV) or human donated plasma for certain virus infections, and by a process demonstrated immunodemciency virus (HIV) or any other known infectious agent were to inactivate and/or remove certain viruses during manufacturing (see reported with the use of GLASSIA during the clinical trials Warnings and Precautions) Symptoms of a possible virus infection include ADVERSE REACTIONS headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, Kaundice The serious adverse reaction1 observed during clinical trials with GLASSIA was exacerbation of chronic obstructive pulmonary disease (C0PD) â&#x20AC;˘ Inform patients that administration of GLASSIA has been demonstrated to raise the plasma level of Alpha1-PI, but that the effect of this augmentation on The most common adverse reactions ( of infusions) in clinical trials the frequency of pulmonary exacerbations and on the rate of progression of were headache ( of infusions or ) and upper respiratory infection emphysema has not been established by clinical trials ( of infusions or ) 1

An adverse reaction is any adverse event which met any of the following criteria: (a) an adverse event that began within hours following the end of product infusion, or (b) an adverse event considered by either the investigator or sponsor to be at least possibly related to product administration, or (c) an adverse event for which causality assessment was missing or indeterminate

Baxter is a registered trademark of Baxter International Inc Glassia is a registered trademark of ,amada Ltd Baxter Healthcare Corporation, 8estlake Village, CA 1 6SA Issued .arch 1 6SBS/ 1/1 -

into the pharmacy profession is still possibleâ&#x20AC;&#x201D;iff youâ&#x20AC;&#x2122;re willing to be flexible about location, type of practice and other variables that may come your way during your job search.

I graduated from the University of the Pacific [in Stockton, Calif.] with my Doctorate of Pharmacy in May 2013, and received licensure in August 2013. Shortly after obtaining licensure, I began to apply for positions predominantly focused in the hospital sector. In total, I submitted more than 80 applications to hospitals all over California. Out of 80-plus applications, the first response I received was from a rural acute care hospital located in southern Monterey County.

â&#x20AC;&#x2DC;With great risk comes great reward, and I believe working for rural hospitals is a risk worth taking.â&#x20AC;&#x2122; This location was not ideal for me, because it placed me out of my normal comfort zone of the urban Northern California Bay Area. However, I went for the interview and despite the fact that I had no hospital experience, this hospital hired me as a full-time clinical staff pharmacist. Iâ&#x20AC;&#x2122;ve been told that I was hired for two reasons. First, I was a new graduate possessing current clinical knowledge of the pharmacy field that the hospital desired. Second, owing to my age, they felt that I was highly computer-literate and would have no problem learning their computer system.

I have been at this position for a year now, and I would like to share my experiences that came as a result of ventur-

Are you a new practitioner and have an interesting story to share?

If so, please send your topic idea to the editor at davidb@mcmahonmed.com

Opinion 45

Pharmacy Practice News â&#x20AC;˘ November 2014

New Practitioners ing out of my comfort zone.

In my current position, I have been encouraged to become involved in patient care by attending daily rounds for ICU and medical/surgical patients as a member of the interdisciplinary team. On the team, I serve as the medication expert, providing drug information and recommendations based on nursing and physician reports.

Rounding has exposed me to and educated me about the many facets of a hospital systemâ&#x20AC;&#x201D;social service, risk management and drug utilization review, to name just a few. I was also presented with many learning opportunities to become certified in Advanced Cardiac Life Support (ACLS), Pediatric Advanced Life Support (PALS) and aseptic technique for compounding various IV medications.

Owing to small size and limited resources, the hospital pharmacy staff is fairly thin: the pharmacy director and myself, plus two limited-duty pharmacists and two full-time technicians. Because of the limited staffing, however, I have been exposed to both clinical and managerial facets of pharmacy. I have gained invaluable knowledge, insight and skills by working in close proximity with and directly assisting my pharmacy director. I believe this unique experience will give me a competitive edge when I choose to advance my career.

Every month, I assist the pharmacy director with quality assurance reports ranging from narcotic waste to automated dispensing cabinet overrides to retrospective emergency room order reviews. I have been involved in writing various clinical care policies, including those for stroke and ST-elevated myocardial infarction (STEMI). Recently, I set up and currently manage the insulin support program, and serve as a member on the advisory committee for the diabetes clinic. At the start of 2015, in conjunction with infection control and the pharmacy director, we plan to implement an antibiotic stewardship program to ensure appropriate antibiotic use to prevent the development of multidrug-resistant organisms.

Regardless of the gloomy news contained in the New Republic article, there will always be an underserved patient population. Where will the underserved and indigent population predominantly be located? Not only in large urban cities, but also in rural areas; thus, I encourage new pharmacists to take a risk. Step outside of your comfort zone and apply to a rural acute care community hospital and/or state prison hospitals located mostly in rural areas. Sacrifice the first two to three years of your long career as a pharmacist to gain invaluable experience, skills and knowledge necessary to advance

your career to a clinical or managerial position. With great risk comes great reward, and I believe working for rural hospitals is a risk worth taking.

References 1. Zavadski K. The pharmacy school bubble is about to burst. New Republic. September 29, 2014. www.newrepublic.com/article/119634/ pharmacy-school-crisis-why-good-jobs-aredrying. Accessed October 17, 2014.

Steven Nguyen, PharmD, a recent pharmacy school graduate (second from left), and his colleagues at Mee Memorial Hospital in King City, Calif.

2. The Use of Medicines in the United States: Review of 2011. IMS Institute for Healthcare Informatics; April 2012. http://goo. gl/3Xu4q5. Accessed October 17, 2014.

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Education are pleased to introduce part 3 of a 3-part interactive CME series featuring challenging cases LQ 10% (DFK DFWLYLW\ SUHVHQWV D FOLQLFDO VFHQDULR that you face in your daily practice. After reading the introduction to the case, consider the challenge TXHVWLRQV DQG WKHQ YLVLW ZZZ &0(=RQH FRP QPE WR ÂżQG RXW KRZ \RXU DQVZHUV VWDFN XS DJDLQVW WKRVH of our multidisciplinary faculty panel.

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-RQ *RXOG 0' Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

-DQ 3DXO 0XOLHU 0' 3K' Bariatric Anesthesiologist St. Janâ&#x20AC;&#x2122;s Hospital Bruges, Belgium

7ULFLD 0H\HU 3KDUP' 06 )$6+3 Departments of Pharmacy and Anesthesiology Scott and White Memorial Hospital Texas A&M University System HSC College of Medicine Temple, Texas

Access this activity at ZZZ FPH]RQH FRP QPE

This activity is jointly provided by Global Education Group and Applied Clinical Education.

Supported by an educational grant from Merck.

46 Policy

Pharmacy Practice News • November 2014

Reimbursement Matters

Q&A: Not Getting Buried by CMS Bundling Rule I

nsurers, including the Centers for Medicare & Medicaid Services (CMS), are experimenting with a variety of payment initiatives that bring providers on board as partners to control costs while improving quality and member satisfaction. Are you ready for the changes that these new payment policies will likely have on how you should be approaching reimbursement at your facility? I’ve posed a couple of questions and answers below to help you understand what to expect. But first, some background.

The models for these initiatives have a variety of names, including “bundled payments,” “consolidated payments,” “payments for episode of care,” and “incremental payment,” among others.

Although the models all differ to some degree, they are all designed to replace traditional fee-for-service payments, which are reimbursed on a line-item basis. CMS describes its approach to these new payments as “packaged services in composite APCs” (Ambulatory Patient Classifications). Regardless of the name, the basic principle remains the same: A fixed inclusive payment is provided for a defined treatment, procedure or condition, with the amount based on cumulated historical payments gleaned from claims data as well as best practice from other sources.

If these initiatives are based on accurate data and are well designed and effectively implemented, they should

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

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

‘It’s frightening to think of all that can go wrong with … [reimbursement] calculations every day, and how relatively little attention pharmacy tends to give to the process.’ be able to reward providers with strong financial incentives. Hospitals, for example, would be incentivized to work collaboratively with providers, and to accomplish this goal, silos within the institution would be broken down from traditional roles and interests. Of course, an accurate procedure-specific tally is essential to understand whether or not these are win-win propositions.

All of these initiatives are detailed in the Hospital Outpatient Prospective Payment System (OPPS) and ambulato-

Table 1. New HCPCS Codes in Hospital Outpatient Settinga

a

HCPCS Code

Long Descriptor

APC

Status Indicator

Q9972

Injection, Epoetin Beta, 1 microgram, (For ESRD On Dialysis)

N/A

E

C9025

Injection, Epoetin Beta, 1 microgram, (Non-ESRD use)

N/A

E

Effective Oct. 1, 2014.

APC, Ambulatory Payment Pay yment Classification; HCPCS, Healthcare Common Procedure Proced dure Coding System

ry surgery center (ASC) payment system proposed rule for calendar year (CY) 2015. The rule was released by CMS on July 3, 2014, and the agency accepted comments through Sept. 2, 2014. The rule was published in the Federal Register on July 14, 2014, and can be accessed at http://1.usa.gov/1nfPT82.

As expected and consistent with the trend that the agency set in past years, CMS is proposing to package more services into composite APCs. At this point, it doesn’t appear that drug administration has been included, although that may change before the final rule is published later this year for a Jan. 1, 2015 start. (Outpatient rules are designed to apply on a calendar year, whereas inpatient rules follow a fiscal year and begin Oct. 1.)

So, on to our brief Q&A session on these new payment policies.

Q: What are some key payment bans that I should expect? Effective Jan. 1, 2015, the proposed OPPS rules state that hospitals won’t receive separate payment for argatroban, bivalirudin

Bonnie Kirschenbaum, MS, FASHP

(Angiomax, The Medicines Company), clevidipine (Clexiprex, The Medicines Company), or topical thrombin “when administered to a patient receiving a comprehensive service,” regardless of pharmaceutical cost.

Q: What other packaged services will affect pharmacy? All packaged services currently in place remain in the proposed rules, including drugs that cost less than a certain threshold per day (currently $90 per day, proposed to rise to $100 per day). Items and services that were “packaged” or included in payment for a primary service in the 2014 OPPS rule include five new categories of supporting items and services: 1. Drugs, biologicals and radiopharmaceuticals that function as supplies when used in a diagnostic test or procedure 2. Drugs and biologicals that function as supplies when used in a surgical procedure, including skin substitutes.

(Skin substitutes were classified as either high-cost or low–cost, and will be packaged into the associated surgical procedures with other skin substitutes of the same class.)

3. Certain clinical diagnostic laboratory tests 4. Certain procedures described by add-on codes 5. Device removal procedures In certain cases, a separate payment will be made if the item or service is provided on a date that differs from the date of the primary service.

Q: Why is the drug administration exclusion so important? Even if the

Table 2. Updated Payment Rates Available for Rebillinga, b Use Date

HCPCS Code

Short Descriptor

APC

Status Indicator

Correct Rate

Co-pay

1.1.14 to 3.31.14

J9171

Docetaxel injection

0823

K

$4.63

$0.93

4.1.14 to 6.30.14

J7335

Capsaicin 8% patch

9268

K

$25.49

$5.10

4.1.14 to 6.30.14

J8700

Temozolomide

1086

K

$6.94

$1.39

4.1.14 to 6.30.14

J9171

Docetaxel injection

0823

K

$4.35

$0.87

7.1.14 to 9.30.14

J9047

Injection, carfilzomib, 1 mg

9295

G

$29.67

$5.93

7.1.14 to 9.30.14

J9315

Romidepsin injection

9265

K

$270.24

$54.05

APC, Ambulatory Payment Classification; HCPCS, Healthcare Common Procedure Coding System a

These changes are not done automatically by the Medicare Administrative Contractor!

b

Effective Oct. 1,, 2014.

Annual Clotting Factor Furnishing Fee Update

E

ach year, CMS determines a furnishing fee that is added to the payment for items and services associated with clotting factors used for Medicare patients regardless of their age. Effective Jan. 5, 2015, this fee will be $0.197 per unit and is included in the published payment limit for clotting factors.

The furnishing fee will be added to the clotting factors payment when no payment limit for the medication is included in the Average Sales Price (ASP) or Not Otherwise Classified (NOC) drug pricing files.

It’s important to remember that your Medicare Administrative Contractor (MAC) must make payment for the clotting factor, as well as for the furnishing fee. For more information on this new payment policy, visit http://tinyurl. com/qbjx8h9 or click on the adjacent 2D barcode.

Policy 47

Pharmacy Practice News • November 2014

Reimbursement Matters drug itself is not being paid for separately, its preparation and administration are being paid for separately through the drug administration fee codes. It’s essential that pharmacy work with the revenue cycle team and with nursing to ensure that these fee codes are being applied correctly with the required documentation. Not doing so is throwing away guaranteed revenue!

The accuracy and completeness of what you’re doing now also will affect future payments if, at some point, drug administration also is rolled into packaged service payments. Remember, future payment is largely based on a nationwide accumulation of claims data.

Q: Why is CMS no longer paying for certain drugs, and yet we still have to buy them? The concept of a bundled payment is that it is inclusive of all of the services, procedures and supplies that you perform or provide—including drug therapy. The actual payment is based on cumulated claims data from years past and may be adjusted for several factors.

The accuracy of your billing, the skill of your revenue cycle team and the robustness of your information technology infrastructure—along with all of these variables submitted by other providers across the country—are all coming into play as these rates of payment are determined. It’s frightening to think of all that can and does go wrong with these data aggregations and calculations every day, and how relatively little attention pharmacy tends to give to the process.

Just as important as the accuracy and completeness of what pharmacy contributes to the bundle through its claims, is the ability to work with the finance team to have the bundled payment appropriately dispersed once it’s received by the facility. Hence the next question to consider: Q: Am I ready for the impact these payment changes will have on my facility? That depends in which of these “status reports” describes your facility: a) The revenue cycle team is on top of this process and is able to parse out payments to the appropriate cost centers; b) I, at least, get the pharmacy component of drug administration fees transferred to my cost center; c) We’ve initiated discussions but nothing’s happening yet; d) My facility hasn’t yet broached this issue.

Be honest with your answer to the last question: Your hospital’s fiscal survival may well depend on it.

CMS Code Alerts CMS has made several recent changes that affect coding and reimbursement.

The changes took effect Oct. 1, so it’s time to ensure that they have been made to both your pharmacy drug master and charge description master and that you consider rebilling where price corrections have been made.

Table 3. Drugs and Biologicals Granted OPPS Pass-Through Statusa

a

HCPCS Code

Long Descriptor

APC

Status Indicator

C9023

Injection, testosterone undecanoate, 1 mg

1487

G

C9025

Injection, ramucirumab, 5 mg

1488

G

C9026

Injection, vedolizumab, 1 mg

1489

G

C9135

Factor ix (antihemophilic factor, recombinant), Alprolix, per i.u.

1486

G

Effective Oct. 1, 2014.

APC, Ambulatory Payment Pay yment Classification; OPPS, Outpatient Prospective Payment Payme ent System

Pay attention, for example, to the status indicator for HCPCS codes J9160 (Injection, denileukin diftitox, 300 micrograms) and J9300 (Injection, gemtuzumab ozogamicin, 5 mg): they will change from SI=K (Paid under OPPS; separate APC payment) to SI=E (not paid by Medicare when submitted on outpatient claims (any outpatient bill type).

For more important code alerts and updates, see Tables 1-3. You can also visit the CMS site at http://goo.gl/M9EjwL. ■

48 Policy

Pharmacy Practice News • November 2014

FDA Watch

FDA Approves Trulicity To Treat Type 2 Diabetes

T

he FDA has approved dulaglutide (Trulicity, Eli Lilly), a once-weekly subcutaneous injection to improve glycemic control in adults with type 2 diabetes. The medication is to be used with diet and exercise.

Dulaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, a hormone that helps normalize blood sugar levels. The drug’s safety and efficacy were evaluated in six clinical trials, in which 3,342 patients with type 2 diabetes received treatment. Patients taking dulaglutide saw an improvement in their glycemic control with reductions in hemoglobin A1c level, according to the FDA. Dulaglutide has been studied as a stand-alone therapy and in combination with other type 2 diabetes therapies, including metformin, sulfonylurea, thiazolidinedione and prandial insulin.

The medication is contraindicated for those e with type 1 diabetes or any diabetic patient with diabetic ketoacidosis or gastrointestinal issues. It should not be used as first-line therapy, according to the FDA. The label carries a boxed warning that thyroid C-cell tumors have been observed in rodent studies, but it is unknown whether dulaglutide causes human tumors. The tumorss were related to dose and treatment duration, according to a company press release. Dulaglutide should not be prescribed for patients with a personal or family history of medullary thyroid carcinoma (MTC) or who have multiple endocrine neoplasia syndrome type 2, which predisposes them to MTC. The FDA approved dulaglutide with a Risk

Evalu uation and Mitigation Strategy (REMS), whic ch consists of a communication plan to inform health care professionals about the serious risks associated with the medication. The FDA A is requiring several postmarketing studies to a assess ongoing safety.

Trulicity comes in a single-dose pen and doess not require mixing, measuring or needle a attachment. Trulicity is administered once week kly, any time of day, and independent of meals, and should be injected subcutaneously in the abdomen, thigh or upper arm. The recomm mended starting dose is 0.75 mg, and can be in ncreased to 1.5 mg for patients who need additional blood sugar control.

Lilly plans to make Trulicity 0.75 and 1.5 mg ssingle-dose pens available for adults in the United States later this year, according to U tthe company.

Relistor Approved for OIC in Noncancer Pain Patients

Obizur Approved For Bleeding Disorder

T

The FDA has approved the antihemophilic factor (recombinant), porcine sequence, Obizur for the treatment of bleeding episodes in adults with acquired hemophilia A. Obizur (Baxter) was given priority review and granted orphan drug status.

Acquired hemophilia A (AHA) is caused by the development of antibodies directed against the body’s own factor VIII (FVIII), a protein important for blood clotting. As a result, patients with AHA experience excessive bleeding that can occur spontaneously or following an event, such as injury or surgery.

Unlike hereditary hemophilia, AHA is not a genetic disorder and affects both males and females. The development of AHA has been associated with other medical conditions or health states, such as pregnancy, cancer or the use of certain medications. However, in about half of cases, no underlying cause can be found. Diagnosis of this condition can be difficult and the severity of the bleeding can make treatment challenging.

“The approval of this product provides an important therapeutic option for use in the care of patients with this rare disease,” said Karen Midthun, MD, the director of FDA’s Center for Biologics Evaluation and Research.

Obizur is the first treatment approved for AHA that allows physicians to manage the drug by measuring factor VIII activity levels in addition to clinical assessments. Obizur contains a recombinant analog of porcine FVIII, which is used because it is sufficiently similar to human FVIII to be effective in blood clotting, but is less susceptible to inactivation by circulating human factor VIII antibodies.

The safety and efficacy of Obizur was evaluated in a multicenter Phase II/III open-label clinical trial of 29 patients. One hundred percent of patients treated with Obizur showed a positive response, meaning an effective or partially effective response with bleeding stopped or reduced and clinical improvement at 24 hours after the initial infusion.

Successful treatment of the initial bleeding episode was seen in 86% of patients. The investigators defined overall treatment success as the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.

The most common adverse reaction, observed in more than 5% of patients, was the development of inhibitors to porcine FVIII.

he FDA has expanded the indication for Relistor subcutaneous injection to include the treatment of opioid-induced constipation (OIC) in patients with chronic noncancer pain.

Relistor (methylnaltrexone bromide, Salix and Progenics) is a peripherally acting μ-opioid receptor antagonist that works by blocking the constipating effects of opioids in the gastrointestinal tract without interfering with analgesic properties.

It was previously approved in 2008 for treating OIC in patients with advanced illnesses in palliative care when response to laxative therapy was not sufficient.

A Phase III, randomized, double-blind, placebocontrolled clinical trial in 312 patients examined the safety and efficacy of Relistor 12 mg. Eligible participants had a history of noncancer pain, were taking opioids for at least one month before the trial and had confirmed OIC defined as less than three spontaneous bowel movements (SBM) per week during the screening period.

Patients were given either Relistor 12 mg or a placebo once a day for four weeks, followed by an eight-week period when they could take medications as needed. Researchers found that 58% of patients who took Relistor 12 mg daily reported three or more SBM per week during the four-week double-blind period, compared with 38% in the placebo group. They also found that 33% of the Relistor group had an SBM within four hours of the first dose; approximately half had an SBM before the second dose. Relistor was well tolerated, according to the researchers. Commonly reported side effects included abdominal pain, diarrhea, nausea and hyperhidrosis.

Nova StatStrip Glucose Hospital Meter System

T

he FDA has approved a new indication for the Nova StatStrip Glucose Hospital Meter System (Nova Biomedical), extending its use to critically ill patients who have been hospitalized. This is the first blood glucose monitoring system (BGMS) cleared by the FDA for use in these patients, according to the agency.

The FDA determined that the Nova StatStrip Glucose Hospital Meter System is simple to use and has a low risk for false results.

Consequently, the agency cleared the test with a waiver under Clinical Laboratory Improvement Amendments (CLIA) that allows many members of the health care team to perform the test at the point of care. (Complex diagnostic tests, in contrast, need to be performed in a hospital or other laboratory, as per CLIA regulations.)

The FDA originally cleared the Nova StatStrip Glucose Hospital Meter System in April 2006 for use in hospitals as an aid in monitoring the effectiveness of a diabetes control program, but not for use in critically ill patients.

Data supporting the clearance included a study of more than 1,650 patients who had a range of medical conditions that were treated in various care settings in the hospital (i.e, cardiac, emergency intensive care and surgical). In all patients tested, results showed agreement in blood glucose results compared with a laboratory glucose analyzer.

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Pharmacy Practice News • November 2014

American Health Packaging

AHP Launches New Unit-Dose Products

A

merican Health Packaging (AHP) recently launched three additional products to its growing unit-dose line: Digoxin 0.125 mg and 0.25 mg tablets (AB-rated to Lanoxin); Fluconazole 200 mg tablets (AB-rated to Diflucan); and Modafinil 200 mg tablets (ABrated to Provigil).

The company’s product line now

contains nearly 400 SKUs, one-quarter of which are industry exclusives, according to AHP. “These unit-dose launches are part of an ongoing commitment to support health systems’ BCMA initiatives while promoting efficiency in pharmacy operations,” the company stated in a press release. “All American Health Packaging unit-dose items are bar coded to the dose level and feature an extended shelf life. In

addition, our cartons feature colorcoded labels with ‘tall man’ lettering to more easily distinguish them in the

pharmacy prior to dispensing.”

For additional information, visit americanhealthpackaging.com.

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As the Contract Pharmacy Network market leader, Walgreens 340B Complete provides • Convenient access to enhanced patient care • Opportunities for drug cost savings • Robust technology and analytics • Proven compliance and reliability† • Efficient and inexpensive implementation • Support that has led to impressive HRSA audit success rates for its contracted Covered Entities† Walgreens 340B Complete alleviates the burden inherent in running a 340B program.

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Visit 340BComplete.com to learn more. ©2014 Walgreen Co. All rights reserved. WGPS-0614-0040-1 †

Source: Based on a compilation of audit and search results from the Health Resources and Services Administration Office of Pharmacy Affairs from 2012 and 2013.

Please see us at Booth #1600 at the ASHP Show in Anaheim

50 Technology

Pharmacy Practice News • November 2014

Ambulatory Care A pharmacist–nurse production

On the Road to Anticoagulation via Telemedicine Austin, Texas—Under a collaborative practice agreement fashioned by Virginia’s Sentara Medical Group (SMG), pharmacists and registered nurses (RNs) have teamed up via telemedicine to support patients treated at the health system’s 15 anticoagulation clinics.

The agreement allows RNs to assess patients, determine doses, and start or discontinue warfarin and oral anticoagulants for all cases covered by protocols that define the scope of practice for clinic nurses. For complex cases requiring additional expertise, RNs can phone a pharmacist who has immediate access to the patient’s medical record.

Two full-time pharmacists, dedicated to the anticoagulation clinics and stationed in Norfolk, are on duty Monday through Friday, 8 a.m. to 5 p.m.

Before the collaborative practice agreement, RNs needed to consult providers and get on-site approval for many medication-related decisions. Often, however, providers weren’t readily available, and so the bottleneck led to collaborative practice and the telepharmacy component.

According to Jessie Lish, PharmD, BCPS, a clinical pharmacy specialist in ambulatory care at SMG, all of the health system’s physicians and other prescribers signed on to the agreement.

“Providers are still at the helm, but RNs and pharmacists take control when seeing patients in the clinics and through remote consults,” she explained. “They don’t need providers to sign off for every medication management decision.”

Currently, 20 to 25 RNs work in the clinics. Each of the two pharmacists conducts consultations for an average

of 30 to 40 patients dailly.

Together, they cover all o of the anticoagulation cliniccs, Dr. Lish said, thus preclud ding the need to staff everry clinic with pharmacists on o site. She estimates that it would require 20 on-sitte pharmacists to provide th he same level of care.

During a three-montth study led by Dr. Lish an nd presented at the 2014 Ameerican College of Clinical Pharmacy annual meetingg (abstract 216), 15 clinic nurses managed 17,704 patient encounters, and the two pharmacists conducted 1,893 interventions (10.7%). Virtually all pharmacist recommendations were accepted, because dosing changes occurred in real time and, under the terms of the collaborative practice agreement, did not require provider authorization.

Dr. Lish anticipates that the tele– pharmacy model will result in decreased costs because of the reduced staffing needs, although she has yet to determine its financial impact. “This is the first time in my clinical experience where I’ve practiced true population management and used very limited pharmacy resources for a large patient population to intervene in many more cases than we could have under traditional care models,” she said. “This is the present and future of health care, and I hope we’ll see many more models like it.”

“I’m an avid supporter of the interprofessional care model they are using and a big proponent of using pharma-

off patients is high enough, it caan easily be a viable service deepending on how you bill for the service.”

More Follow-up Needed

‘This is the present and future of health care, and I hope we’ll see many more models Iike it.’

—Jessie Lish, PharmD, BCPS cists as the providers of antithrombotic services,” commented Kelly Epplen, PharmD, BCACP, an associate professor of clinical pharmacy practice and administrative sciences at the James L. Winkle College of Pharmacy, University of Cincinnati. “This model of care is being used across the country, and has been for years.”

The future of such programs, Dr. Epplen added, will depend on the reimbursement model and strategies for pharmacist services. “I know firsthand that this is deemed to be a more efficient use of resources, and that if the volume

Determining the full effect of D the program is difficult, accordingg to Seena Haines, PharmD, FA ASHP, the associate dean for facculty and a professor at Palm Beeach Atlantic University, Gregoryy School of Pharmacy, in West Paalm Beach, Fla. That is partly du ue to the fact that patients aaffected by interventions reprresented just 10% of the overall population, and the study duration was fairly short, Dr. Haines pointed out. “It would be important to find out more about follow-up and monitoring, which is essential for ambulatory patient populations, who often have problems with adherence to therapy,” she said.

Still, this care model could be very practical at facilities where staffing is limited, such as rural hospitals and clinics, Dr. Haines noted. “Health care providers are becoming more interested in remote access and remote care,” she said. “In the current health care environment and with efforts to bring down the number of uninsured and underinsured patients, being innovative and looking at nontraditional mechanisms to reach patients are warranted and can help to compensate for shortages of clinicians.”

—Steve Frandzel None of the sources had any relevant financial conflicts of interest to disclose.

Virtual Chart Reviews Boost Savings, Outcomes Austin, Texas—By conducting virtual chart reviews for Medicare enrollees in advance of scheduled visits with health care providers, pharmacists in Virginia can identify medication mananagement issues and recommend d interventions days before providers meet with patients.

The care model, which went into effect early in 2014, enables providers to start each encounter betteer informed and perhaps more inclined d to take a comprehensive view of caree decisions, according to pharmacistts involved with the program. It also haas resulted in substantial cost savings.

“The information supplied by th he pharmacists helps providers preparre

‘If we were physically present where the visits occur, we might be able to see just one patient for every 10 we “see” virtually.’

—Candace Minter, PharmD, BCACP

more thoroughly for the visit,” said Candace Minter, PharmD, BCACP, a clinical pharmacy specialist in ambulatory care at Sentara Medical Group, in Norfolk, Va., and lead author of a study to assess the effects of the model, presented at the 2014 American College of Clinical Pharmacy annual meeting (abstract 215).

“Providers might consider actions they otherwise might not have, such as ordering lab tests before the visit or considering a drug substitution or discontinuation.” She added that when patients present with a specific complaint—joint pain or a cough, for instance—providers are less likely to spend time addressing chronic conditions. “It helps to make them aware of the big picture,” she said.

Technology 51

Pharmacy Practice News • November 2014

Ambulatory Care Dr. Minter and her colleagues identified patients enrolled in the Medicare Advantage plan offered by Sentara’s insurance subsidiary, Optima Health.

Several days before an office visit, a Medicare enrollment visit or a hospital discharge meeting, Sentara pharmacists situated in Norfolk reviewed the patient’s chart via the electronic medical record (EMR).

During the three-month study period beginning Jan. 1, pharmacists reviewed charts for 396 patients and proposed 813 clinical interventions, including medication initiation and discontinuation, brandto-generic drug interchange, formulary interchange, lab monitoring, medication interaction alerts and dose adjustments.

They transmitted the recommendations to providers through the EMR’s messaging feature 24 to 48 hours before the providers met patients. The pharmacists also conducted an additional 2,239 postvisit chart reviews and hospital transition reviews, and they monitored prescriptions issued during the visits in real time.

Of the recommended interventions, providers accepted 70%. (Updated information shows that the acceptance rate climbed to 80% during the three months after the study.) The researchers estimated that the annualized cost savings derived from the interventions totaled $65,186, with the greatest impact coming from medication discontinuation and generic interchange. The savings were calculated based on Optima’s reimbursement schedules.

“If we were physically present where the visits occur, we might be able to see just one patient for every 10 we ‘see’ virtually,” Dr. Minter said. “A pharmacist does not need to approve every prescription, so there’s no delay or disruption of workflow, but we can intervene in real time if we see any potential medication issues, and providers know that we’re behind the scenes doing a doublecheck. This would be a great model for health systems to adopt in order to improve the quality of care delivered to an identified patient population and optimize pharmacotherapy.” Providers and patients can speak by phone directly with a pharmacist if necessary.

Overall, the findings are “impressive,” said Seena Haines, PharmD, FASHP, the associate dean for faculty and a

professor at Palm Beach Atlantic University, Gregory School of Pharmacy in West Palm Beach, Fla. However, additional data are needed for a more thorough evaluation of the program’s strengths, weaknesses and long-term viability. “Clearly, the pharmacists are having a clinical and financial impact from the interventions and achieving cost savings from actions such as generic interchange. But I would like to know, for instance, how the return on investment and clinical intervention acceptance rates compare with those

in prior years before the remote chart reviews began and when pharmacists were physically present.”

She added that hospitals are under a great deal of pressure to improve outcomes and narrow the gap for lack of access to care. “That makes innovative practices such as this one more important, but we have to analyze the benefits and costs to be certain we’re providing the best care to our patients. The three pillars I always consider are efficiency, economy and quality of care.”

Karen Williams, PharmD, BCPS, the

lead primary care clinical pharmacist at the Carilion New River Valley Medical Center, in Christiansburg, Va., also saw potential for the virtual chart reviews.

“The prospective nature of the reviews is a true strength, as is the ability to communicate recommendations to providers before they see patients,” she said.

Dr. Minter hopes to publish the complete study in early 2015.

—Steve Frandzel None of the sources had any relevant financial conflicts of interest to disclose.

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52 Technology

Pharmacy Practice News • November 2014

Ambulatory Care

Can Anyone Build a Good Tracking System?

Existing software not meeting needs of ambulatory pharmacy

W

hen it comes to tracking the clinical impact of their interventions, ambulatory and outpatient pharmacists are left with almost no options. Available systems are designed for the inpatient setting, are out of the financial reach of modest-scale hospitals or fall short in their functionality, experts say.

“Current ambulatory care pharmacist intervention tracking systems are designed to assign a dollar value to your work, but linking these interventions to clinical outcomes has been and remains a holy grail,” said Jerry Fahrni, PharmD, a pharmacy consultant based in California.

Some ambulatory pharmacists have had to adopt inpatient systems like Sentri7 (Pharmacy OneSource) and mega-systems, like EPIC and Cerner, but these still do not document outcomes, said Ernest Anderson Jr., MS, RPh, a consultant in Brockton, Mass.

“There might be a space for progress notes, but these are not necessarily written in a standardized format, and it is difficult, if not impossible, to retrieve useful information from a paragraph of text,”

Mr. Anderson said. “You have to search for the data you need to correlate your interventions with, rather than having the software show you which patients aren’t meeting their treatment goals.”

These partially useful systems are also too costly for some pharmacies, said Doug Haskins, RPh, MBA, who is an assistant director of pharmacy at Mount Auburn Hospital in Cambridge, Mass.

“The large vendors offer a good product, but with our current utilization, the numbers did not justify the return on investment,” he said.

In an email, a representative at Vigilanz, a health information technology company that offers pharmacy intervention tracking and reporting software for the inpatient setting as part of a bundle, said the company is developing systems to meet the needs of ambulatory and outpatient pharmacies.

He said he was not aware of any ambulatory care pharmacies using the inpatient software.

Similarly, David Bordewyk, a spokesperson foe Truven Health Analytics, said

‘The large vendors offer a good product, but with our current utilization, the numbers did not justify the return on investment.’

—Doug Haskins, RPh, MBA its Micromedex 360 Care Insights solution gives inpatient pharmacists the ability to identify opportunities for interventions and also to track their outcomes, but he too did not know of any ambulatory care pharmacies using the product.

“I think the overall premise of running a system like ours would be similar in the inpatient and outpatient environment, but one would need to have a somewhat large volume of digital data to run the product’s analytics,” Mr. Bordewyk said, noting that smaller clinics, or those that are not part of a larger health system, may not have that volume of data. “However, we’re starting to see the amount of care provided in the ambulatory setting scale up, which means products like ours will be appropriate for more ambulatory pharmacies.”

He estimated the cost of Truven Health’s product is three to four times lower than that of other clinical surveillance software that serves the same function, but even that cost could be prohibitive for smaller ambulatory pharmacies, he said.

A Homegrown System?

ASHP Set To Launch Ambulatory Pharmacy Tracking Tool

H

aving identified their ambulatory members’ need for effective and affordable intervention and outcomes tracking software, the American Society of Health-System Pharmacists (ASHP) is developing a system of its own. It uses standardized terminology to categorize interventions and outcomes and places them in discrete fields, precluding the need for text notes, explained Robin Coleman, who is acquisitions editor at the ASHP. “PACT is built using SNOMED CT [Systematized Nomenclature of MedicineClinical Terms], which is a universal way of talking about medicine,” Mr. Coleman explained. “If the code is widely adopted, it will allow us to have a much more unified and cohesive discussion of what ambulatory pharmacists do. It will give us apples-to-apples data. At the moment, there’s no universality in the language of ambulatory care pharmacy.”

Because it is a universal language, the gathered data could potentially be used to generate benchmarks that can then be used to demonstrate a pharmacy’s clinical and financial impact to the C suite.

“It’s a big data system, so it will not facilitate looking at outcomes on an individual patient level, but It will allow pharmacists to track key performance measures on a population level,” Mr. Coleman noted.

PACT is still under development, and at the moment there is no plan to integrate it with electronic health records (EHRs), he added.

“Like many other systems, PACT requires pharmacists to document their work twice—once in EHR and once in PACT—but we’ve designed it to be really easy,” he said.

—D.W.

Facing the cost barrier, Mr. Haskins’ department is instead considering using Google forms to document basic data, such as the type of intervention conducted and the time required to perform the intervention. However, privacy concerns mean these forms cannot include patient information, he said, and obtaining a picture of the effect of pharmacy interventions would be only partial.

“Making sure HIPAA information is protected makes it a challenge to build your own Internet-based system,” he added.

Robin Coleman, who is acquisitions editor at the American Society of HealthSystem Pharmacists (ASHP), noted that only medication therapy management (MTM) systems are specifically designed for ambulatory pharmacies.

Although products like the Assurance System (Medication Management Systems, Inc.), MTM Exchange (MedKeeper) and OutcomesMTM (Outcomes, Inc), serve their stated purpose of guiding MTM, he pointed out that ambulatory care pharmacists are conducting an increasing variety of clinical services.

“These systems don’t match up fully

to the needs of what we think of as ambulatory care pharmacists, who generally do more than MTM, like provide management of chronic disease states,” Mr. Coleman said. He and others at the ASHP are designing a tool that they hope will meet some of the needs of ambulatory care pharmacists who are searching for an affordable way to track interventions and related outcomes (see sidebar).

‘These systems don’t match up fully to the needs of what we think of as ambulatory care [pharmacy]….’

—Robin Coleman Echoing Mr. Coleman’s point, Mr. Anderson noted that as reimbursement shifts toward bundled payments, “we’re being asked to look after the broader health of the patient.” That demand requires the ability to document outcome measures such as blood pressure, low-density lipoprotein, glycated hemoglobin A1c and asthma for some at-risk populations, Mr. Anderson explained.

“What we need is a way to identify whether we’re getting patients to goal, whatever that goal may be, and at the moment there are not many ways to do this,” he said, noting a product called ReMedia is designed for the ambulatory environment and tracks some of these parameters.

Despite the disappointing list of offerings available for those wishing to measure the effect of their interventions in the ambulatory environment, Mr. Anderson said he is hopeful that the shift toward ambulatory care will raise demand to a level that vendors will no longer want to ignore.

“I think we’ll see vendors offering more products tailored to the ambulatory care pharmacies,” he said.

—David Wild Mr. Haskins, Mr. Coleman and Dr. Fahrni reported no relevant conflicts of interest.

Mr. Anderson is a consultant to ReMedia, a software developer.

Technology 53

Pharmacy Practice News • November 2014

Informatics Q&A: Mark Cullen, CEO, mscripts

Drug Adherence for the Digital Age The explosive growth of cell phones and other mobile technology has been a boon to mscripts. The San Francisco-based provider of mobile applications for pharmacies has developed a wide range of text-based reminders and other digital tools that help patients become more engaged in their own drug therapy regimens.

Pharmacy Practice News recently spoke with mscripts CEO Mark Cullen for his views on the many benefits that patients and pharmacies can expect from using the company’s communication tools.

PPN: Since its launch in 2008, mscripts has been using text messaging as its primary tool for promoting drug compliance. Why is that the case?

Mr. Cullen: At the very beginning, I had a sense that this was going to be the easiest and simplest way to reach patients with our core refill and adherence reminders. But it really hit home after I did a bit of off-the-cuff research in a Sprint store, where I asked a technician what the average teenage customer was doing in terms of text messages per month. I figured it would be 200, maybe 300 texts. Well, it was more like 2,500 to 3,000. That really helped me understand the potential of this technology. We knew that if we could figure out a way to make text messaging work in a HIPAA-compliant manner— and we did solve that, of course—we would have a very powerful tool for promoting adherence.

So we started with text messaging on simple flip phones. Then the first iPhone was launched and smartphones really took off. We’re at the point now where 99.9% of all cell phones have texting capabilities. So it remains one of the easiest and most effective ways to reach patients.

A home screen from an mscriptspowered mobile pharmacy app shows patients that they can use their smartphone to refill prescriptions, manage family medications, receive pickup and dosage reminders, transfer prescriptions, get coupons, and more.

PPN: You were one of the early innovators in mobile compliance reminders.

But there are a lot of players in this market today. What is unique about the mscripts approach?

Mr. Cullen: One important distinguishing feature is that we are not just focused on refills and reminders, and

we don’t rely only on texting to reach the patient. Rather, what we offer is a comprehensive mobile pharmacy and digital patient engagement platform.

That means reaching patients with the right content, in the right format, based on their particular needs and preferences. For some individuals, texting is the best tool. But for others, a digital

app for their smartphones is a better fit because it gives them the ability to track much more than prescription adherence. They can track family members’ medications, for example. We also have Web browser applications for patients who prefer that medium. It’s basically an any-screen-anywhere, anytime approach to getting patients connected to their pharmacy and pharmacist.

But we knew early on that to make all of those features truly effective, and to make the information we push out

•

see ADHERENCE, page 54

Read Pharmacy Practice News Anywhere, Anytime!

54 Technology

Pharmacy Practice News • November 2014

Informatics

ADHERENCE continued from page 53

to patients as relevant and convenient to access as possible, we had to become highly integrated with the back end of major pharmacy systems and dispensing platforms. We’ve made great strides in that area, and this is another component of our system that really sets us apart.

PPN: Patients have to opt in to the system, so how do you accomplish that in a way that gets maximum numbers of signups without burdening the participating pharmacies?

Mr. Cullen: That’s another area where that back-end integration comes in. It enables us to collect data in real time and use that data to streamline the signup process, which can take place right at the pharmacy counter. Our goal was to get the sign-up process under 20 seconds, so that we could minimize the impact on the pharmacist or pharmacy technician at any given time. So now, at the point of service, the pharmacist or technician can simply say, “Would you like us to send you a notification when your prescription is ready for pickup?

We think it will take 20 minutes to fill but you can go shop or spend time with your family, etc., and we’ll let you know when it’s ready for pickup in the willcall bin.”

That may not seem like a big shift in customer service, but it really is significant: Now we’ve enabled the pharmacy to be associated in the patient’s mind with convenience. In essence, we are leveraging the trust the pharmacist already has with that patient, and if we do a good job protecting that trust, we can then build on it by sending textbased messaging out to the patient on an ongoing basis, whether for refills, pickup reminders, dosage reminders, etc.

And patients soon realize that the texts are not being sent to harass them or sell them something; they actually represent an opportunity to improve their own health. Once that kicks in, patients respond very quickly and modify their behavior in small ways. And we know that small modifications in behavior can

For more information on the services offered by mscripts, visit http://www. mscripts.com/MobilePharmacy.

‘At the end of the day, we are very cognizant that pharmacy and the pharmacist is our most important customer, and that is where we can have the most impact.’

—Mark Cullen, CEO have very large effects overall on medication adherence.

PPN: N How do you get patients to opt in for the other services that you offer beyond texting, such as video patient education and disease-specific messaging?

Mr. Cullen: It all starts with text messaging and then we build from there. Once that platform is built, we can go to work understanding what a patient’s prescription list looks like, their refill history, degree of compliance etc. Based on that, we are really good at sending out just the right message at just the right time. Once the patient trusts that process, then it’s relatively easy for us to send out a text telling them that a mobile app for their smartphone is available that they can use to further manage their own and/ or their family’s medications in an even more organized and interactive manner.

We can also do signage inside the pharmacy; some pharmacies have links to our offerings on their websites, others will do direct advertising, etc. Whatever form the outreach takes, it’s done in a way that strengthens and deepens the trusting relationship that pharmacists and pharmacies have with their patients.

PPN: Every pharmacy has its own unique base of customers, with lots of regional variations in health state, degree of technological savvy, etc. Can your system recognize those variables and adapt, so that you’re not taking a “one-size-fits-all” approach?

Mr. Cullen: Absolutely, we have that capability, and that again speaks to the benefits of being integrated with backend pharmacy systems and dispensing platforms in a real-time manner. That enables us to tweak our systems and match it to the needs of a patient or pharmacy in a way that’s never been done before. We can now measure the effectiveness of a particular text message, for example, or a particular tactic based on how it’s affecting an individual’s refill behaviors. So we’ll send out text messages with varying content, see how many patients respond, how long it takes them to respond and adjust our messaging accordingly. It’s certainly not a static system, no matter who our client is.

Our flu shot messaging has evolved and improved as a result of this process. We realized that [if ] the patient reacts to your texts as an attempt to

sell them something, they don’t react well to that. If the message is developed in a manner that first emphasizes the health benefits of getting the flu shot, then the responses are much more favorable. We found out pretty quickly, using real-time data, what the better approach was and modified our flu vaccine messaging for our clients accordingly.

PPN: N We’ve talked a lot about the benefits to the patient. What can a hospitalbased outpatient pharmacy, for example, expect to get out of an mscripts partnership?

Mr. Cullen: Our approach gives pharmacies a great tool for strengthening their brand. In fact, you’ll never see an “mscripts” text message, app or website when accessing our systems. Rather, we encourage our partners in pharmacy, whether they are a chain, hospital, specialty pharmacy, etc., to use their own branding when introducing these digital programs to patients.

But we also realize the decision to bring on any technology comes down to finances at some point, so we take a lot of time helping prospective clients understand the return on investment (ROI) they can expect from our system.

The factors that can influence ROI are the ones you’d expect, such as reduced returns to stock that result from boosting a pharmacy’s overall refill and pickup rates. But some ROI influencers were actually a surprise to us. In one case, we determined that it was actually cheaper for one of our pharmacy clients to build a text message into their system that told patients the pharmacy would be happy to drive the prescription to their house at a certain time if they could not pick it up on their own. The pharmacy ascertained that it was less expensive for them to pay a driver to deliver the medication than it was for a pharmacist or technician to restock it.

Whatever the particulars, we can provide any client with simple calculation tools to assess the ROI of adopting our digital compliance technologies. For example, we can help them get a snapshot of their gross profit per script, the percent of medications that are being returned to stock and the loss that represents if not dealt with proactively. In fact, we’ve often found that these calculations and analyses give prospective clients the first hard data of this type

Patients using an mscripts-powered mobile app can see all of their prescriptions and dosages in one place. (The participating pharmacy’s name would be used at the top of the app for branding purposes.)

that they’ve ever seen. It can be a real eye-opener in terms of how it can affect their business.

PPN: N What’s your customer mix like these days?

Mr. Cullen: It’s weighted toward national and regional chain pharmacies—we’re working with 16 different chains right now. But we also work with four outpatient hospital pharmacies, including Henry Ford Hospital in Detroit and Fairview Health Services in Minneapolis, and two specialty pharmacies. In fact, we recently announced a partnership with Pharmacy Advantage, a Michigan-based specialty pharmacy.

We built a “PharmAdv” app for them that would not have been possible without our tapping into their EnterpriseRx [McKesson] pharmacy system. We hope that this partnership is the beginning of our becoming a big player in the specialty pharmacy arena, given the huge growth of this practice model.

We’re also looking to partner with other stakeholders who can help us get our adherence message a bit further upstream, so that we can affect the firstfill portion of a prescription. That’s a crucial component, because that first fill is critical. We’ve all seen the sobering statistics on how many initial prescriptions are never picked up by the patient.

That has an enormous impact on the cost of health care in this country, so we have our eyes on that as well.

Having said that, as we expand into those other markets, we want to be sure we’re doing so in a manner that is helpful to the pharmacy. Because at the end of the day, we’re very cognizant that the pharmacy and the pharmacist is our most important customer, and that is where we can have the most impact.

—Reported by David Bronstein

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NOVEMBER NOVEMBER 2014 2014

REPORT The Drug Quality and Security Act

A New Reality for the Practice Of Outsourcing Compounded Sterile Preparations wo years ago, the sterile compounding industry was stunned by an outbreak of fungal meningitis that was traced back to the New England Compounding Center (NECC) in Framingham, Massachusetts. More than 750 people were affected, resulting in 64 deaths across 20 states.1 This tragedy prompted action by Congress, the FDA, and health care leaders to draft and pass the Drug Quality and

T

Security Act (DQSA) in an effort to regulate organizations that produce compounded drugs.2,3 On November 27, 2013, President Obama signed the DQSA into law with the goal of strengthening the oversight and regulation of the sterile compounding industry.3 Compounded products range from tailor-made preparations prescribed for individual patients, to anticipatory

Faculty Andrew J. Donnelly, PharmD, MBA, FASHP

James G. Stevenson, PharmD, FASHP

Director of Pharmacy University of Illinois Hospital & Health Sciences System Clinical Professor of Pharmacy Practice University of Illinois at Chicago College of Pharmacy Chicago, Illinois

President, Hospital and Health Systems Services Visante, Inc. Saint Paul, Minnesota Professor University of Michigan College of Pharmacy Ann Arbor, Michigan

Patricia C. Kienle, RPh, MPA, FASHP Director, Accreditation and Medication Safety Cardinal Health Innovative Delivery Solutions Houston, Texas

Raymond T. Lake, RPh, MS Corporate Director, Pharmacy Operations MedStar Health Elkridge, Maryland

Eugene R. Viscusi, MD Professor of Anesthesiology Director, Acute Pain Management Department of Anesthesiology Thomas Jefferson University Philadelphia, Pennsylvania

Supported by

REPORT

products, such as prefilled syringes (eg, succinylcholine) used in the operating room,4 to outsourced hospital pharmacy compounding, to large volumes of material distributed nationwide.5,6 Outsourced sterile compounding fills an important need for hospitals nationwide. The lack of facilities able to comply with US Pharmacopeia (USP) Chapter <797> requirements, and a shortage of properly trained personnel and staff are drivers to outsourcing certain sterile admixtures.7 Additionally, drug shortages have intensified demand for outsourcing compounded drugs.8 DQSA not only set standards for safe compounding, it added track-and-trace legislation that had been pending in Congress for some time and is intended to address security in the pharmaceutical supply chain.

The combined legislation forms Titles I and II of the DQSA.3,9-11

It is important to understand that the DQSA contains 2 sets of measures: Title I is designed to more rigorously regulate the compounding pharmacy sector, and Title II is intended to better secure the pharmaceutical supply chain.11

FDA-registered facilities, and, in turn, motivate the nonregistered facilities to become registered with the FDA if their business model applies. Of the approximately 3,000 sterile compounding facilities in the United States, to date, more than 50 have registered with the FDA under Section 503B.13 Following initial registration, outsourcing facilities are required to register annually between October 1 and December 31.14 After registration, these facilities will be inspected by the FDA and must meet the reporting requirements specified by the law. Reports on compounded products and ingredients must be submitted; a pharmacist must supervise the compounding process; and compounding must be in compliance with applicable current Good Manufacturing Practice (cGMP) requirements. Those who register as 503B outsourcing facilities are required to meet specific labeling requirements (statements that include This is a compounded drug, Not for resale, and Office use only). y 3,15 Traditional 503A compounders are subject to the provisions of the DQSA, oversight by the state board of pharmacy, and must compound in compliance with USP standards.12,15

Title I (The Compounding Quality Act)

FDA Guidance

In Title I, the DQSA amends Section 503A and adds Section 503B to the Federal Food, Drug, and Cosmetic Act (FD&C Act) to distinguish between traditional compounders that make compounded drugs with or without a prescription.3,12 Title I also adds a new Section 503B to regulate outsourcing facilities that compound products in anticipation (non–patient-specific) of health care facility and prescriber demand.3,9,10 The law also contains a provision to enhance communication between the FDA and state boards of pharmacy, which are required to notify the agency in the event of observations or other actions relevant to compounders in their state. Conversely, the FDA will notify any state board of pharmacy if it determines that a pharmacy is acting contrary to provisions of Section 503A. The National Association of Boards of Pharmacy and the FDA will collaborate on the communication provisions. 3,9,10

On December 4, 2013, the FDA published several important draft guidance documents relating to implementation of the DQSA.14,16,17 These guidance documents, plus others published in 2014, included guidelines for registering with the FDA as outsourcing facilities under Section 503B of the FD&C Act.18 On July 1, 2014, interim draft guidance for cGMPs was issued.19 Individual FDA guidance documents were released earlier in 2014 to define reporting requirements and user fees. Revisions to the FDA’s current list of drug products that may not be compounded because they have been withdrawn or removed from the market after being declared unsafe or lacking efficacy are in process.20 Final FDA guidance was also published for individuals or pharmacies that intend to engage in traditional compounding under Section 503A.12 This guidance generally restates the provisions of Section 503A, describes the FDA’s interim policies regarding specific provisions that require implementing regulations or other actions, and contains a nonexhaustive list of potential enforcement actions against individuals or pharmacies that compound human drug products in violation of the FD&C Act.20 A pharmacy compounding advisory committee will be created as advisors to the FDA in relation to the compounding of drugs for human use.21 Requests for nominations for advisory committee members were published in the Federal Register. r 21 Additionally, drug lists pertinent to compounding regulations are being developed. These lists are as follows: • Bulk substances for 503A compounding: Bulk drug substances may be used when in compliance with a USP or National Formulary monograph; the substance is a component of an FDAapproved human drug or appears on the list of bulk drug substances for use in compounding provided by the FDA A17 • Bulk substances for 503B compounding: Bulk drug substances may be used for compounding when a drug appears on the FDA’s drug shortage list or when there is a clinical need22 • Drugs not to be compounded from bulk substances in either 503A or 503B settings: Drugs designated by the FDA as demonstrably difficult to compound may not be compounded from bulk substances.23

Understanding the DQSA

Title II (Drug Supply Chain Security Act) Title II outlines the development of an electronic, interoperable system that identifies, tracks, and traces pharmaceutical drug distribution in the United States.11 Over the next 10 years, the program will verify drug movement through the supply chain at a single-package level. The new system will permit medication verification, enhance detection of illegitimate drugs, and facilitate recalls.11 Title II of the Act does not apply to FDA-registered 503B outsourcing facilities.3

Implementation of the DQSA The DQSA clarifies the roles of traditional pharmacies (503A) and outsourcing facilities (503B) that compound and delineates the regulation of both types of compounders. State boards of pharmacy will continue to oversee traditional 503A compounders whose preparations are pursuant to individual prescriptions, whereas outsourcing facilities that produce anticipatory 503B-compounded products without prescriptions will be primarily regulated by the FDA.3,9,10 The DQSA legislation creates a voluntary system by which compounding facilities can register as “outsourcing facilities” with the FDA.3 Legislators hope that hospitals, physician offices, and providers will have a greater confidence in sterile products purchased from

2

REPORT

Finally, the FDA intends to update Title 21 of the Federal Code of Regulations, Section 216.24 (21 CFR 216.24), which contains a list of drugs that are unsuitable for compounding because they are unsafe or lack efficacy. 24 The drugs listed in Section 216.24 cannot be used in compounding. The FDA is already accepting nominations to the list, which should be submitted as comments to the proposed rule. 24 The Federal Registerr requested comments July 2, 2014; the FDA is now reviewing comments received.24 Several aspects of DQSA implementation are not yet in place.

Most notably, the channels of communication between the states and the FDA are being developed. In the interim, state pharmacy board submissions regarding citations of 503A compounders

and state queries are to be submitted by email (StateCompounding@fda.hhs.gov) until the communication processes are developed and implemented.15

Monitoring Traditional and Outsourcing Facility Compounding As part of the DQSA, Sections 503A and 503B provide unique oversight, and compounders are regulated differently (Table 1).3,9-11 Individual state boards of pharmacy will continue to provide oversight of 503A compounders, but will be required to share information directly with the FDA.15,20 Outsourcing facilities identify themselves by voluntarily registering with the FDA, which requires an annual fee of $15,000 as well as inspection by the FDA and

Table 1. Traditional (503A) and Outsourcing Facility (503B) Compounders 503A

503B

Traditional Compounders

Outsourcing Facility Compounders

Drugs compounded must meet these requirements: - For an individual patient

May be compounded for individual patients with a specific prescription

- Approved by a prescribing practitioner

Anticipatory compounding permitted

- Compounding is performed by a licensed pharmacist or physician on prescriptiona

Must operate under the supervision of a pharmacist

Describes conditions exempting a compounder from: b

Must comply with applicable cGMP

- cGMP

Must report adverse events

- Labeling with adequate directions for use - FDA approval before market

Must provide the FDA with information about products compounded

Regulated by state boards of pharmacy

Registration, inspection, and oversight by the FDA

Drug preparation is in compliance with USPc

Must follow applicable cGMP

An individual or a firm can compound for interstate distribution only 5% of the total prescription orders dispensed unless the state and FDA agree on a Memorandum of Understanding

No restriction on interstate distribution but subject to state licensing requirements

State board of pharmacy regular inspections

Inspection by FDA Risk-based factors: - Compliance history - History of recalls - Inherent risk of drugs manufactured - Adverse events

cGMP, current Good Manufacturing Practice; USP, United States Pharmacopeia a

Compounding before receipt of a prescription is valid for patients who have a history of using the compounded medication or who have an established relationship with the compounding pharmacist or physician, or who will provide a prescription.

b

501(a)(2)(B); 502(f)(1); and 505.

c

United States Pharmacopeia, or National Formulary monograph.

Based on references 3,9-11.

3

REPORT

requires the FDA to share information with the respective state board of pharmacy.3,16 In a memorandum to the Michigan Health and Hospital Association dated September 10, 2014, Dykema Gossett PLLC summarized federal regulations of compounding entities (Table 2).25

Section 503A Section 503A cites conditions that exempt traditional compounding pharmacies from cGMP, requiring new or abbreviated drug applications (NDA/ANDAs), and from the labeling provisions of Section 502(f)(1). 20 Traditional compounding methods must comply with USP Chapters <795>, Pharmaceutical Compounding—Non-sterile Preparations, and <797>, Pharmaceutical Compounding—Sterile Preparations, the first enforceable guidelines for compounded sterile preparations (CSPs).20 For example, specific conditions apply to ingredients that may be used in compounding products under Section 503A: Bulk drug substances must appear on a list developed by the FDA, be accompanied by valid certificates of analysis, comply with USP standards, and not be cited on an FDA list of withdrawn or difficult-to-compound substances.17,23 A bulk drug substances list is in development by the FDA, and will appear in the Federal Register.22 The bulk substances rule will not be fully enforceable until publication of this list.8 Other regulations apply to 503A compounders: Source drugs must not be filthy, putrid, decomposed, or packaged under unsanitary conditions; must not differ in purity, strength, or quality from standards set forth in compendia; and must be packaged and labeled per compendia. 20 Interstate distribution of compounds prepared by 503A compounders is restricted to an amount less than 5% of total compounded product, unless there is an executed Memorandum of Understanding between the FDA and the state indicating otherwise.20 Some health care professionals have expressed concern that the 5% rule may not deter interstate distribution of CSPs by unscrupulous compounders. It may be difficult to identify compounding facilities that do not register with the FDA but continue to deliver compounds outside their state. Compounders operating within the 5% rule also could potentially produce large volumes

of CSPs solely within their state, and therefore present a possible intrastate public health threat. Traditional compounding is limited to patient-specific prescriptions and, with the increase in communication between federal and state entities, there will be greater oversight of compliance by traditional compounders. Enforcement of the 5% rule by the FDA will commence 90 days after finalizing the Memorandum of Understanding and making it available to the states.3,12

Section 503B Under Section 503B, outsourcing facilities are required to operate under the supervision of a pharmacist, but are not required to be pharmacies.3 Additionally, these facilities may or may not obtain prescriptions for identified individual patients.3 Outsourcing facilities are subject to an FDA inspection frequency based on known safety risks, which are derived from compliance history and the inherent risk associated with the drugs compounded.3 Under Section 503B, outsourcers must identify and provide information for all CSPs compounded by the facility in the previous 6 months and twice each year thereafter (Table 3).3,14 These reports will be submitted electronically to the FDA, by email in the near term, and ultimately by website.3,14 Compounders also are required to disclose whether the facility compounds CSPs from nonsterile bulk drug substances.3,16

FDA Oversight of Outsourcing Facilities The FDA will oversee and inspect all 503B-registered outsourcing facilities. Whereas the requirements for reporting drugs compounded during the past 6 months and twice each year thereafter have been defined, how the FDA intends to interpret “short supply” and other reasons for outsourcing production of sterile products remains subject to further FDA discretion.3 In a letter to state board of pharmacy colleagues dated January 8, 2014, Margaret A. Hamburg, MD, commissioner of the FDA, indicated that “states play a critical role in the oversight of pharmacy compounding.” She also wrote that, “one opportunity afforded states by the new section 503B is the ability to encourage out-ofstate compounding pharmacies that ship compounded drugs into the state to register with the FDA as outsourcing facilities. Once

Table 2. Summary of Federal Regulations of Compounding Entities Entity Type

Federal Licensure Or Registration

Prescription Required

Subject To cGMP

Adequate Use Labeling

New Drug Approval Required

Compounding pharmacy (503A)

No federal registration

Yes

No

No

No

Outsourcing facility (503B)

Voluntary federal registration

No

Yes

No

No

Drug manufacturer

Mandatory federal registration

No

Yes

Yes

Yes

cGMP, current Good Manufacturing Practice Based on reference 25.

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facilities are registered, states could be assured that the FDA will inspect the facilities on a risk-based schedule, hold them to cGMP requirements, monitor the adverse event reports they are required to submit to the agency, and, through these activities, help improve the quality of drugs being compounded.â&#x20AC;?26 Dr. Hamburg also issued a letter to pharmacy and hospital purchasers. In it she underscored the role of purchasers in ensuring the quality and safety of products obtained for patients. As such, purchasers were urged to consider requiring the outsourcing pharmacies they work with to register with the FDA as outsourcing facilities. Dr. Hamburg cites increased FDA oversight and cGMP requirements as key factors in assuring the safety of compounding products.27

Variability in State Regulation and Oversight In an attempt to create standards for the compounding of sterile preparations, USP Chapter <797> was introduced in 2004 to standardize practices that would protect patients from potential contamination.28 Oversight by boards of pharmacy differs significantly by state. Based on a 2011 study of state-level USP Chapter <797> adoption, Douglass and colleagues characterized compliance levels as direct, indirect, or no reference. Direct compliance indicates that state laws cited and coincided exactly with USP specifications; states with indirect compliance did not cite Chapter <797> within the laws but had regulations in place regarding sterile compounding.

There was no distinct verbiage pertaining to sterile compounding in states designated as no reference. Currently, 22 states have incorporated all or part of USP <797>, 4 states have no reference to USP Chapter <797>, and the remaining states have some regulations in place regarding sterile compounding at the time of publication.29,30 Required labeling statements and the ability to track specific medication use are issues that may affect patients who receive CSPs. Typically, health systems determine the appropriateness of medications and document medication use for each individual patient. In contrast, this may not be done in some settings. The use of CSPs by facilities that do not have these processes in place may result in inappropriate medication use or an inability to track CSPs. Currently, there is no provision in place for the surveillance for

appropriateness of use outside of health care systems. For example, clinics and physician offices may not be part of a health system, and there may be no surveillance of compounded medications for appropriateness and no tracking of delivery of specific compounded agents to patients. Furthermore, contamination of large lots of compounded drugs would not be traceable in some facilities. These facilities may not have pharmacy oversight and there often is no documented chain of custody from when the medication is received through administration to the patient.

Ensuring High-Quality and Safe Sterile Products for Patients Most hospital pharmacies compound some CSPs and obtain other sterile products from outside sources. Because hospitals assume responsibility for the quality of all medications, many have developed methods to assess outsourcing facilities and expect to continue using them.31,32 A number of health care systems use the American Society of Health-System Pharmacists (ASHP) recommendations for evaluating outsourcing sterile compounding services.31,32 More recently, the ASHP Foundation developed a tool that may be used in grading outsourcing facilities. Hospitals typically first identify outsourcing needs and then assess potential outsourcing facilities. Health-system personnel who are subject-matter experts may be included in a site-visit team for 503A pharmacies or 503B outsourcing facilities. Once an outsourcing facility is selected, many hospitals require quarterly safety and quality assurance reports.31,32 Other resources are available to aid in the selection of an appropriate outsourcing facility, whether for 503A or 503B services (Table 4.)

Health-system pharmacy leaders need to develop standards for evaluating and selecting outsourcing vendors. In some cases,

Table 4. Resources Related to Pharmaceutical Compounding Safety and Source Evaluation Organization

Website www.ashp.org

Table 3. Information Required by the FDA for All Drugs Compounded by Outsourcing Facility

Health-System Pharmacists ASHP Foundation

www.ashpfoundation. org

Centers for Disease Control and Prevention

www.cdc.gov

NDC number

Institute for Safe Medication Practices

www.ismp.org

Dosage form and route of administration

FDA

www.fda.gov

Package description

National Association of Boards of Pharmacy

www.nabp.net

US Pharmacopeial Convention

www.usp.org

Active ingredient and strength of active ingredient per unit Source of the active ingredient (bulk or finished drug)

Number of individual units produced NDC, National Drug Code Based on references 3 and 14.

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health care systems have implemented system-wide standards for selecting and using an outsourcing facility, thereby broadening the available expertise and decreasing the work for each facility within the system. Additionally, this develops standardization among the facilities. This minimizes vendors and quality reports at the respective facilities—for Joint Commission as well as other accreditation organizations—as well as those who will have access to these reports. Regardless of which evaluation strategy is used, it is essential to identify those facilities that understand the scope of control needed with regard to the entire process of sterile compounding. Some of the elements of an outsourcing facility and ongoing quality assurance plan include: • Regulatory compliance: Assess outsourcing facilities’ registration history and compliance with the DQSA, and determine whether distributed products are in alignment with its registration. Request documentation of the process utilized to assess the purity and potency of bulk ingredients used in compounding and whether nonsterile bulk compounds are used in formulating sterile preparations.33 • Quality and safety measures: Environmental controls should be in place, and the compounder should demonstrate compliance with USP Chapter <797> or applicable cGMPs regarding sterile transfers, staff competency, and extended beyonduse date testing. Outsourcers should have an airflow and surface sampling plan in place that documents measurements.

It is also important to review general and professional liability insurance.33 • Product and medication information: Product safety information, formulation, and purification specifics and information relevant to the delivery system should be available from the compounder.33 • Training: Ask to see the sterile product and cGMP training documentation of staff working for the outsourcing facility.

FDA observations are typically reported using FDA Form 483, which details findings from an inspection and will likely provide useful information about the facility.34 The form typically begins with a reference to a cGMP requirement and includes a statement of conditions observed during an inspection. 21 Learning what types of infractions a facility has experienced, how the infractions have been remedied, and whether problems persisted over time provide indications of the quality of work at the facility. The FDA makes all issued Form 483s available on its website, allowing customers to make informed decisions about accepting products from a compounding facility. Site inspections and issuance of Form 483 have been common since the NECC tragedy. The details of the Form 483 observations noted for each outosurcing facility have differed; but the information provided is a healpful resource for health care providers choosing an outsourcing compounder. Nearly every 503B voluntary registrant that have undergone a complete inspection by the FDA has received a Form 483.13 Many of these were inspections based on the full cGMPs for drug manufacturers, before issuance of the Draft Guidance Current Good Manufacturing Practice—Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act. The base frame of reference has changed dramatically from prior years’ state-based inspections, which may or may not include USP <797> requirements. One overarching perspective is that the evolving federal

6

standards for sterile product preparation will be much higher than traditional state-based inspections, resulting in higher overall quality. The industry continues to move as swiftly as possible to meet the forthcoming requirements.

In the future, health care systems may evaluate orders from prescribers for compounded preparations more carefully, and they are expected to increase vigilance of oversight of all compounding sources. In many cases, unless there is a clearly documented need, hospitals prefer to obtain compounded drugs from their own pharmacy or from an outsourcing facility that has been thoroughly investigated. Pharmacists would prefer more input and involvement from physicians who may not be fully aware of the complexity of drug compounding. In any event, the risk–benefit decision to use a compounded medication instead of a manufactured alternative is one that requires collaboration between medical and pharmacy leaders within a health system.

Outsourcing facilities that have registered with the FDA have sent an important message to their health-system partners. Registration with the FDA represents a willingness and ability to comply with more stringent regulations and processes. It is important to recognize that all regulatory standards have not been finalized and that FDA inspections will occur over a period of time. Health care professionals responsible for outsourcing may be reluctant to use 503B outsourcing facilities based on FDA registration alone, and there is some skepticism about whether all the registered organizations will complete the process. As shown by previous problems with contamination of sterile compounds, CSPs produced in large quantities are a potential threat to patients, and continued diligence is warranted. Professional societies, such as ASHP, may help health care professionals choose an outsourcing facility. Some health care professionals may find the ASHP tool for assessing compounding pharmacies helpful, as it provides suggested criteria for evaluating the competencies of staff, safety procedures, licensure and environmental conditions or controls.32

Conclusion The DQSA has created a new reality for the practice of outsourcing sterile product preparations. Signed into law in November 2013, the DQSA regulates organizations that produce compounded drugs in the aftermath of the outbreak of fungal meningitis associated with contaminated compounded corticosteroid preparations made and distributed by NECC in 2012. This new law sets forth a plan to better ensure patient safety, promote product quality, and prevent future tragedies.

The DQSA clarifies the roles of traditional and outsourcing compounding facilities, and delineates the regulation of these 2 types of compounders. State boards of pharmacy will continue to oversee traditional compounders, and outsourcing facilities will be regulated directly by the FDA. Importantly, this legislation creates a voluntary registration system by which 503B-registered outsourcing facilities will be inspected by the FDA. After initial registration, outsourcing facilities are inspected and must meet the reporting, labeling, and cGMP requirements specified by the law. This process strengthens FDA oversight and reduces the risk for inconsistent state regulations.

Concern persists among some health care professionals that outsourcing facility registration is voluntary rather than mandatory and

REPORT

that some facilities may escape appropriate regulation. To counter this concern, health care systems should continue vigilance in the oversight and selection of all compounding sources.

Outsourcing facilities that have voluntarily registered with the FDA have demonstrated a commitment to ensuring the safest compounded sterile admixtures for their patients and health care system partners: By initiating the process and submitting to more rigorous inspection, labeling, and guidelines, they demonstrate a desire to rise to the more stringent, highest-quality requirements outlined in the DQSA. The FDA has moved quickly to structure the industry since the DQSA was passed. The FDA published guidance documents,

began inspecting outsourcing facilities, and issued numerous Form 483s and warning letters to facilities inspected before implementation of the new act and the issuance of draft guidance applicable to cGMPs. Recalls have followed some of the inspections.

The challenge and opportunity for compounding companies is to re-evaluate and quickly address the shortcomings in their individual practices and to align all compounding outsourcing facilities with evolving standards and requirements as outlined in Section 503B. As medical treatments continue to advance, it is imperative that the sterile compounding industry, pharmacists, and other health care professionals evolve and collaborate to ensure patient safety with CSPs.

References 1.

Centers for Disease Control and Prevention. Multistate outbreak of fungal meningitis and other infections. http://www.cdc.gov/ hai/outbreaks/meningitis.html. Accessed October 31, 2014.

2.

American Pharmacists Association. American Pharmacists Association statement on rare meningitis outbreak. http://www. pharmacist.com/american-pharmacists-association-statementrare-meningitis-outbreak. Accessed October 7, 2014.

3.

Drug Quality and Security Act, H.R. 3204, 113th Congress (2013). https://www.congress.gov/bill/113-congress/housebil/3204. Accessed November 5, 2014.

4.

PharMEDium Services, LLC. Succinylcholine O.R. anesthesia. http://www.pharmedium.com/compounding/service/50/ Succinylcholine/?lineld=1. Accessed October 31, 2014.

5.

American Society of Health-System Pharmacists. Sterile compounding: Hospital Administration Discussion Guide. http:// www.ashp.org/compounding_discussion_guide. Accessed November 5, 2014.

6.

American Society of Health-System Pharmacists. Together we make a great team. http://www.ashp.org/DocLibrary/Advocacy/ASHP-Supports-Pathway-for-Antibiotic-Development. pdf. Accessed October 31, 2014.

7.

Kastango ES, Bradshaw BD. USP chapter 797: establishing a practice standard for compounding sterile preparations in pharmacy. Am J Health Syst Pharm. 2004;61:1928-1938.

8.

Barlas S. New Congressional bill attempts to aid pharmacy response to drug shortages. PT. 2014;39(1):51-54.

9.

Food and Drug Administration. Compounding Quality Act. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Accessed October 31, 2014.

12. United States Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Pharmacy compounding of Human Drug Products under Section 503A of the Federal Food, Drug, and Cosmetic Act. Draft Guidance. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ ucm377052.pdf. Accessed October 31, 2014.

13. Food and Drug Administration. Registered Outsourcing Facilities. http://fda.gov/DrugsGuidanceComplianceRegualtoryInformation/PharmacyCompounding/ucm378645.htm. Accessed October 31, 2014.

14. United States Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Interim product reporting for human drug compounding outsourcing facilities under section 503B of the Federal Food, Drug and Cosmetic Act. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm377050.pdf. Accessed October 31, 2014.

15. Food and Drug Administration. FDA Implementation of the Compounding Quality Act. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm375804.htm. Accessed October 30, 2014.

16. Food and Drug Administration. Registration for Human Drug compounding outsourcing facilities under Section 503B of the Federal Food, Drug and Cosmetic Act. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/ ucm377051.htm. Accessed October 31, 2014.

17. Bulk drug substances that may be used to compound drug products in accordance with section 503A of the Federal Food,Drug, an Cosmetic Act; revised request for nominations.

Fed Regist. 2014;79(127):37747-37750.

10. Food and Drug Administration. Text of Compounding Quality Act. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm376732.htm.

Accessed October 31, 2014.

18. Food and Drug Administration. Compounding. http://www.fda. gov/drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/. Accessed October 30, 2014.

11. Food and Drug Administration. Drug Supply Chain Security Act (DSCA) Title II of the Drug Quality and Security Act of 2013. http://www.fda.gov/Drugs/DrugSafety/DrugIntegrityand SuppChainSecurity/DrugSupplyChainSecurityAct/.

Accessed October 31, 2014.

19. Food and Drug Draft guidance for industry on current good manufacturing practiceâ&#x20AC;&#x201D;interim guidance for human drug compounding outsourcing facilities under the Federal Food Drug and Cosmetic Act; availability. Fed Regist.

2014;79(127):37743-37747.

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20. United States Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Pharmacy compounding of Human Drug Products under Section 503A of the Federal Food, Drug, and Cosmetic Act. Final Guidance. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/guidances/ ucm377052.pdf. Accessed October 31, 2014.

21. Advisory Committee; pharmacy compounding advisory committee. Fed Regist. 2014;79(8):2093-2094.

22. Bulk Drug Substances that may be used to compound drug products in accordance with 503B of the Federal Food and Cosmetic Act, concerning 0utsourcing facilities; request for nominations proposed rule. Fed Regist. 2013;78(233):7283872840.

23. Drug products that present demonstrable difficulties for compounding under section 503A and 503B of the Federal Food, Drug and Cosmetic Act. Request for Nominations. Proposed rule. Fed Regist. 2013;78(233):72840-72841.

24. Additions and modifications to the list of drug products that have been withdrawn or removed from the market for reasons of safety and effectiveness. Fed Regist. 2014;79(127):3768737695.

25. Reed KA. Memorandum: update on federal and state compounding pharmacy laws. http://www.mha.org/mha/weeklymailing/2014/091514/compound_pharm_dykema.pdf.

Accessed October 31, 2014.

26. Hamburg MA. Letter to Colleagues from Dr. Hamburg, Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/ PharmacyCompounding/UCM380597.pdf. Accessed October 31, 2014.

27. Hamburg MA. Letter to Hospital/Purchasers. http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm380599.pdf. Accessed November 3, 2014.

28. Newton DW, Trissel LA. A primer on USP Chapter <797> “Pharmaceutical Compounding—Sterile Preparations” and USP process for drug and practice standards. http://www. nhia.org/members/documents/usp_797_primer.pdf. Accessed October 31, 2014.

29. Douglass K, Kastango E, Cantor P. State regulations impact USP <797> compliance. Pharm Purcha and Prod.

2012;9(4):18.

30. Regulatory status levels of states/DC. http://www.criticalpoint. info/Statemap/story.html. Accessed November 3, 2014.

31. Rinehart JR, Chan D, Cunningham M, et al. American Society of Health-System Pharmacists. ASHP guidelines on outsourcing sterile compounding services. Am J Health Syst Pharm.

2010;67(9):757-765.

32. American Society of Health-System Pharmacists. Outsourcing sterile products preparation: contractor assessment tool. http://www.ashpfoundation.org/MainMenuCategories/PracticeTools/SterileProductsTool/SterileProductsAssessmentTool. aspx. Accessed October 7, 2014.

33. Eberts MW, Cecere DA, Mark S. Ensuring the safety of sterile admixtures prepared outside of the institution. Hosp Pharm.

2013;48(3):248-252.

34. Food and Drug Administration. Inspections, compliance, enforcement, and criminal investigations: FDA form 483 frequently asked questions. http://www.fda.gov/ICECI/Inspections/ucm256377.htm. Accessed October 31, 2014.

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

Copyright © 2014, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Disclosures: Drs. Donnely, Lake, Kienle, and Viscusi have nothing to disclose. Dr. Stevenson has served on advisory boards for Baxter and Centralized Admixture Services (CAPS).