October 2014

The Pharmacist’s News Source

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Volume 41 • Number 10 • October 2014

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in this issue UP FRONT

4

Patients with advanced dementia getting drugs of questionable benefit.

CLINICAL

6 7 10 12

Failure to stop glyburide in the hospital causes spike in hypoglycemia.

Duke protocol slashes surgical site infections by 75%.

Antimicrobial stewardship program tames drug resistance, lowers costs.

CDC fears Ebola outbreak is now a global health issue.

POLICY

22

New drugs for melanoma, severe aplastic anemia, partial-onset seizures, and more.

OPERATIONS & MGMT

24

Is connectivity overload eroding your leadership skills?

Rx Authority Helps Pharmacists Ensure SUP Is Appropriate

W Clinicians in the operating room continue to struggle with drug shortages.

W Web-based “hubs” help bolster patient assistance programs.

W More coverage from the American College of Clinical Pharmacy annual meeting.

Robin Williams Suicide Shines Light on PD, Depression Link A

Austin, Texas—Giving pharmacists the authority to monitor, and if necessary, change medications for stress ulcer prophylaxis (SUP) significantly reduced the average duration of their use in critically ill patients, from 5.4 to 3.3 days ((P=0.006), after the launch of a program at a teaching hospital in Phoenix.

The initiative, which extended prescriptive authority to the pharmacists at Banner Good Samaritan Medical Center, also resulted in far fewer ICU patients being discharged on an inappropriate acid-suppressive agent, from 29.9% before the program’s launch to 3.6% afterward ((P<0.001; abstract 43). Another analysis, looking at the program’s effect on nonICU patients, found similar results, the team reported at the 2014 annual meeting of the American College of Clinical Pharmacy (abstract 96).

Beginning in October 2011, pharmacists were allowed not only to stop an acid-suppressive agent if it

s media attention on the August suicide of Robin Williams—reported to be in the early throes of Parkinson’s disease—wanes, clinical pharmacists and other health care professionals are being urged to heed at least one legacy of the actor/comedian’s death: the need to remain cognizant of how often depression and anxiety occur in the movement disorder.

Indeed, as many as half of the million or so people with Parkinson’s disease (PD) in the United States experience some depressive symptoms during their lives ((Mov Disord d 2010;25[2]:157-166).

That association may warrant a rethinking of how PD patients are assessed and managed, with pharmacists playing a key role in such efforts, according to Sarah Melton, PharmD, an associate professor at the Bill Gatton College of Pharmacy, East Tennessee State University (ETSU), in Johnson City, Tenn. At her clinical practice in the Johnson City Community

see RX AUTHORITY, Y page 26

see ROBIN WILLIAMS, page 18

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A Life Preserver For the Flood Of Boxed Warnings

WEB EXCLUSIVES

pharmacypracticenews.com

Pharmacists urged to keep comorbidity top-of-mind

•

It’s Time To Get Less Touchy About Taming Spread of Infection

ith the labels of almost 5,000 drugs marketed in the United States having a boxed warning, it can be daunting to stay abreast of the safety alerts. Fortunately, there are software programs and other tools for surviving this flood of information.

Christine M. Cheng, PharmD, might understand the deluge more than most. When she was an assistant clinical professor at the School

W Washington —Health care facilities, offices and hotels are germy places. At least that’s the finding of a study conducted by Charles P. Gerba, PhD, a microbiologist at the University of Arizona in Tucson, who placed a harmless virus on a few items in these public buildings and tracked how it traveled through the facilities. Then, he and his research team introduced an intervention to see if they could reduce the spread of the virus.

“We wanted to develop scenarios to not only learn how viruses move in these kinds of environments, but to allow us the opportunity to look at interventions,” said Dr. Gerba, who presented his research at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy.

The researchers used a tracer virus to document the spread of contamination. Within two to four hours of placing the tracer virus on one or two commonly touched surfaces, such as a doorknob, the virus contaminated between 40% and 60% of other commonly touched objects.

see BOXED WARNINGS, page 21

see TOUCHY, Y page 16

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New Product Keytruda approved for advanced or unresectable melanoma.

See page 22

NOW available! iPad App

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 • October 2014

Capsules

Web Exclusives

Patients With Advanced Dementia Continue Receiving Drugs of Questionable Benefit

Visit us online for Web-exclusive content. Links to all the stories below can be found at: pharmacypracticenews.com/webex/1014.

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Blood Transfusions Lessen Sickle Cell Brain Injury in Children

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egular blood transfusions prevent recurrent blockage of blood vessels in the brain, a serious neurologic side effect that occurs in one-third of children with sickle cell anemia (SCA), according to a study in The New England Journal of Medicine ((2014;371:699-710). The evidence is so compelling that an expert panel recently convened by the National Heart, Lung, and Blood Institute (NHLBI) recommended that periodic blood transfusions be given to children with SCA to reduce the risk for stroke.

The e ABCs of New CMS Pay Rules

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nsu urers, including the Centers for Medicare and Medicaid Services (CMS), are experimenting with a variety of pa ayment initiatives that bring providers on board as partners to control costs while improving qualp ity 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? Here are some starter tips from Bonnie Kirschenbaum, our resident reimbursement expert.

Generic Statins a Better Bet than Branded?

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aking a generic statin instead of a branded produ uct may improve medication adherence and reduce the n number of cardiovascular events and death, according to o a new study by researchers at Brigham and Women’s Hospital (BWH), Harvard Medical School and CVS Health.

ore than half of nursing home residents with advanced dementia, which is a terminal illness, receive medications of questionable benefit, such as lipid-lowering and antiplatelet agents, according to a recent study.

“Our findings have important implications because the use of prescription medications in patients with advanced illness presents a burden to the health care system and to patients,” said coinvestigator Jennifer Tjia, MD, MSCE, of the University of Massachusetts Medical School, in Worcester.

Using a long-term care pharmacy database, the researchers reviewed medications given to nursing home residents with advanced dementia during a 90-day period. Advanced dementia is characterized by severe cognitive and functional impairment that leaves patients bedridden, unable to speak and unable to handle even their most basic needs. Often they cannot swallow and are placed on feeding tubes.

Of the 5,406 nursing home residents with advanced dementia, 53.9% (2,911) received at least one medication of questionable benefit (JAMA Intern Med. Published online Sept. 8, 2014). The most commonly prescribed medications were the dementia therapies cholinesterase inhibitors (36.4%) and memantine hydrochloride (25.2%), as well as cholesterol-lowering medications (22.4%). Fewer than 10% of patients also received antiplatelet agents, used to prevent heart attacks; and less than 2% received hormone antagonists, leukotriene inhibitors, sex hormones, cytotoxic chemotherapy and immunomodulators, according to the study results. Some patients received more than one unnecessary medication.

Medication use varied by the location of the nursing home, ranging from 44.7% in the Mid-Atlantic census region to 65% in the West South Central census region. The likelihood of receiving medications of questionable benefit was lower for patients with eating problems, a feeding tube, a do-not-resuscitate order or who had enrolled in hospice.

However, living in a nursing home with a prevalence of feeding tube use greater than 10% was associated with a greater likelihood of being prescribed questionably beneficial medications compared with residents who lived in nursing homes where the use of feeding tubes was lower (5% or less).

The average 90-day cost for a medication of questionable benefit was $816 and that accounted for 35.2% of the total average 90-day medication expenditures for patients with advanced dementia, the researchers said. They added that in 2001 an estimated $3.5 billion was spent for medications in long-term care facilities and costs in nursing home care were rising about 8% per year.

The Institute of Medicine recommends clinicians minimize interventions in patients with life-limiting disease and instead focus on maximizing quality of life.

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

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6 Clinical

Pharmacy Practice News • October 2014

Diabetes Care

Poorly Managed Glyburide Linked to Hypoglycemia Austin, Texas—Failure to discontinue glyburide after diabetes patients are hospitalized increases their risk for developing hypoglycemia during their stay. The risk is particularly acute among patients who are aged 65 years and older or who have kidney problems, according to a study presented at the 2014 annual meeting of the American College of Clinical Pharmacy.

The retrospective analysis, which involved 77 non-ICU adults hospital-

ized in 2013, recorded the number of episodes of hypoglycemia in patients receiving at least one dose of glyburide, an oral sulfonylurea drug, after their admission to Lakeland Regional Medical Center (LRMC), in Fla. (abstract 2).

In all, 33 hypoglycemia episodes (blood glucose ≤70 mg/dL) occurred during 311 glyburide-consuming patient-days, with 25 of those episodes developing in patients aged 65 and older and eight among younger patients ((P<0.0001).

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

4 CONTRAINDICATIONS None.

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

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

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

Discontinue GRANIX in patients undergoing a sickle cell crisis.

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

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

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

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

“The results were pretty remarkable regarding the patient age,” said Georgia Keriazes, PharmD, BCPS, the lead researcher and pharmacist quality improvement specialist at LRMC. Specifically, Dr. Keriazes noted the nearly fivefold increase in relative risk (4.9) in the older age group for developing hypoglycemia per glyburide patient-day.

The Florida researchers also identified significantly more episodes per glyburide-consuming days in patients

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

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

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

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

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

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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

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

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

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

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

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

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40188 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

with creatinine clearance (CrCl) less than 60 mL/min than in those with higher levels ((P=0.0179). The difference was 17 hypoglycemia episodes per 100 glyburide-consuming days compared with 15 hypoglycemia episodes per 191 glyburide-consuming days. (CrCl was not available for one of the 33 episodes.)

In its 2012 guidelines, The Endocrine Society noted that continuing oral medications for diabetes in the hospital is challenging, given that many of the agents are contraindicated if other complications, such as renal failure or sepsis, arise during a patient’s stay ((J Clin Endocrinol Metab 2012;97:16-38). The society’s guidelines also state that selected patients “may be candidates” for the drugs if they are clinically stable, eating regular meals and do not have any contraindications.

Paul Milligan, PharmD, a system medication safety pharmacist at BJC HealthCare Center for Clinical Excellence, in St. Louis, agreed that such patients can be continued on oral diabetes drugs. However, “that’s not a high percentage of people going to hospitals now. Except for that small group, most people should not be on [these oral regimens].”

The LRMC analysis illustrates how hospital pharmacists can get a better handle on their facilities’ use of these oral drugs, Dr. Milligan said. “They’ve now got the data for their own hospital to go get buy-in to start reducing [this] oral agent use for their own patients.”

Data collected at BJC HealthCare also showed an elevated risk for hypoglycemia in patients taking oral diabetic agents, including sulfonylureas. From 2001 to 2003, use of the diabetes medications was reduced by as much as 60% at the non-profit system’s hospitals.

In late 2013, the findings on hypoglycemia at Lakeland Regional were presented to the Pharmacy and Therapeutics Committee, according to Samantha Bailey, PharmD, BCPS, a clinical coordinator at the hospital who also participated in the research. Early this year, glyburide was removed from the hospital’s formulary.

Other oral diabetes drugs are being reviewed, but no decisions have been made about their use, the pharmacists said. Clinicians also were considering whether glyburide should be available as a formulary option for patients being treated on observation status of less than 24 hours, who are eating a normal diet, but have not been admitted, Dr. Bailey said. So far, no decision had been reached.

—Charlotte Huff Drs. Bailey, Keriazes and Milligan reported no relevant financial conflicts of interest.

Clinical 7

Pharmacy Practice News • October 2014

Infectious Disease It’s not just the bundle; it’s the buy-in

Duke Protocol Reduces Colorectal SSIs by 75% A

bundle of preventive measures can significantly reduce surgical site infections (SSIs) after colorectal surgery, but the strategy probably requires a “village” to be successful, a new study suggested.

“You cannot do this alone,” said coinvestigator Christopher R. Mantyh, MD, a colorectal surgeon and surgical oncologist in the Department of Surgery, Duke University Medical Center in Durham, N.C. “I had a lot of buy-in from people, and there was not much pushback at all.”

In the study, a group of preventive measures was bundled and implemented pre-, during and post-colorectal surgery, which resulted in an almost 75% reduction in both superficial SSIs (5.7% after the intervention vs. 19.3% before; P<0.001) and postoperative sepsis (2.4% vs. 8.5%; P=0.009) ((JAMA Surgg 2014 Aug. 27. [Epub ahead of print]).

Bundles, which combine specific interventions, have become popular in infection control, according to Joseph Kuti, PharmD, an associate director of clinical and economic studies at the Center for Anti-Infective Research and Development at Hartford Hospital in Hartford, Conn., whose area of research is the use of bundles to improve outcomes in patients with infection.

“By putting the bundle through as a package, the intent is that every single piece of the bundle will be followed,” said Dr. Kuti, who is also president of the Society of Infectious Diseases Pharmacists.

“We think the sum is greater than the whole,” Dr. Mantyh explained. “If you did one [intervention], you might see a small improvement. If you add together five or 12 of these actions, there is an even greater improvement. I do not think any one action would move the needle significantly.”

The colon and rectum are full of bacteria, so anytime a surgical procedure is performed in those areas, there is a high risk for infection; the risk for SSI from such surgical contamination ranges from 15% to 30%, according to the paper.

The first step was recognizing this as a problem and not the norm. “It was an acceptable fact of life that when you operated on the colon or the rectum, you would see a surgical site infection in about one-fourth of your patients,” Dr. Mantyh said.

After Duke began participating in the American College of Surgeons National Surgical Quality Improvement Program, which provides prospective 30-day postsurgical outcomes data, the physicians became aware that their 20% rate of infection was a little higher

Table. Components of Prevention Protocol Pre-op (5 measures) 1.

2.

3.

4.

5.

Educate patients about SSI preventive measures and objectives.

Have patient shower with chlorhexidine.

Perform mechanical bowel prep with oral antibiotics.

Administer ertapenem within 1 h of incision.

Standardize preparation of surgical field with chlorhexidine alcohol.

During surgery (6 measures) 1.

2.

3.

4.

5.

6.

Use fascial wound protector.

Change gown and gloves before fascial closure.

Have a dedicated wound-closure tray.

Limit OR traffic.

Maintain euglycemia.

Maintain normothermia during surgery.

Post-op (5 measures) 1.

2.

3.

4.

5.

Remove sterile dressing within 48 h.

Wash incision daily with chlorhexidine.

Maintain euglycemia.

Maintain normothermia in the early preoperative period.

Reinforce patient education about SSI preventive measures and objectives.

Source: JAMA Surgery y 2014 Aug. 27. [Epub ahead of print].

than some other institutions.

“When I initially tried to start this in 2010, I was kind of doing this on my own, and I met a lot of failure,” Dr. Mantyh admitted. “My realization was that I had to involve other folks, such as nursing and anesthesia, and once I did that, it became a lot easier.”

The (Medical) Village A multidisciplinary team, including surgeons, anesthesiologists, clinic nurses, operating room (OR) staff, unit nurses, house staff and hospital midlevel providers were involved in either putting together the bundle or its implementation. The team looked at the entire colorectal surgery process from pre-op to post-op before deciding which measures to include in the bundle (Table). Some of the measures were evidence-based and others were commonsense ideas that presented little patient risk, but had the potential to reduce infections, Dr. Mantyh told Pharmacy Practice News.

“We chose these [actions] for our bundle because they were easy to do, low cost and everyone was on board with them,” he said. (The largest cost was a $10,000 outlay for 10 fascial closure tray packages.)

There were a few areas that saw some heavy discussion among the team members. One was the use of mechanical bowel preparation and prophylactic antibiotics. “This is a controversial area,” Dr. Mantyh said. “There are some studies that show it does not improve SSI rates, maybe even makes them worse and some

that show it does [improve rates]. But the most recent data that have come out in the last few years [[Dis Colon Rectum 2012;55:1160-1166] indicate that it is beneficial to decrease the SSI rates if you provide the bowel prep with antibiotics.”

After a discussion with the infectious disease staff, the team also decided to limit operating room (OR) traffic.

“Anesthesia and surgery had to get together and make sure we did not have extraneous people coming and going through the OR because the ID [infectious disease] people said that was a great way to introduce airborne bacteria into your room,” he said.

Another controversial area was the use of fascial wound protectors with reports in the literature both supporting and not endorsing their use. “We felt that if we began to use them especially for our open cases, it could decrease the bacterial count in the subcutaneous space.” Dr. Mantyh said. (For a positive study on the protectors, see Surg Infect 2010;11:501-503.)

The input surrounding the antibiotic choice demonstrates the type of interaction that was used throughout the process. As a teaching hospital, residents are frequently the ones providing postoperative care at Duke. “We found that our residents were redosing antibiotics inappropriately,” he said.

A discussion with the infectious disease physicians led to the idea of using ertapenem (Invanz, Merck) because it is only dosed once before surgery. When they talked with the pharmacist, however, there was some concern about super

selection of bacteria with this drug. But a review found that this was not an issue at Duke, so the idea was brought before the team and added to the bundle.

“The great thing about ertapenem is you give one dose preoperatively and that’s it. With that single act, we got in compliance with perioperative antibiotics,” Dr. Mantyh said.

They began implementing the bundle on July 1, 2011 and the adherence to the protocol was very high. In addition to the staff buy-in, the bundle had a champion in Dr. Mantyh, who met regularly with various departments to review recent SSI results and address any implementation problems.

The use of the team approach to determine and implement the bundle and the champion were probably instrumental in the program’s success, according to Dr. Kuti.

“This is about culture change,” Dr. Kuti said. “You need lots of education, and the support from key opinion leaders, well-respected individuals and the administration. Then you need to collect data and analyze that data after implementation to demonstrate the intervention worked and can therefore be expanded—in this case, expanded to the other colorectal surgeons.”

‘Phenomenal’ Results To determine whether the bundle helped reduced SSIs, the Duke researchers conducted a retrospective study and looked at surgeries performed between Jan. 1, 2008 and Dec. 31, 2012.

They reviewed the medical records of 559 patients—346 underwent colorectal surgery before implementation of the bundle and 213 underwent surgery after implementation—and found that the bundle was associated with a substantial reduction in SSIs. Indeed, the nearly 75% reduction in SSIs documented in the JAMA Surgery study was “a phenomenal” result, said Ira L. Leeds, MD, MBA, who wrote an accompanying editorial in the journal. But he stressed that “one needs to interpret them in the right context.

Their SSI rate going into the [research] was something they made an intentional effort to reduce.”

Results like this require changing behavior and that can be difficult, especially in medicine, added Dr. Leeds, the Halsted Surgical Resident at Johns Hopkins University School of Medicine, in Baltimore. “Even within a single health care institution, there are awfully high fences between departments, and these firm and sharp

•

see COLORECTAL SSIs, page 8

8 Clinical

Pharmacy Practice News â&#x20AC;˘ October 2014

Infectious Disease

Hepatitis C Patients With Two Cancers Pose Rx Challenge Chicagoâ&#x20AC;&#x201D;Patients with hepatitis C who develop both a liver cancer and a non-liver malignancy appear to respond poorly to traditional antiviral therapies such as pegylated interferon and ribavirin.

In data published in conjunction with the 2014 annual meeting of the American Society of Clinical Oncology (abstract e15092), sustained virologic response (SVR) was achieved in 65% of patients who had a non-liver primary

malignancy but only 29% of those with both a non-liver malignancy and hepatocellular carcinoma (HCC) as a second primary ((P=0.05).

In this retrospective caseâ&#x20AC;&#x201C;control evaluation, 75% of the 32 cases with both liver and non-liver malignancies received hepatitis C virus (HCV) treatment, reported Harrys A. Torres, MD, an assistant professor in the Department of Infectious Diseases at the University of Texas MD Anderson Cancer

Center, in Houston. Based on the low rate of SVR, Dr. Torres suggested that HCV-infected individuals with two primary malignancies may be particularly resistant to treatments available at the time when these patients were initially managed. A better alternative, he noted, would be the use of newer direct-acting antiviral agents, although he acknowledged that a prospective trial is needed.

Data from the 32-patient study also

Rationale, Reversal, and Recovery Of Neuromuscular Blockade 3DUW $ 0XOWLGLVFLSOLQDU\ $SSURDFK WR 2SWLPL]LQJ 6DIHW\ DQG (IÂżFLHQF\ Case Study Brenda is a 78-year-old woman undergoing open abdominal surgery to correct symptomatic pelvic organ prolapse.

Current Symptoms Â&#x2021; Pelvic organ prolapse failing conservative therapy Vital Signs Â&#x2021; Height: 175 cm Â&#x2021; Weight: 85 kg 6LJQLÂżFDQW 0HGLFDO +LVWRU\ Â&#x2021; Dyslipidemia Â&#x2021; Type 2 diabetes mellitus Â&#x2021; Glaucoma &XUUHQW 0HGLFDWLRQV Â&#x2021; Ezetimibe Â&#x2021; Glyburide Â&#x2021; Insulin glargine Â&#x2021; Pravastatin Anesthesia is induced with fentanyl 100 mcg, propofol 150 mg, and rocuronium 50 mg and maintained with GHVĂ&#x20AC;XUDQH LQ DLU R[\JHQ $PSLFLOOLQ VXOEDFWDP 3 g is given intravenously as well. At 90 minutes after induction, the surgeon reports tension in the surgical ÂżHOG DQG UHTXHVWV DGGLWLRQDO UHOD[DWLRQ 1R PRQLWRULQJ of neuromuscular function is performed.

Global Education Group and Applied Clinical 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

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Supported by an educational grant from Merck.

confirm that HCV patients remain at risk for HCC even after developing a non-liver malignancy. When the cases were compared with 17 matched controls, nearly twice as many cases as controls had solid primary tumors as opposed to hematologic malignancies (82% vs. 47%), although the difference was not significant ((P=0.07).

Amit G. Singal, MD, MS, a liver cancer specialist at the University of Texas Southwestern School of Medicine, in Dallas, said the study â&#x20AC;&#x153;helps highlight the benefit of treatment in HCV-infected patients, given that HCV eradication is able to significantly reduce risk of HCC and other cirrhosis-related complications.â&#x20AC;? â&#x20AC;&#x201D;Ted Bosworth Dr. Torres reported a ďŹ nancial relationship with Genentech. Dr. Singal reported no relevant ďŹ nancial relationships.

COLORECTAL SSIs continued from page 7

divisions really make it difficult to implement something system-wide. â&#x20AC;&#x153;This bundle was built from the ground up. There was a physician champion, but he got buy-in from the nursing staff, the techs. On top of that, they invited comment from all the people who are involved in the procedure,â&#x20AC;? he said, adding that the future of quality improvement in health care will require grassroots interventions like this.

For Duke, Dr. Mantyh said, the bundle has become the standard of care for colorectal surgery, and surgeons in other areas with a high SSI rate, such as hepatobiliary surgery, are reviewing the results. â&#x20AC;&#x153;We are beginning to look at these other areas, but each is a little different,â&#x20AC;? he said, so the bundle would have to be tweaked by the staff in that department.

Dr. Leeds said that is the way infection prevention should be done. These interventions are less about duplication and mandates and more about a process and buy-in, he explained. â&#x20AC;&#x153;When the people who are ultimately responsible for the performance measure are the people designing the program, it becomes infused with a sense of ownership you cannot mandate.â&#x20AC;?

He said people lampoon â&#x20AC;&#x153;committee think,â&#x20AC;? but a deliberative process can help improve quality. â&#x20AC;&#x153;Everyone in the operating room plays a very specific role, and they see things from very different perspectives. Unless you engage each of those individuals, you are going to end up with a solution that is not optimized for each individualâ&#x20AC;&#x2122;s role.â&#x20AC;? â&#x20AC;&#x201D;Marie Rosenthal

Clinical 9

Pharmacy Practice News • October 2014

Infectious Disease

Fidaxomicin May Be Best Choice for C. difficile Infections W Washington —Overall treatment costs for cancer patients with Clostridium difficile infection (CDI) appear lower with fidaxomicin than with vancomycin, resulting in a potential cost savings of $9,051 per patient, according to new data presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014).

“Patients with cancer represent a vulnerable population who are at high risk for CDI, often resulting from their compromised immune system. CDI can be a devastating addition for patients who are already battling preexisting conditions,” said lead investigator Sebastian Heimann, a health economist at the University Hospital of Cologne, Germany.

The pharmacoeconomic model combined data from a study exploring CDI in cancer patients treated with fidaxomicin or vancomycin, and a recent cost-ofillness analysis on CDI conducted at the University Hospital of Cologne in Germany (abstract K-364). Fidaxomicin is marketed as Dificlir (Astellas) in Europe and as Dificid (Cubist) in the United States.

Laboratories Given Short Shrift Additionally, only 26% of respondents in this survey said they always request a laboratory test for patients presenting with diarrhea that is not clearly attributable to an underlying condition or therapy, despite recent epidemiologic data suggesting the incidence of CDI is increasing in Europe. Interestingly,

physicians believed 25% of clinically significant CDI cases remain undiagnosed in a hospital setting, increasing to as much as 45% in the community. This is supported by a recent epidemiologic study that revealed that as many as 39,000 cases of CDI may be missed each year in Europe.

“CDI is a huge economic and societal burden and causes additional and

unnecessary suffering to already sick patients, so there is clearly more that needs to be done to improve patient care and CDI management,” said Professor Oliver A. Cornely, University Hospital of Cologne, Germany.

—Marie Rosenthal Dr. Heimann is a research contractor for Astellas, Gilead, Merck and Pfizer. Dr. Cornely is a research contractor for 3M, Actelion, Astellas, Basilea, Bayer, Biocryst, Celgene, Cubist, F2G and Genzyme.

Complete Confidence

The Cost of an Infection Although the study looked at European hospitals, CDI is a serious and costly problem in U.S. hospitals. An estimated 107,700 cases of hospital-acquired CDI occur in the United States each year, according to the Centers for Disease Control and Prevention (CDC). The estimated cost of treating these cases ranged from $6,408 to $9,124, according to a 2003 CDC report (http://1.usa.gov/RUbCoo). Based on current health care costs, that financial burden may well be higher, the federal investigators noted.

The ICAAC analysis explored direct cost parameters including drug costs, treatment on the general ward and intensive care unit as well as microbiological diagnostics for C. difficile. Mean overall treatment costs per patient treated with fidaxomicin and vancomycin were $35,867 and $44,910, respectively.

The lower costs associated with fidaxomicin were primarily due to the significantly lower rate of recurrence in patients treated with fidaxomicin compared with vancomycin.

In other data presented at ICAAC, physician perceptions of the burden of CDI and the negative health effects of recurrent infection were assessed.

Nearly all of the 1,567 European health care professionals surveyed accepted that a recurrence of CDI would have a medium or strong effect on patient health, in particular immunocompromised patients and those with a severe underlying disease. Despite this, most respondents (60%) did not often consider this impact in their treatment decisions (abstract K-350).

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10 Clinical

Pharmacy Practice News • October 2014

Infectious Disease

Antimicrobial Stewardship in the Valley Valley Presbyterian Hospital’s strategy for combating resistance, lowering costs Brandi Acevedo, PharmD, BCPS Pharmacy Clinical Coordinator

Darryl Toy, PharmD Director of Pharmacy For the Valley Presbyterian Hospital Antimicrobial Stewardship Team Van Nuys, California

T

he discovery of penicillin more than half a century ago spurred the modern era of antibiotics, which has helped mitigate and in some cases even cure a wide range of life-threatening infectious diseases. But those successes also carry some unforeseen challenges. By far the most pressing has been the increase in resistant organisms, in part due to the overuse or misuse of antibiotics.

Valley Presbyterian Hospital (VPH), a 350-bed, nonprofit community hospital in Van Nuys, Calif., has addressed this challenge by developing a detailed antibiotic stewardship program (ASP).

The primary goal of the ASP, similar to many others, is to minimize antibiotic resistance, improve outcomes/toxicity and reduce treatment costs. (The efforts also ensure that the hospital is in compliance with California Senate Bill 739, which requires that all general acute care hospitals develop ASPs.) VPH takes a collaborative approach to its stewardship program; the ASP team

• Pharmacokinetic dosing • IV-to-oral switch • Renal dose adjustment • Formulary usage criteria and empiric regimens

includes clinical pharmacists, infectious disease (ID) physicians, infection control, microbiology specialists and an information systems analyst. Stewardship strategies include monitoring the use of broad-spectrum agents, with pharmacist-driven recommendations for streamlining and de-escalating treatment regimens. Dose optimization and IV-to-oral switch also are employed, with all of the initiatives aimed at reducing unnecessary antimicrobial exposure and cost. Throughout this process, a variety of outcomes, including antimicrobial utilization, cost and resistance, are delineated to evaluate the effectiveness of VPH’s interventions.

Table 1. Cost Reductions From ASP Initiativea

Year

Anti-Infective Cost/1,000 APD, $

Average Monthly Anti-Infective Cost/1,000 APD, $

Anti-Infective Cost/ Patient-Day, $

2008

13,939.88

1,161.66

13.94

2009

13,918.76

1,159.90

13.92

2010

14,957.28

1,246.44

14.96

2011

15,104.66

1,258.72

15.10

2012

7,707.83

642.32

7.71

2013

8,366.99

697.25

8.37

APD, adjusted patient-day; ASP, antimicrobial stewardship program a

Formalization of ASP resulted in 50% reduction in anti-infective cost per patient-day. However, clinical outcomes should be emphasized and additional treatment that increases short-term cost may be needed to provide appropriate care.

Early Adopters In the past five years, VPH pharmacists have been steadily expanding the scope of ASP interventions (Figure 1). In the early stages, the ASP team developed pharmacy protocols for pharmacokinetic dosing/monitoring of vancomycin and aminoglycosides and renal adjustments for dose optimization and safety.

IV-to-oral conversion protocols helped increase patient satisfaction and cost savings and shortened patient stays. For dose optimization and cost savings, the team implemented the Zosyn (piperacillin-tazobactam) extended (fourhour) infusion protocol for patients in the ICU. Considering the critical status of these patients, greater accessibility of multiple IV lines and higher risk for infections with Pseudomonas, the fourhour infusion was well accommodated by both patients and nursing.

In 2011, VPH expanded its ASP to include microbiology in reporting multidrug-resistant isolates in real time by calling the clinical pharmacist for immediate culture evaluation and intervention. As

part of those efforts, the team improved several methods for presenting sensitivity data to prescribing physicians. In one enhancement, “selective reporting” of antibiotic-susceptibility panels were added. Such reporting “hides” the display of sensitivities for broader-spectrum agents if the organism is susceptible to a narrower agent. For example, if a urine culture isolates Escherichia coli that is susceptible to ciprofloxacin, then imipenem-cilastatin is not displayed on the physician report view. (All sensitivities are available from microbiology on request). This tactic has been useful in guiding prescribers to select the narrowest spectrum agent whenever possible.

Annually, VPH uses microbiology antibiograms to ensure that the hospital-recommended empiric regimens for common infectious diseases are appropriate for optimal coverage and susceptibility.

In 2012, the addition of an ASP ID advisor, working in conjunction with clinical pharmacists, helped to achieve timely antibiotic de-escalation/escala-

• Microbiology calls for multidrug-resistant isolates

• ASP team with infectious diseases physician collaboration

• Susceptibility panel selective reporting

• Days of therapy (DOT) tracking

• Select broad-spectrum agents tracking

• Cost per patient-day using DOT data

• Zosyn-extended infusion protocol

• Expansion of ASP interventions • Case management meetings

Figure 1. Valley Presbyterian Hospital antimicrobial stewardship program (ASP) timeline.

• Preprinted order forms to guide therapy, sepsis bundle

tion, streamlining or discontinuation of therapy. The team reviews a daily report from the hospital’s electronic health record (EHR) system, which lists all patients on anti-infective agents. The report is a helpful tool for identifying potential patients for de-escalation.

In general, patients on broad-spectrum agents are reviewed within 48 to 72 hours and duration of therapies is tracked for clinical improvement and potential discontinuation.

The following communication methods have proven effective in facilitating ASP interventions: 1. Notifying the ASP ID advisor via secure email or phone call, who intervenes with the ordering physician directly; 2. Direct communications between pharmacists and physicians; and 3. Pharmacist-to-physician chart notes.

Furthermore, the ASP ID advisor at VPH has been extremely helpful during interventions on complicated patient cases and ensuring the appropriateness of the interventions. To demonstrate the effect of pharmacists’ intervention, VPH extracted intervention category totals (e.g., de-escalation, escalation, alternative regimens, discontinuation of therapy, IV-to-oral conversion, empiric regimens, pharmacokinetic/ dynamic) from the EHR. There were 2,632 interventions for 2013, an increase from 2,002 in 2012. Pharmacist-driven interventions have expanded with the formalization of ASP. In comparison, there were 1,218 interventions for 2010 (preformalization period).

To measure antimicrobial utilization, VPH initially tracked broad-spectrum or restricted anti-infective agents (imipenem-cilastatin, piperacillin-tazobactam, linezolid, daptomycin and caspofungin).

From 2011 to the present, carbapenem

Clinical 11

Pharmacy Practice News • October 2014

Table 2. Pharmacist’s ASP Interventions

950

Intervention Type

900 850 800 750

Count, 2013

Culture & sensitivity

104

81

Unnecessary double coverage

39

33

Escalation

13

27

700

Alternative therapy

52

96

650

Anti-infective IV-to-PO

80

92

Discontinue medication

107

145

600

68a

Empiric therapy

Se us t pt em be r O ct ob N er ov em be D ec r em be r

ly Ju

A ug

Ju

ne

ay M

Ja

A pr

il

550

2013

2012

Figure 2. Days of therapy (DOT) per 1,000 adjusted patient-days.

14 12 10 8 6 4 2 0 2009

2010

2011

2012

2013

Anti-infective cost per 1,000 adjusted patient days

Figure 3. Anti-infective cost per 1,000 adjusted patient-days.

usage has decreased by about 20%.

Data Mining In 2012, VPH added an information systems analyst to the ASP team to facilitate EHR data extraction for reporting stewardship outcomes. Antimicrobial utilization tracking was expanded to include all anti-infectives to track days of therapy (DOT) per 1,000 adjusted patient-days (APDs). An EHR customized report was created to capture any dose of antibiotic charged during a 24-hour period, to represent one DOT. With the implementation of bedside medication verification, this report will be changed to capture doses of antibiotics administered.

Several improvements have occurred

61

37

Pneumonia indication

35

31

Initiation, adjustment per level

1,008

1,532

Renal dose

423

541

Infusion duration

80

17

2,002

2,632

Grand Total a

16

2008

Urinary, abdominal, other indication

Pharmacokinetic/dynamic

Month

$, Thousands

Count, 2012

De-escalation or escalation

nu ar Fe y br ua ry M ar ch

DOT per 1,000 Adjusted Patient-Days

Infectious Disease

as a result of formalizing the VPH stewardship program. For example, the mean ± SD for DOTs per 1,000 APDs for all antiinfective agents in 2013 was 723.43±46.39 compared with 772.13±47.01 in 2012 (95% confidence interval [CI], –67.77 to –29.63; P<0.05). The hospital also documented cost savings that accrued as a result of the initiative. Antimicrobial cost was obtained from DOT data (individual antimicrobial counts) multiplied by the cost of each antimicrobial received. The mean ± SD for anti-infective cost per 1,000 APDs in 2012-2013 was $8,037.41 ± $466.09 compared with $14,480.15 ± $638.93 in 2008-2011 (95% CI, $610.77$1,2274.71; P<0.05) Yearly trend is displayed in Table 1 and Figure 3.

Not specified

We used annual antibiograms to track percentages of drug-resistant isolates (e.g., methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, extended-spectrum betalactamase (ESBL)–producing organisms, and carbapenem-resistant Enterobacteriaceae [CRE]). Considering that CRE has increased nationwide over the past decade, according to the Centers for Disease Control and Prevention (http://1.usa.gov/1poOh7r), the incidence data may have greater significance. Although immediate change in bacterial resistance is not expected, VPH anticipates the ability to identify hospital trends in the long term.

The progression of VPH’s ASP from a pharmacy initiative to a multidisciplinary program has been instrumental in optimizing antimicrobial utilization, reducing unnecessary antimicrobial exposure and cost, slowing the emergence of resistance and improving patient safety.

Suggested Reading • Centers for Disease Control and Prevention.

Vital signs: carbapenemase-resistant enterobacteriaceae. http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm6209a3.htm. Accessed September 3, 2014.

• Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America and Society for Healthcare Epidemiology of America guidelines for developing an institutional program to

enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:159-177.

• Drew RH, White R, MacDougall C, et al.

Insights from the Society of Infectious Diseases Pharmacists on antimicrobial stewardship guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Pharmacotherapy.

2009;29:593-607.

• MacDougall C, Polk RE. Variability in rates of use of antibacterials among 130 US hospitals and risk-adjustment models for interhospital comparison. Infect Control Hosp Epidemiol.

2008;29(3):203-210.

• Polk RE, Hohmann SF, Medvedev S, Ibrahim O. Benchmarking risk-adjusted adult antibacterial drug use in 70 US academic medical center hospitals. Clin Infect Dis. 2011;53:1100-1110.

Valley Presbyterian Hospital Antimicrobial Stewardship Team: Brandi Acevedo, PharmD, BCPS, pharmacy clinical coordinator; Darryl Toy, PharmD, director of pharmacy; Jean Rico, senior vice president of quality; Jerrold Dreyer, MD, FACP, infectious disease physician advisor; Ivan Acevedo, CPhT, BCS, clinical applications analyst; Nera Ismail, NP, infectious disease nurse practitioner; Jing-Ting Tung, PharmD, BCPS, clinical pharmacist; Julie Philip, CLS, director of laboratory services; Aleli Tiu, CLS, microbiology supervisor; Neha Kanungo, MPH, CIC, infection prevention and control manager.

Special acknowledgment to Larry Clemens, PharmD The sources had no relevant financial conflicts of interest to disclose.

Web Exclusive Late-breaker from ICAAC: hospital-wide antibiotic stewardship program saves facility more than $600,000 annually, slashes rate of C. difficile-associated diarrhea.

To access, scan the 2D barcode.

12 Clinical

Pharmacy Practice News • October 2014

Infectious Disease

U.S. Ramps Up Response to Ebola Outbreak C

ontaining the largest Ebola outbreak in history, which has already infected more than 5,000 people, is not just about stopping a dangerous virus and restricting its spread to neighboring countries. It is about preventing economic collapse in three already fragile countries and the domino effect that could have on their trading partners.

The Ebola outbreak that is raging through West Africa is going to get worse before it gets better, President Obama said, when he announced that the United States would establish a military command center in Liberia, sending 30,000 troops to support civilian efforts to fight the outbreak.

The effort is sorely needed, according to Keiji Fukuda, MD, the assistant director general for global security at the World Health Organization (WHO).

“We don’t have enough health workers, doctors, nurses, drivers and contact tracers” to handle the increasing number of cases. “Most of the infections are happening in the community, and many people are unwilling to identify themselves as ill. And if they do, we don’t have enough ambulances to transport

Laboratory Findings In Ebola Patients

L

aboratory findings at admission may include leukopenia (frequently accompanied by lymphopenia), followed later by elevated neutrophils and a left shift. Platelet counts are often decreased in the 50,000 to 100,000 range. Amylase may be elevated, reflecting pancreatic involvement (inflammation/ infection). Hepatic transaminases are elevated with aspartate aminotransferase exceeding alanine aminotransferase. Proteinuria may be present. Prothrombin and partial thromboplastin times are prolonged and fibrin degradation products are elevated, consistent with disseminated intravascular coagulation.

This digitally colorized scanning electron micrograph image depicts filamentous Ebola viral particles (green) budding from a chronically infected cell (orange). Source: CDC.

them or beds to treat them,” he said.

Dr. Fukuda added that insufficient

health care personnel and facilities to house the growing number of cases

CDC: Ebola Unlikely in U.S., but Best To Be Prepared

T

he longer the Ebola epidemic continues, the greater the chance the virus will enter the United States, although it probably would not become widespread in this country, according to Tom Frieden, MD, MPH, the director of the Centers for Disease Control and Prevention, in Atlanta.

The ease of travel today and the long incubation period for the Ebola virus (eight to 21 days before symptoms develop) makes it conceivable that an infected person could unwittingly bring the virus into the United States. “It is certainly possible we will see cases elsewhere [outside Africa],” Dr. Frieden said. “That is why we are alerting clinicians throughout the United States to think of Ebola in people who have been traveling to countries that have been affected and to rapidly test for it.”

The CDC has been helping laboratories throughout the country become better equipped to test for Ebola safely and accurately. “That is in place now, so testing can be done quickly,” he said.

U.S. clinicians should keep Ebola in the differential diagnosis for anyone who has traveled recently to West Africa (within three weeks) and presents with the nonspecific symptoms that appear early in the disease—particularly, fever, chills, myalgias and malaise. The most common presenting signs are fever higher than 101.5 F, anorexia and asthenia or weakness.

Patients can progress from the initial nonspecific symptoms after about five days to gastrointestinal symptoms, such as severe watery diarrhea, nausea, vomiting and abdominal pain. At this point, some patients develop a diffuse erythematous maculopapular rash that can desquamate. Other symptoms include chest pain, shortness of breath, headache or confusion and conjunctival injection.

Seizures and cerebral edema have been reported later in the course of disease. Hemorrhage is not present in all cases, but can manifest in later stages as petechiae, ecchymosis or bruising, oozing from the venipuncture sites and mucosal hemorrhage, but frank hemorrhage is less common, according to the CDC. Pregnant women have

experienced miscarriages.

Any suspected case should be tested because early recognition is critical for infection control. Laboratory findings at admission may include leukopenia frequently, with lymphopenia followed later by elevated neutrophils and decreased platelet counts (box). There are no approved treatments. Clinical management centers around supportive care of complications, such as hypovolemia, electrolyte abnormalities, refractory shock, hypoxia, hemorrhage, septic shock, multiorgan failure and disseminated intravascular coagulation.

Patients should be isolated, and standard contact and droplet precautions are recommended for the management of hospitalized patients with known or suspected Ebola hemorrhagic fever. Additional infection control measures might be warranted if the patient has a comorbidity, such as tuberculosis or multidrug-resistant organisms, according to the CDC. “We don’t think Ebola would spread widely within the United States,” Dr. Frieden explained. “Routine health care infection control would probably prevent most transmission.”

Hemorrhagic viruses like Ebola are indeed rare in the United States. In the past decade, there have only been five cases of hemorrhagic viruses (four Lassa and one Marburg) reported, according to Dr. Frieden. These were isolated incidents that did not spread to anyone else in the country.

“Even though they were not identified in the hospital before they were diagnosed, even though people did not take special precautions, there was not a single secondary spread from [those cases],” he said.

Several U.S. aid workers became infected with the virus while working in West Africa, although they were not specifically handling Ebola virus patients; they were part of a charity that was providing non–Ebola-related medical care in Liberia, Africa. All of the patients recovered with supportive treatment in a U.S. hospital, with one still hospitalized at press time.

—M.R.

was fueling the spread of the epidemic because families were being forced to care for sick family members at home, putting them and their contacts at risk.

Patients aren’t the only ones at risk: In addition to the many West African physicians who have become infected with the Ebola virus, at least one pharmacist and four pharmacy technicians died in Sierra Leone after caring for Ebola-infected patients, according to the International Pharmaceutical Federation.

Logistics Because logistical constraints continue to hamper humanitarian efforts, President Obama said the military would “create an air bridge to get health workers and medical supplies into West Africa faster.”

To do this, the military will establish a staging area in the Republic of Senegal to distribute personnel and aid more quickly. Additionally, the United States plans to accomplish the following: • Create a new site to train thousands of local health workers so they can more effectively and safely treat the thousands who are sick.

• Set up new field hospitals in Liberia.

• Deploy personnel from the U.S. Public Health Service to work in these facilities.

• Distribute supplies and information kits to hundreds of thousands of families so they can protect themselves.

“We are also going to build additional treatment units, including new isolation spaces and more than 1,000 beds,” the president said.

The U.S. response is necessary because the window of opportunity to “tamp down” the Ebola epidemic is closing, warned Tom Frieden, MD, MPH, the director of the Centers for Disease Con-

Clinical 13

Pharmacy Practice News • October 2014

Infectious Disease trol and Prevention (CDC), in Atlanta.

“This virus is moving faster than anyone anticipated,” he said in a press conference held on Sept. 2 after returning from a tour of the area. “We need action now to scale up the response. For every day’s delay, it becomes that much harder to stop.”

Dr. Frieden stressed that “this is not just a problem for Africa; it is a problem for the world, and the world needs to respond.” Because the global community is so interconnected, he added, “what happens in West Africa has a direct bearing on our own ability to go about our lives.”

What About the U.S.?

In addition to the international interventions, the president outlined the steps that are being taken to keep the virus from spreading to the United States.

He said that the likelihood of an outbreak occurring in the United States was extremely low because of the precautions that have been taken. The government is working with countries in West Africa to increase screening at airports so that an infected person does not board a plan bound for the United States.

If someone infected with the Ebola

virus does enter the United States, the government has instituted new measures to make sure it is prepared, most notably: • Helping flight crews identify people who are sick; • Making sure U.S. labs have the capacity to quickly test for the virus; • Ensuring that doctors, nurses and medical staff are trained and ready to deal with a possible case.

To date, four cases of Ebola have appeared in the United States, all physicians who contracted the virus while doing medical missionary work in West

Africa. Two of the physicians have made a full recovery and the third, at press time, was “steadily improving,” according to his doctors. The fourth case, a physician who was working for the WHO, is being treated at Emory University Hospital.

The continuing recovery of these physicians might be one piece of good news about the Ebola outbreak.

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

‘This is not just a problem for Africa; it is a problem for the world, and the world needs to respond.’

Unit Do s Bar Cod e, in Pharma g, c Nursing y & Supp Experts ly !

—Tom Frieden, MD, MPH President Obama reiterated this interconnectivity when he made the announcement of military assistance, saying that this epidemic threatens global security. “If the outbreak is not stopped now, we could be looking at hundreds of thousands of people infected, with profound political and economic and security implications for all of us.”

He said the epidemic threatens not only regional security, but is a “potential threat to global security if these countries break down, if their economies break down, if people panic.”

The effects of such a breakdown would be profound, the president emphasized.

The WHO estimates that before it ends, approximately 20,000 people will be infected with the Ebola virus, and the cost to combat the disease will be an additional $800 million on top of the $96.1 million from international donors that has already been provided for the effort. The United Nations issued a statement estimating the outbreak could be stopped in six to nine months, but “only if a massive global response is implemented.”

Volunteers Needed topping this epidemic requires a major effort, including deploying people with highly specialized training to work in the areas of Ebola treatment. Specifically, there is a need for doctors, nurses, health administrators, emergency managers and laboratory personnel.

The United States is looking for experienced health care personnel to volunteer in West Africa. For more information, visit http://www. usaid.gov/ebola/volunteers.

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14 Clinical

Pharmacy Practice News • October 2014

Infectious Disease

ProCESS Trial May Lead to Sepsis Protocol Tweaks

T

hirteen years ago, a seminal study on early, protocol-driven therapy for severe sepsis showed that the aggressive intervention boosted survival in these critically ill patients. Now, a new look at the treatment strategy suggests that such a rigid approach may be no more effective than current bedside treatments for the bloodstream infection.

The original single-center study ((N Engl J Med d 2001;345:13681377) found that in-hospital mortality was significantly reduced in patients with severe sepsis or septic shock who were treated based on a six-hour protocol of early goal-directed therapy (EGDT) than in those who were provided usual care (30.5% vs. 46.5%, respectively). The protocol consisted primarily of central venous catheterization to monitor central venous pressure and oxygen saturation, along with a targeted resuscitation strategy.

To determine if the findings from that study are still generalizable, and to assess whether all of the protocol components are still needed, investigators conducted the ProCESS (Protocolized Care for Early Septic Shock) trial ((N Engl J Med 2014;370:1683-1693). They enrolled 1,341 patients from 31 emergency departments across the United States, of whom 439 were randomly assigned to EGDT, 446 to protocol-based standard therapy and 456 to usual care. Resuscitation approaches varied regarding the observation of central venous pressure and oxygen, and the use of vasopressors, inotropes, intravenous fluids and blood transfusions.

At 60 days, there were 92 deaths in the EGDT group (21%), 81 in the protocolbased standard therapy (18.2%) and 86 in the usual-care group (18.9%). These differences in mortality were not statistically significant, the investigators reported. There also were no major disparities

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‘[In the future], perhaps we select an end point other than [survival], such as health care resources or patient quality of life [to better assess sepsis therapy].’

in 90-day mortality, one-year mortality and the necessity for organ support. As a result, the researchers concluded that there was no substantial advantage, with respect to death or illness, of protocolbased resuscitation over the current standard of bedside care.

Some Kudos for Study Design

—Ishaq Lat, PharmD

The design of the ProCESS trial has several merits compared with the ear-

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.

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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 15

Pharmacy Practice News • October 2014

Infectious Disease lier research, according to Ishaq Lat, PharmD, FCCM, the clinical coordinator of critical care at University of Chicago Medical Center, who was not involved with either study. He noted, for example, that the randomized controlled trial design of ProCESS was impressive, given the challenge of screening and enrolling patients with severe sepsis in hectic critical care settings. Moreover, “including patients from all over the country makes [the newer study] a better representation of patients with severe sepsis and septic shock than before, and gives it a

broader level of relevance.”

But he stressed that the ProCESS study results should be interpreted in the context of acknowledging the last decade of improved sepsis management. “The initial NEJM M trial called for early recognition to institute treatment with antimicrobial agents, timely administration of fluids and vasopressor agents, and conservative transfusion thresholds—all of which are now reflective of the care in most institutions today,” Dr. Lat said.

That would explain, he added, why survival in the usual-care arm of the Pro-

CESS trial was significantly increased compared with survival in the original goal-directed resuscitation study. “This may well be representative of the dramatic improvement in sepsis treatment that we’ve seen in recent years,” he said.

To make future studies more relevant to real-world clinical practice, “perhaps we select an endpoint other than [survival], such as health care resources or patient quality of life,” Dr. Lat suggested.

“Or maybe we should design smaller studies that won’t impact a heterogeneous pool of patients with the syn-

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.

•

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Hemophagocytic ssyndrome.

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drome.” Such a study, he added, would include patients with symptoms that are unique to severe sepsis, thus “leading to more patient-specific treatment strategies, such as those that have been developed for heart failure or hypertension.”

The study was supported by a grant from the National Institute of General Medical Sciences, part of the National Institutes of Health.

—Paul Bufano The sources reported no relevant financial conflicts of interest.

16 Clinical

Pharmacy Practice News • October 2014

Infectious Disease

TOUCHY continued from page 1

By eight hours, up to 100 high-touch objects, such as bed rails, light switches, tabletops, countertops, faucets, other doorknobs and computer equipment, were contaminated. Additionally, the organism was found on the hands of up to 60% of workers and visitors ((P<0.05 for all end points). A person’s probability of developing an infection from touching surfaces in public buildings—even health care facilities—is about 80%, he added.

Regardless of the work setting, the first area to be contaminated was the break room, which is a common area for people to congregate and chat, according to Dr. Gerba. The phone was also a commonly contaminated item as people brought the virus to their workstation.

“Most people are talking dirty and they don’t realize it,” joked Dr. Gerba, who suggested people try to be the first person in the break room every day because coffee pot handles are a “hotspot.”

Every time a person touches a surface, he or she picks up about 30% to 40% of

Pathogen falls on fomites (objects such as phones and computers).

the organisms (benign or virulent) on that surface, Dr. Gerba explained. “Once every three or four minutes, people touch their face, their nose, mouth or eyes. And every time you touch your face, you risk infecting yourself,” he said.

Norovirus a Concern When Dr. Gerba and his colleagues planned their research, they were concerned about the spread of norovirus, which is the leading cause of all gastroenteritis in the United States.

Outbreaks of norovirus are common Sick people touch objects and contaminate them.

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

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

Figure. Role of fomites in transmission of a disease.

in health care facilities, including nursing homes and hospitals, with more than half occurring in long-term care facilities, according to the Centers for Disease Control and Prevention (CDC). Every year, norovirus causes an estimated 19 million to 21 million illnesses, of which 56,000 to 71,000 require hospitalization. Up to 800 cases are fatal in the United States, according to the CDC. The virus can be introduced into health care facilities by infected patients—who may or may not be showing symptoms—or by staff, visitors or contaminated foods. Outbreaks in health care settings can sometimes last for months, according to the CDC. Illness can be more severe, occasionally even fatal, in hospitalized or nursing home patients compared with other-

Fast Fact:

• 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

Every year, norovirus causes an estimated 19-21 million illnesses; 56,000 to 71,000 require hospitalization.

Image source: CDC.

Clinical 17

Pharmacy Practice News • October 2014

Infectious Disease More Hand Hygiene Data

People pick up the pathogen by touching the contaminated fomite.

They then touch their nose, eyes or mouth with contaminated hands and become infected.

wise healthy people. Because of this public health concern, the researchers chose a benign organism for the tracer virus used in the first phase of the study that was similar in shape, size and susceptibility to norovirus, Dr. Gerba noted. Once they found that the tracer virus spread easily among staff and visitors, the researchers sought to determine whether an intervention could decrease the spread. They focused on that outcome in the interventional phase of the study, in which a cleaning crew was given disinfectant wipes containing a quaternary ammonium compound (QUAT) and asked to use them at least once a day on surfaces. (QUATs are commonly used compounds in disinfectants because they interact with cytoplasmic membranes of bacteria and the lipids of viruses.)

In addition, half the staff agreed to use hand sanitizers and to wipe their desks once a day with the disinfectant wipe.

The intervention reduced the number of fomites on which virus was detected by 80% or more, and the concentration of the virus was reduced by at least 99% ((P<0.02).

“What surprised us is only half of the people agreed to use hand sanitizers and disinfectants, yet there was a dramatic effect on the spread of the viruses,” Dr. Gerba said. Hand hygiene along with the use of disinfecting wipes containing QUATs “reduced virus spread by 80% to 99%.”

There are 90 different QUAT-based formulations available under 1,500 different brand names that are registered with the Environmental Protection Agency as being able to reduce norovirus on solid surfaces. “The results show that viral contamination of fomites in facilities occurs quickly,” Dr. Gerba said, adding that “a simple intervention can greatly help to reduce exposure to viruses.”

The value of hand hygiene in controlling the spread of infection—helped by a healthy dose of peer pressure—was also evident in a study in the October issue of Infection Control and Hospital Epidemiology (2014;35:1298-1300).

Researchers at the University of Iowa’s Carver College of Medicine, in Iowa City, used a custom-built badge system to estimate hand hygiene compliance and opportunities during a 10-day period for 24 hours a day. Badges were randomly provided at the start of each

shift to physicians, nurses and critical care staff. The badges collected information from health care workers within proximity and hand hygiene compliance when entering and exiting a patient room. More than 47,000 hand hygiene opportunities were recorded.

The estimated hand hygiene adherence rate was 7% higher when health care workers were in close proximity to peers (28%) than when health care workers were alone (21%).

Generally, the researchers found that the magnitude of the peer effect

increased in the presence of additional health care workers.

“Social network effects, or peer effects, have been associated with smoking, obesity, happiness and worker productivity. As we found, this influence extends to hand hygiene compliance [as well],” said co-investigator Philip Polgreen, MD, MPH, associate professor of internal medicine at the College.

“Health care workers’ proximity to their peers had a positive effect on their hand hygiene adherence.”

—Marie Rosenthal

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18 Clinical

Pharmacy Practice News • October 2014

Psychiatric Pharmacy

ROBIN WILLIAMS continued from page 1

Health Center, a federally qualified primary care facility run by ETSU’s College of Nursing, Dr. Melton often encounters patients with PD, some of whom also have depression, and a small percentage of those with indicators of suicidality.

She stressed that PD patients with depression require continual monitoring. “The most important thing is that you are very conscientious about following up to make sure the medication is working and they’re not having any adverse effects. And you always want to ask about suicidal ideation.”

Dr. Melton added that drawing out suicidal thoughts is often overlooked in clinical practice. “A lot of providers are reluctant to ask the tough questions,” she said. These queries include “Have you thought about hurting yourself?” or “Have you ever thought the world would be better off if you weren’t here?” It is important for pharmacists in primary care to ask those

been rare reports of suicide in patients taking dopaminergic agents to control PD symptoms, and the package insert for carbidopa-levodopa contains language cautioning clinicians to carefully observe patients for signs of depression

—Sarah Melton, PharmD electrodes are implanted to control electrical activity in more advanced Parkinson’s patients who are no longer responding to medications (Brain 2008;131[Pt 10]:2720-2728).

The Pharmacist’s Role

‘Depression in Parkinson’s disease, left untreated, can increase the physical manifestation of Parkinson’s and worsen [its] progression.’

—Talia Puzantian, PharmD questions, she stressed, so that patients who express those thoughts can be referred to a higher level of treatment.

Lawrence J. Cohen, PharmD, BCPP, a board-certified psychiatric pharmacist and a professor of pharmacotherapy at the University of North Texas System College of Pharmacy, in Fort Worth, said Williams’ progression from depression to suicide was tragic, but understandable.

“People get depressed pretty quickly,” he said. “Patients find out that they have Parkinson’s disease and as part of that, they have the behavioral depression that goes along with realizing that they’re not going to live forever and their movements might get in the way of being able to take care of themselves and be independent. You can imagine how it all starts to snowball.”

Link to Medications?

Williams’ suicide also has raised questions about whether the medications he may have been taking for PD or depression played a part in his death. Antidepressants have been associated with suicidality in a small group of patients during initial treatment, according to the FDA, which proposed in 2005 that new warnings on the association be included in the labeling for all antidepressant medications (http://1.usa. gov/1o0L1zI). Additionally, there have

‘A lot of providers are reluctant to ask the tough questions [such as] “Have you thought about hurting yourself?” or “Have you ever thought the world would be better off if you weren’t here?”’

and “concomitant suicidal tendencies” (http://bit.ly/1ARjzKn).

Although there is no sure way of knowing, a more likely scenario is that Williams’ suicide was probably the result of his documented, long-term battle with depression and perhaps the knowledge that PD would eventually destroy his immense comic gifts.

Talia Puzantian, PharmD, a boardcertified psychiatric pharmacist with a private practice in psychopharmacology consultation, agreed that Williams’ case, along with the suicides reported in adults taking antidepressants, begged the question, “was it the medication or the underlying disease that caused the suicides?”

“Often, years before any of the symptoms of Parkinson’s disease appear, patients may develop signs of depression,” Dr. Puzantian said. “Depression in Parkinson’s disease, left untreated, can increase the physical manifestation of Parkinson’s and worsen [its] progression.”

However, the research data “have not shown an association between anti-Parkinson’s medications and the development of depression or suicidality,” she stressed. “The only clinical evidence of any increase in suicidality with any treatment for Parkinson’s is with deepbrain stimulation,” a procedure in which

In addition to asking patients about suicide ideation, Dr. Melton said there are a handful of simple and effective tools available online to aid pharmacists and other care providers in questioning PD patients about suicidal thoughts. Dr. Melton said her clinic uses the Geriatric Depression Scale (http:// bit.ly/1mbweGI).

Dr. Cohen agreed that pharmacists at all practice levels, from inpatient care to community pharmacies, are well positioned to monitor PD patients and help manage their often complicated medication regimens. Being vigilant for potential adverse drug interactions is a particularly useful service that they can provide, he noted. For example, he said, medications for hypertension (e.g., methyldopa, reserpine), antidepressants (e.g., amitriptyline/nortriptyline), antipsychotics (e.g., chlorpromazine, thioridazine, risperidone), metoclopramide, phenytoin, papaverine, certain sedatives (e.g., benzodiazepines such as chlordiazepoxide/diazepam) and tryptophan can interact with a dopaminergic agent such as carbidopa-levodopa.

Many of these potential problems can be uncovered during medication reconciliation, Dr. Cohen suggested. Such efforts “should be performed any time there is a change in medication, level of care or location of care.” For patient safety, he added, “it is critically important to reconfirm all medications are medically necessary and are intended to be continued when patients move from one service in a hospital or healthsystem to another (e.g., ER to ICU or an inpatient room or back home).”

He pointed out, however, that “the assessment of somebody with uncontrolled Parkinson’s disease can be a pretty scary scenario. It can be hard to get accurate and reliable information from somebody with [pronounced symptoms.] So, you really need to know from caregivers and other people about how long a patient has had the symp-

toms” and about all of the medications they may be taking.

When a patient with PD also has a psychiatric disorder, that compounds the difficulty, Dr. Cohen stressed. “It is really complicated, because you’re balancing neurotransmitters in different ways. Most difficult would be a patient who has a psychotic disorder and parkinsonism, because basically you’re kicking up the level of dopamine with Parkinson’s treatments, and you’re bringing down dopamine at the receptor when patients are treated with antipsychotics. So in a way it’s in direct opposition.”

Non-pharmacologic Options Medications are not the only treatment options that work for depressed PD patients. At the Johnson City clinic, “we use a lot of cognitive behavioral therapy, which often is just as effective as using a medication,” Dr. Melton said.

“Parkinson’s patients can really benefit if they have a therapist who works with them on depressive symptoms and on changing the way they process the different thoughts they have, especially if they become suicidal.”

Patients who are referred to her clinic by a primary care provider, she said, can spend an hour with the therapist when they undergo “really tough cognitive therapy,” but she is available to collaborate when the therapist believes the patient needs a different medication.

The Johnson City facility is located in southern Appalachia, where patients are mostly uninsured or under-insured.

Many are also elderly and living on fixed incomes, so the primary care they receive at the clinic is crucial to maintaining their health. For some PD patients, free care from a neurologist may be available by referral through a program called “Project Access.” But there often is a long wait for the limited number of slots, Dr. Mellon said, so most of the care is provided at the clinic.

Dr. Cohen said this partial shift to primary care will likely continue, ideally with pharmacist involvement in patientcentered medical homes and other similar settings. But whatever the treatment setting, he stressed, “access to and compiling a comprehensive drug therapy history will be a key to success.”

—Bruce and Joan Buckley The sources reported no relevant financial conflicts of interest.

Product Name

Fast-Acting

Long-Lasting

Betamethasone Sodium Phosphate & Betamethasone Acetate* Injectable Suspension, USP

Kenalog g速 (Triamcinolone Acetonide) Injectable Suspension, USP 速 Depo-Medrol p

(Methylprednisolone Acetate Injectable Suspension, USP)

Recommended Doses for Intra-articular Injection Size of Joint

Location

Dose (mL)

Very Large Large Medium Small (metacarpophalangeal, interphalangeal, sternoclavicular)

Hip Knee, Ankle, Shoulder Elbow, Wrist Hand, Chest

1.0 - 2.0 1.0 0.5 - 1.0 0.25 - 0.5

A portion of the administered dose of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is absorbed systemically following intra-articular injection. In patients being trated concomitantly with oral or parenteral corticosteroids, especially those receiving large doses, the systemic absorption of the drug should be considered in determining intra-articular dosage. For additional dosing information please refer to package insert on our website at www.DualAgentBeta.com

Kenalog速 is a registered trademark of Bristol-Myers Squibb. Depo-Medrol速 is a registered trademark of Pfizer Inc.

*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, and ophthalmic. 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.

Please see next page for Brief Summary of Full Prescribing Information BB034 Rev. 7/2014

One Luitpold Drive - PO Box 9001 - Shirley, NY 11967 | 800-645-1706

www.DualAgentBeta.com

Betamethasone Sodium Phosphate and Betamethasone Acetate

Injectable Suspension, USP

6 mg per mL

Rx only DESCRIPTION Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP is a sterile aqueous suspension containing betamethasone 3 mg per milliliter as betamethasone sodium phosphate, and betamethasone acetate 3 mg per milliliter. Inactive ingredients per mL: dibasic sodium phosphate 7.1 mg; monobasic sodium phosphate 3.4 mg; edetate disodium 0.1 mg; and benzalkonium chloride 0.2 mg as a preservative. The pH is adjusted to between 6.8 and 7.2.

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

Policy 21

Pharmacy Practice News • October 2014

Medication Safety 14

BOXED WARNINGS

12

continued from page 1

10

of Pharmacy, University of California in San Francisco, she was given a simple task: to make a list.

“I was asked for a list of drugs with boxed warnings, and I thought, ‘Oh sure, no problem, this won’t take long.’ It has turned into a long pursuit,” said Dr. Cheng, who has written several papers, abstracts and reports about boxed warnings and their implications for medication safety in the United States.

Her most recent report found that more than one-third of recent drug approvals for novel therapeutics, which are new molecular or biologic entities that had never been marketed before in the United States, have at least one boxed warning implemented by the FDA at the time of approval or after the drug was marketed ((JAMA Intern Med 2014 Aug 15. [Epub ahead of print]).

Dr. Cheng and her colleagues examined 522 novel therapeutics (441 pharmacologic and 81 biologic) approved between 1996 and 2012 to determine the frequency of premarket (when approved) and postmarket boxed warnings, as well as safety-related withdrawals. They found that 180 had received a boxed warning and 11 products were withdrawn. Of those, 105 had received premarket warnings, 50 received postmarket warnings and 25 received a boxed warning pre- and postmarket.

The warnings were more common among biologic than pharmacologic drugs (31% vs. 22%; odds ratio, 2; 95% confidence interval, 1.2-3.3).

“About one-third were affected by a boxed warning,” said Dr. Cheng, now of the Disease Decision Support Group at First Databank, Inc., San Francisco.

“Most were implemented at the time of approval, but many got the first boxed warning or an additional boxed warning after the drug reached the market.”

8 6 4 2 0 1996

1998

2000

2002

2004

2008

2010

2012

2013

Figure. Number of postmarket boxed warnings issued to novel therapeutics, 1996-2013.

‘You are always going to find out more about a drug five years after it was on the market than when it was approved, just because of the sheer number of people prescribed the medication.’

—Matthew Grissinger, RPh, FASCP the data. “After 2004, there clearly was a burst of postmarket boxed warnings,” Dr. Cheng said. “We can’t pinpoint the exact reason for this increase, although we speculate that events occurring in 2004 contributed to it.”

The warnings appear to coincide with the highly publicized withdrawal in 2004 of Merck’s $2.5 billion blockbuster arthritis drug, Vioxx, due to its risk for heart attack and stroke, Dr. Cheng said. “It was also the year that the FDA laid out plans to strengthen safety surveillance,” she added. “It was a pivotal year for drug safety.”

Another recent paper also found an increase in boxed warnings and withdrawals among novel therapeutics ((Health Afff 2014;33:1453-1459). Although not proving causality, the researchers found that medications approved after passage of the 1992 Prescription Drug User Fee Act—legislation designed to accelerate the FDA’s new drug-approval

‘[Boxed warnings have] been around for decades, but given that there is no official repository for [them] .. they can be hard to keep track of and are even missed.’

—Christine M. Cheng, PharmD The median time from approval to first postmarket boxed warning or withdrawal was 4.2 years—2.3 years for drugs with premarket warnings and 4.9 years for drugs without the added risk warning.

The researchers used 1996 as a starting point because that was the year that safety-related notices and label changes were posted online to the website for MedWatch, the FDA’s safety and adverse event reporting program. This enabled the researchers to electronically gather

2006

process—were more likely to receive a boxed warning or be withdrawn from the market than drugs approved before the act was passed (26.7 vs. 21.2 per 100 drugs). “New drugs have a one-in-three chance of acquiring a new black box warning or being withdrawn for safety reasons within 25 years of approval.”

A Flawed Approval Process?

The problem could be with the nature of the approval process itself. It would be

near impossible to test a newly approved medication in every user under every circumstance for an extended period.

“Studies to get drugs approved can be limited,” explained Matthew Grissinger, RPh, FASCP, the director of error reporting programs at the Institute for Safe Medication Practices. “You are always going to find out more about a drug five years after it was on the market than when it was approved, just because of the sheer number of people prescribed the medication.”

The fact that more drugs have boxed warnings could be a reflection of a better reporting process and incoming data that allow the FDA to recognize risks earlier, he suggested. “In 1996, there was barely an Internet, so reporting was less instantaneous.”

Whether it’s a case of better reporting and recognition, flaws in the approval process, more high-risk products being brought to market or increased caution due to highly public withdrawals, boxed warnings are a fact of life in medicine today. However, with nearly 5,000 drug labels carrying a boxed warning, it can be difficult for prescribers to educate themselves about the boxed warning and prescribe accordingly.

Dr. Cheng performed another study that found that 35% or 4,940 of 14,264 drug labels listed on the National Library of Medicine DailyMed website contained at least one boxed warning (Therapeutic Innovation & Regulatory Science. Published online on July 26, 2013).

“I can speak from my experience in patient care, drug information and drug policy: Managing boxed warnings is challenging,” Dr. Cheng said. “[They’ve] been around for decades, but given that there is no official repository for these warnings, and [their] passive nature—present as part of the

drug label—they can be hard to keep track of and are even missed. Often, hospitals and clinicians are just looking at the high-profile ones.”

In fact, clinicians often are unaware a product has a boxed warning. “As a pharmacist, you have to be proactive, but it’s tough for me to remember to stop everything to look at the FDA’s website once a week [to find out about the label changes],” Mr. Grissinger said. “It is one thing for pharmacists to know, but what about the people writing the orders?”

He suggested that pharmacists sign up for email alerts from MedWatch, which will send notices about drug safety.

Safety information also is being integrated into electronic health records so that it is accessible to clinicians at the point of care, Dr. Cheng noted.

She added that she has helped develop a module for First Databank that integrates boxed warning information directly into the physician’s electronic workflow (http://bit.ly/1BNlHFs).

Once a pharmacist knows about a safety issue with any product, there is an immediate need to communicate that risk to the rest of the hospital, Mr. Grissinger said. “Discussion on boxed warnings should be a regular part of P&T committee meetings.”

—Marie Rosenthal Martin Leung contributed to this story.

Mr. Grissinger reported no relevant financial conflicts of interest.

Boxed Warnings

A

boxed warning usually highlights one of the following situations: • A life-threatening or permanently disabling adverse reaction that thus needs to be factored into weighing the risks and benefits of using the drug • A serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug • The FDA approved the drug with restrictions to ensure safe use because the agency concluded that the drug can be safely used only if distribution or use is restricted.

Infrequently, a boxed warning also can be used to highlight warning information that is especially important to the prescriber (e.g., reduced effectiveness in certain patient populations). Information included in the Warnings and Precautions and Contraindications sections should therefore be evaluated to determine whether it warrants inclusion in a boxed warning.

Source: FDA

22 Policy

Pharmacy Practice News • October 2014

FDA Watch by Marie Rosenthal

Keytruda Approved for Advanced Melanoma

T

he FDA granted accelerated approval to pembrolizumab (Keytruda, Merck) for the treatment of patients with advanced or unresectable melanoma who are no longer responding to other therapies.

Pembrolizumab is the first approved drug that blocks a cellular pathway known as PD-1, which restricts the body’s immune system from attacking melanoma cells. Pembrolizumab is intended for use following treatment with ipilimumab (Yervoy, Bristol-Myers Squibb), an immune therapy, and a BRAF inhibitor, a therapy that blocks activity of BRAF F gene mutations.

The FDA granted pembrolizumab breakthrough therapy designation because Merck demonstrated that the drug may offer a substantial improvement over available therapies. It also received priority review and orphan product designation.

The drug’s efficacy was established in 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with pembrolizumab, either at the recommended dose of 2 mg/kg or at a higher dose of 10 mg/kg. In the half of the participants who received pembrolizumab at the recommended dose of 2 mg/kg, about 24% saw their tumors shrink. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients. A similar percentage of patients saw their tumor shrink at the 10 mg/kg dose.

Pembrolizumab’s safety was established in a trial of 411 participants with advanced melanoma. The most common side effects reported were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia and diarrhea.

Although rare, the drug was also linked to severe immune-mediated side effects.

Promacta Gains New Indication for Severe Aplastic Anemia

T

he FDA approved a supplemental New Drug Application for once-daily eltrombopag (Promacta, GlaxoSmithKline) for patients with severe aplastic anemia (SAA), who have experienced an insufficient response to immunosuppressive therapy (IST).

Eltrombopag gained breakthrough therapy designation status from the FDA in January 2014 and priority review in April 2014. This new indication was based on results from an investigator-sponsored Phase II study conducted by the National Heart, Lung, and Blood Institute.

In the single-arm, single-center,

open-label Phase II study, eltrombopag was evaluated in 43 patients with SAA who had had an insufficient response to at least one prior IST and who had a platelet count of 9/L. The median age of the treated population was 45 years and 56% were male.

Eltrombopag was given at an initial dose of 50 mg per day and increased to a maximum dose of 150 mg per day.

The study demonstrated a hematologic response in treated patients: • 40% (95% confidence interval) of patients (17) experienced a hematologic response in at least one lineage— platelets, red blood cell, or absolute neutrophil count (ANC)—after week 12.

• 91% were platelet transfusion–dependent at baseline; the platelet transfusion–free period in responders ranged from eight to 1,096 days.

• 86% were RBC transfusion–dependent at baseline; the RBC transfusion–free period in responders ranged from 15 to 1,082 days.

In an extension phase, eight of the 17 patients with a hematologic response achieved a multi-lineage response. Four patients subsequently tapered off treatment and maintained the response (median follow-up, 8.1 months).

The most common adverse reactions during the trial were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%) and headache (21%).

In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight had a new abnormality. If new cytogenetic abnormalities are observed, consider discontinuing eltrombopag, according to a company press release.

FDA Approves New HIV Drug

T

he FDA approved a new oral triple combination therapy for the treatment of HIV. Triumeq (abacavir/dolutegravir/lamivudine) is ViiV Healthcare’s first dolutegravir-based fixeddose combination, offering many people living with HIV the option of a single-pill regimen that combines the integrase strand transfer inhibitor (INSTI) dolutegravir, with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine.

The approval was based primarily on data from two clinical trials: the Phase III study (SINGLE) of treatmentnaive adults, conducted with dolutegravir and abacavir/ lamivudine as separate pills and a bioequivalence study of the fixed-dose combination of abacavir, dolutegravir and lamivudine when taken as a single pill compared with the administration of dolutegravir and abacavir/lamivudine as separate pills.

In the SINGLE study, a non-inferiority trial with a prespecified superiority analysis, more patients were undetectable (HIV-1 RNA <50 copies/mL) in the dolutegravir and abacavir/lamivudine arm than in the efavirenz/emtricitabine/tenofovir (Atripla, Bristol-Myers Squibb and Gilead) arm. The difference was statistically significant and was driven by a higher rate of discontinuation due to adverse events in the Atripla arm.

At 96 weeks, 80% of participants on the

dolutegravir-based regimen were virologically suppressed compared with 72% of participants on Atripla.

Reported adverse reactions included insomnia, headache and fatigue.

Triumeq alone is not recommended for patients with a history of resistance to any of its components, resistanceassociated integrase substitutions or clinically suspected INSTI resistance because the dose of dolutegravir in Triumeq is insufficient in these populations.

Before initiating treatment with abacavir-containing products, screening for the genetic marker, the HLAB*5701 allele, should be performed in any HIV-positive patient, regardless of racial origin. Products containing abacavir should not be used in patients known to carry the HLA-B*5701 allele.

Triumeq will have a boxed warning concerning the risk for hypersensitivity reactions, lactic acidosis and severe hepatomegaly and exacerbations of hepatitis B. Patients with underlying hepatitis B or C virus may be at increased risk for worsening or development of various hepatic symptoms.

Vimpat Granted New Indication For Partial-Onset Seizures

T

he FDA recently approved a supplemental New Drug Application for lacosamide C-V (Vimpat, UCB) as monotherapy in the treatment of partial-onset seizures in epilepsy patients aged 17 years and older. The FDA also approved a new single-loading dose administration option for all formulations of the drug.

Lacosamide currently is indicated in the United States as adjunctive treatment for partial-onset seizures in patients in this age group.

The new monotherapy approval for lacosamide is based on a Phase III study, which was a historical control, multicenter, randomized study that evaluated the efficacy and safety of conversion to lacosamide 400 mg per day monotherapy in adult epilepsy patients with partial-onset seizures. The study enrolled 425 patients, ages 16 to 70 years, on stable doses of one or two antiepileptic drugs and experiencing two to 40 partial-onset seizures per 28 days during the eight-week prospective baseline period.

Patients were randomized to lacosamide 400 or 300 mg per day (3:1 ratio), starting at 200 mg per day (100 mg per day twice daily) and titrated over three weeks (100 mg per day each week) to the randomized dose. Patients then entered the 16-week lacosamide maintenance phase, which included a six-week background antiepileptic drug withdrawal phase and a 10-week lacosamide monotherapy phase. Patients were evaluated from the first day of tapering of the background antiseizure drug and required to discontinue the study if they experienced any of the predefined exit events defined by an increase in seizure frequency, duration or severity.

The primary efficacy assessment was the percentage of patients receiving lacosamide 400 mg per day who met one or more of the predefined exit criteria by day 112 (end of lacosamide maintenance phase) compared with the historical control. The historical control consisted of a pooled analysis of the control groups from eight studies of similar design, which used a subtherapeutic dose of an antiepileptic drug as a control. For the lacosamide 400 mg per day group, the estimated percentage of patients meeting at least one exit criterion by day 112 was 30% (95% confidence interval [CI], 24.6%-35.5%).

The upper limit of the two-sided 95% CI (35.5%) was below the threshold of 65.3% derived from the historical control data, meeting the prespecified criteria for efficacy.

The most common reported adverse event that led to discontinuation of lacosamide was dizziness.

The new single-loading dose option allows the initiation of lacosamide as a single-loading dose of 200 mg (oral or injection), followed approximately 12 hours later by a 100 mg twice-daily dose (200 mg per day).

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09/14

24 Operations & Management

Pharmacy Practice News • October 2014

Leadership in Action

Is Connectivity Causing a ‘Poverty of Attention’?

Y

ou are a busy pharmacy manager. Multitasking is the only way to accomplish the many tasks at hand. You balance several projects at once. The balls are in play and heaven forbid you drop one. That could mean your job, your reputation and your future. So you work more hours in the day. You’ve got your smartphone on your belt, in your pocket or purse; your tablet in your hand or case until you get back to the office to glue yourself to your computer.

You’re always connected. And I’m only talking about your work life. Then there are the family obligations: the kids’ sports games, piano lessons and the PTA. You feel like a bus driver sometimes, going to this game and that. While at the game you’re still connected; your smartphone in hand allows you to do a few things while you’re at the game or the recital or whatever your children’s activity is today. Not surprisingly, your child wants his or her own smartphone.

What are the pros and cons of that? No time to think it through; your weekends are a blur. And now it’s Monday again and back to the barrage of emails, phone calls and calendars. Whew, I’m tired even thinking about it all. How about you? Familiar? Can you relate?

In 1977, Nobel Prize–winning economist Herbert Simon, writing about the coming flood of information at our fingertips, warned that information consumes “the attention of its recipients. Hence, a wealth of information creates a poverty of attention.” Daniel Goleman, the best-selling author of “Emotional Intelligence,” recently penned a new book, “Focus, The Hidden Driver of Excellence” (HarperCollins 2013) that mines many similar themes. Over the next several months, we will examine the principles of focus in emotional intelligence as they apply to our “attention” and our leadership in pharmacy. We will look at our brain function, brain development (neuroplasticity) and the application of these vital mechanics of our mental life.

Why bother? Partly because there is a connection between our attention and excellence in performance. And this is not mere speculation: Researchers, using magnetic resonance imaging and other sophisticated brain scans, have documented the firing of neurons in certain locations in our brains, and have associated that brain activity with our feelings and actions.

As for which of those feelings and actions are most relevant to effective pharmacy leadership, I suggest reading Goleman’s “Emotional Intelligence” or “Working with Emotional Intelligence.”

According to Goleman, we need to focus on three aspects in every area of our

“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

Paying more attention to truly important events in your life can be learned; the more you exercise such focus, the more it becomes a habit. lives: our inner self, our relationship to others and our outer focus. Inner focus puts us in synch with our intuitions and guiding principles, enabling better decisions. Focus on others is fundamental to connecting with people. Our outer focus puts everything into perspective based on the world in which we live. Attention to these areas can be learned; the more you exercise your focus, the more it becomes a habit of your life.

The Connectivity Conundrum Now, what about the question of the proper use of a cell phone, email and other personal communications? And at what age should a child have a smartphone? I recently listened to a podcast by Daniel Friedland, MD, of “Super Smart Health” ((www.supersmarthealth. com) m and learned, among many other valuable insights, about “mirror neurons.” These neurons allow you to sense the atmosphere in a room of people or the countenance of the person with whom you are going to have an interaction before any words are spoken. For example, we’ve all sensed that sickening tension in the air when something bad is about to happen. We have learned these intuitions through our past interactions, where you sense the other person’s mirror neurons. Adults or children who only interact with their electronic devices and communicate via text messages, Facebook, tweets and emails fail to develop these mirror neurons. Take a look around the restaurant the next time you’re dining out and look at the interactions of the patrons. How many

people are glued to their smartphones and not interacting with their friends or relatives at the table? Can you resist the urge to check your phone when it signals that a text or email just came in? When we do, we tell the people we are with that they are “not as important as this electronic communication.” Our focus continually fights distractions, both inner and outer. As pharmacists, we know the medications for attentiondeficit hyperactivity disorder are growing rapidly. Are we just not training our minds to focus?

The Basics of Focus Next time you are at a social gathering, look around the room and pick out the people who demonstrate focus.

These are the people in conversation with another individual, eye contact intact, nodding in agreement, responding when appropriate. Contrast that with individuals in a conversation with another person, but their eyes wander, they check out other activities in the room and they feign listening. These individuals probably do not comprehend what is being said to them.

I have a successful friend in the business world who demonstrates focus. He knows everyone’s name, it seems. He can pick up on a conversation he had with someone a year ago, asking how that new venture is going, stating that he wants to get an update since the last time the two had talked. He focuses on the person at hand, and then moves on to the next person repeating that habit of focus. He is highly respected and

everyone knows him because he has made it a point to focus.

We can train our minds to focus and learn the task at hand. To do so, we often have to tune out distractions and maintain our concentration. I watch successful athletes who have learned to focus. They tune out the roar of the crowd and focus on the next pitch, or the next pass to a teammate. Even as I write this article, I am practicing tuning out the sensory distractions around me, concentrating on my task and not allowing my mind to wander. This engages the prefrontal cortex of my brain where high-level thinking occurs.

Are You in the Flow?

You may have heard someone being described as being “in the flow.” We visualize this person as fortunate to be doing what they love. They are energetic, consumed, positive, successful, devoting full attention to their work with a sense of great purpose. Contrast that with the person who is underperforming, doing just enough to get by, surfing the Web, bored out of their minds and disengaged. Now there is a third place where I find too many pharmacy leaders living.

These are the ones whom I described at the beginning of this article. The pharmacy leaders who are frazzled, overburdened, shooting from one thing to another. These people have an adrenalin overload, constant worry besieges them and they are on the road to emotional burnout. We sometimes describe this as “going limbic.” The solution? As Daniel Goleman says: “Full focus is the potential doorway to flow.”

Take Time To Reflect Do you ever take the time to think and reflect without interruption? Often, this is creative problem-solving time. There also are occasions when you come up with a solution to a problem that you had given up on that you were not really concentrating on. It could come to you lying on a beach or in the shower.

As Goleman stated: “Creative insights flowed best when people had clear goals but also had the freedom in how they reached them. And, most crucial, they had protected time—enough to really think freely.” How about you?

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26 Operations & Management

Pharmacy Practice News • October 2014

Ambulatory Care

Rx AUTHORITY continued from page 1

was being used inappropriately, but also to start one and to switch drug classes between a proton pump inhibitor (PPI) and a histamine-2 receptor antagonist (H2RA), said Mitchell Buckley, PharmD, the project leader and clinical pharmacy specialist at Banner Good Samaritan Medical Center.

“If we didn’t have the prescriptive authority, I think this program probably would have failed,” Dr. Buckley told Pharmacy Practice News. The alternative—tracking down physicians to get their approval of a suggested change in treatment—“would have been much more time-consuming,” he said.

During the first few weeks of the program, the pharmacists were a little nervous when adjusting to their new prescriptive autonomy, Dr. Buckley noted.

“Once they felt comfortable that they weren’t getting [pushback] from the physicians, it became more streamlined.”

A Link to C. difficile Concerns about unnecessary use of SUP have been increasing in recent years, as some of the drugs included in the acid-suppression regimens have been associated with various risks, including pneumonia or infections caused by Clostridium difficile. In early 2013, as part of five recommendations submitted by the Society of Hospital Medicine to the American Board of Internal Medicine Foundation’s “Choosing Wisely” initiative, the professional society advised against prescribing the drugs as a prophylaxis measure in non-ICU patients who are not at high risk for gastrointestinal complications.

Even though changing prescribing practices has been difficult, the payoffs are twofold—both better patient care and potential cost savings, according to Robert MacLaren, PharmD, a professor in the Department of Clinical Pharmacy at the University of Colorado Scaggs School of Pharmacy, in Aurora. The drugs themselves aren’t costly, but the potential risks are, he said. “If you stop one adverse event like an infection downstream, you have paid for approximately half a pharmacist’s time for the year.”

Prescriptive Autonomy The initial rates of inappropriate SUP identified at Banner Good Samaritan are pretty typical, said Dr. MacLaren, who helped author a 2014 study published online July 2 in the Journal of Critical Care (10.1016/j.jcrc.2014.06.025), documenting frequent, poorly considered SUP in ICU patients. That analysis, which looked at prophylaxis use in 584 patients from 58 ICUs, identified inappropriate administration in 22% of patients. The rate was even high-

‘If you stop one adverse event [from SUP drugs] like an infection downstream, you have paid for approximately half a pharmacist’s time for the year.’

—Robert MacLaren, PharmD er, 32%, when researchers excluded patients already on the drugs before hospitalization. Broken down by risk group, the drugs were appropriately used in 92% of high-risk patients and 71% of low-risk patients.

Dr. MacLaren cited a mixed bag of contributing factors, with a need for ongoing education. “Not all patients admitted to intensive care units are critically ill to the point that they require [SUP],” he said.

The patient might have been admitted in the middle of the night by doctors still in training, who selected prophylaxis as part of an order set, he explained. Alternately, the patient might have been taking the medications at home, and it was unclear why. So clinicians decided “better safe than sorry—we continue these agents.”

At Banner Good Samaritan, clinicians knew that they prescribed the acid-suppressive medications “pretty liberally,” Dr. Buckley said. “We all acknowledged and recognized that it was something we needed to tackle, and that the problem was pretty much hospital-wide; it wasn’t just any one patient population.”

As he discussed the problem and related strategies with the medical center’s intensivists and pharmacy leadership, Dr. Buckley said he encountered little resistance. Particularly key, he noted, was the support of the chief medical officer, who helped navigate various committees to provide pharmacists prescriptive authority. Beginning in 2011, the hospital’s pharmacists assumed their new role. Risk factors for prescribing the drugs appropriately included coagulopathy, solid organ transplant or use of mechanical ventilation.

In a separate, retrospective analysis involving non-ICU patients, the medical center also tracked similar reductions before and after the pharmacist-managed program. Pre- and post-program analyses reported that the mean duration of acid-suppression therapy decreased from 4.4 to 2.1 days ( <0.001). The rate of patients inappro(P priately continued on prophylaxis after discharge declined from 36.2% to 5.4%, respectively ((P<0.001).

The program’s approach and results proved to be “very powerful,” said Henry Cohen, PharmD, FCCM, a professor of pharmacy practice at Long Island University and chief pharmacotherapy officer at Kingsbrook Jewish Medical Center, in New York City. “By giving the pharmacist the collaborative drug therapy agreement, the approval to make these changes, it eliminates

the delay in calling prescribers and persuading them to discontinue therapy if it were not needed or to switch therapies,” Dr. Cohen said. “Sometimes the delays could be a day or two.”

In particular, Dr. Cohen cited the notable reduction—from 29.9% to 3.6%— among ICU patients who were no longer being sent home inappropriately on prophylaxis. “I think that speaks volumes,” he said. “Because that means that one out of every three of those patients were going home on these medications that they didn’t need.”

“They end up back home and keep on filling the prescription,” he said. That prolonged use, Dr. Cohen noted, could then boost the individual’s risk for a hip fracture or developing community-acquired pneumonia. (In 2010, FDA officials issued a safety warning based on epidemiological data that taking prescription PPIs for more than a year could potentially increase the risk for hip, spine and wrist fractures, although they noted that thde precise mechanism is unclear.)

New Guidelines on the Way Dr. Cohen chairs the American College of Critical Care Medicine’s Gastrointestinal Task Force for Stress Ulcer Prophylaxis, which will soon publish new guidelines in Critical Care Medicine, likely by late 2014, he said. The guidelines, which were developed with input from the American Society of Health-System Pharmacists, will include an algorithm regarding when SUP drugs should be used, guidance on pharmacotherapy and assistance for clinicians as they reevaluate that prescribing decision on an ongoing basis, Dr. Cohen said.

Dr. Cohen declined to detail much else about the guidelines before their publication. (The existing guidelines were published in 1999; Am J Health Syst Pharm 56:347-379.) But speaking more broadly, he echoed Dr. MacLaren’s concerns that today’s clinicians should move away from increasing reliance on PPIs, given their association with C. difficile infection and pneumonia.

“We’ve learned that they are not as safe as one would think,” Dr. Cohen said.

“They cause such a prolonged and profound and sustained effect on the acid suppression in the gut.”

In the recent Journal of Critical Care study, PPIs were by far the most common drug class prescribed for SUP, with 70% of patients taking one of the agents in this

drug class. Another recent study that Dr. MacLaren coauthored found higher rates of gastrointestinal hemorrhage, pneumonia and C. difficile in mechanically ventilated patients prescribed a PPI versus a H2RA ((JAMA Intern Med d 2014;174;564574). The odds ratios of GI hemorrhage (2.24), pneumonia (1.2) and C. difficile (1.29) were greater with PPIs.

Shifting Away From PPIs Another benefit of prescriptive authority is that it enabled Banner Good Samaritan pharmacists to achieve a substantial reduction in their hospital’s use of PPIs, Dr. Buckley said. “We found that PPIs were our go-to drug before the program” for ICU patients who met risk factor criteria, he said. Indeed, prior to the program, 82.4% of all patient-days involved the prescribing of a PPI, compared with 10.9% after the program was implemented. (The researchers said they focused their analysis on patient-days, as each admission might include a mix of days with appropriate and inappropriate prophylaxis use.)

The medical center didn’t need to add more staff to make the program work, researchers said. But providing the pharmacists autonomy for making the medication changes likely reduced the time they would have used reaching the doctor for approval, said Sandra KaneGill, PharmD, an associate professor at the University of Pittsburgh School of Pharmacy and another researcher on the project. The autonomy also may have freed up some time on the doctor’s part, she said.

The analysis did not detect a statistically significant difference in outcomes studied, including GI bleeds, pneumonia, C. difficile and thrombocytopenia.

However, given that those events aren’t common, the sample size may not have been large enough for an effect to be seen, Dr. Buckley said.

The pharmacist-managed approach, which the researchers said could be replicated at other institutions, is already being expanded at Banner Health, which operates 25 hospitals in seven states. As of early fall, Dr. Buckley noted, at least one hospital in the large nonprofit system was implementing a similar program, and others were considering such an initiative.

—Charlotte Huff The sources had no relevant financial conflicts of interest to disclose.

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