The September 2012 Digital Edition of Pharmacy Practice News by McMahon Group

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in this issue UP FRONT

Low-dose steroid option approved for asthma, COPD, RA and other conditions.

POLICY

Drug-tracking registry targets diversion, helps monitor recalls. FDA rejects Congressional claims that it’s to blame for drug shortage crisis.

CLINICAL

13 14

Study supports tadalafil use in pediatric pulmonary arterial hypertension. Tips for dealing with fallout from negative interferon/ MS trial.

OPERATIONS & MGMT

Ernie Anderson Jr.: conflict management starts at the top.

EDUCATIONAL REVIEW

Evolving Treatment Paradigms in Non-Small Cell Lung Cancer Visit pharmacy practicenews.com

Volume 39 • Number 9 • September 2012

40th ANNIVERSARY YEAR 1972–2012

Med Management Standards From JC Still a Challenge

Automation Shines Light On ‘Black Hole’ of OR Drugs

Bedside drug carts speed access, reduce diversion risk

ear after year, the same medication management standards head the list for noncompliance during Joint Commission surveys. “The top [medication management-related] standards for noncompliance haven’t changed in 10 years,” according to Darryl S. Rich, PharmD, MBA, FASHP. “Organizations continue to struggle with medication security, medication orders and pharmacist review of orders.” In a recent online seminar, Dr. Rich reviewed the most problematic medication management standards, as well as new requirements, current interpretations of key standards and strategies to increase compliance. At the time of his presentation, Dr. Rich was a Joint Commission surveyor, but he has since joined the Institute for Safe Medication Practices, in Horsham, Pa., as a medication safety specialist. According to Dr. Rich, the standards that ranked highest for noncompliance include medication storage (33%

•

see JC UPDATE, page 9

Fidaxomicin Slows Cancer-Related C. difficile Diarrhea High cost remains a barrier London—For cancer patients with Clostridium difficile–associated diarrhea (CDAD)—a common and troublesome complication—fidaxomicin is more effective than standard vancomycin therapy at producing a clinical cure and keeping patients symptom-free over a sustained period of time, according to a presentation at the European Congress of Clinical

•

Baltimore—Ask pharmacy directors to cite a major safety or regulatory concern, and lack of control over medications used in the operating room will be on nearly everyone’s short list, according to Stephen L. Speth, RPh, the pharmacy manager at Indiana University Health Bloomington Hospital (IUHB), in Bloomington. “For quite some time, this was a black hole for us,” Mr. Speth said. “I felt we had decent control of pharmaceuticals, but you never really know what goes on behind closed doors when there is no real-time information on medication use and little to no pharmacist oversight.” That all began to change in March 2011, when IUHB placed automated anesthesia dispensing carts (ADCs) in its 14 ORs. By 2012, the strategy had achieved major gains in several medication management outcomes, including a 90% decrease in controlled substance discrepancies and a more than 50% reduction in the time needed for cart restocking, Mr. Speth reported in a poster (41-T) at the 2012 Summer

see FIDAXOMICIN, page 16

see BLACK HOLE, page 18

Pharmacist Interventions Fall Short In Avoiding Heart-Patient Med Errors

ntervention by pharmacists, in ncluding efforts to help patients wh ho have low health literacy, did no ot significantly reduce a high ratte of clinically important medi-cation errors and preventable adverse drug events (ADEs) in a randomized controlled trial of cardiac patients. Of these patients, 50% had a significant medication error within one month after dis-charge from the hospital, accord ding to the study, published in the

Annals oof Internal Medicine (2012;157:110). In a small but troubling percentage of paatients, the missed errors were severre enough to result in trips to the emeergency room. The error rate did not decline T siignificantly with efforts by pharmacists to ensure prescribing m aaccuracy, educate patients during hospitalization and at discharge, h and follow up by phone with patients at home. The study was conducted at

•

The Book Page Best Practices for Hospital and Health-System Pharmacy 2011-2012

see INTERVENTIONS page 20

New Product

American Society of Health-System Pharmacists

Teva Health Systems introduces Methotrexate Injection, USP.

See page 21.

See page 14.

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Pharmacy Practice News • September 2012

Capsules

surf

SEPTEMBER 2012

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Smart Pumps Get Better Grades After QI Initiative. 2. Building a Better CPOE System Via MEDMARX Data. 3. Adding Bar Codes to IV Rooms Offers Multiple Benefits. 4. Tales of Success in Boosting HCAHPS Scores. 5. Carfilzomib Gets Approved for Multiple Myeloma: Practice Changer? Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘You’re not going to stop

all errors [by mandating patient education on highalert drugs], but I’ll bet you would cut into them dramatically.’ -Michael R. Cohen, RPh, MS

See article, page 20

Rayos Approved for Rheumatoid Arthritis, Other Indications he FDA has approved Rayos, a delayed-release formulation of low-dose prednisone (Horizon Pharma), to treat rheumatoid arthritis (RA) and other diseases and conditions, including polymyalgia rheumatica, psoriatic arthritis, chronic obstructive pulmonary disease and asthma. Rayos is available in 1, 2 and 5-mg tablets. Known as Lodotra in Europe, Rayos has a four-hour time lag in its pharmacokinetic profile compared with immediate-release prednisone formulations, according to a company press release. “Rayos, as studied in its clinical trials with 10 p.m. dosing, reduces the overnight rise of inflammatory mediators, which results in less pain and stiffness for patients as they begin their day,” Michael Schiff, MD, a clinical professor of medicine in the Division of Rheumatology at the University of Colorado School of Medicine, in Aurora, stated in the press release. The effectiveness of Rayos was assessed in the CAPRA-2 (Circadian Administration of Prednisone in Rheumatoid Arthritis) trial, a 12-week, randomized controlled study in patients with active RA (N=350). The patients had been receiving nonbiologic disease-modifying antirheumatic drug (DMARD) therapy for at least six months, with an incomplete response. Patients were randomized to Rayos 5 mg (n=231) or placebo (n=119) administered at 10 p.m. in addition to DMARD therapy. Patients treated with Rayos showed significant improvement in the primary end point of American College of Rheumatology 20 response criteria compared with the placebo group (47% vs. 29%; P=0.001). As a secondary end point, the investigators measured the relative change from baseline in duration of morning stiffness at 12 weeks. The Rayos group had a median decrease in duration of morning stiffness of 55 minutes compared with 33 minutes for placebo (P=0.001). According to the Rayos prescribing information, common adverse reactions for corticosteroids such as Rayos in clinical trials include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes and increased appetite and weight gain. —George Ochoa

CORRECTIONS An article in the August issue (page 1) about mushroom toxicity carried an inaccurate photo. The image should have depicted a mushroom containing amatoxin, such as Amanita phalloides (shown on right). The mushroom depicted in the article was Amanita muscaria, which does not contain the toxin.

An article in the August issue (page 1) incorrectly identified the owner of MEDMARX as the United States Pharmacopeia (USP). In 2008, USP transferred rights and ownership of MEDMARX to Quantros.

EDITORIAL BOARD

ART/PRODUCTION STAFF

ADMINISTRATION

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

Frank Tagarello, Senior Art Director/Managing / Director, r MAX Graphics

Ernest R. Anderson Jr., MS, RPh, Boston, MA

Volume 39 • Number 9 • September 2012 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

INTERNAL MEDICINE

EDITORIAL STAFF

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NUCLEAR PHARMACY

BIOTECHNOLOGY Jeffrey Norenberg, PharmD, Albuquerque, NM

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Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

CARDIOLOGY

ONCOLOGY

C. Michael White, PharmD, Storrs, s CT

Robert T. Dorr, PhD, RPh, Tucson, AZ

Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Contributing Editors

CNS/PSYCHIATRY

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James Prudden, Group Editorial Director

Charles F. Caley, PharmD, Storrs, CT

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Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA Larry Ereshefsky, PharmD, San Antonio, TX COMPLEMENTARY AND ALTERNATIVE MEDICINE

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Cathy Rosenbaum, PharmD, Cincinnati, OH CRITICAL CARE

PEDIATRICS

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THERE’S JUST NO SUBSTITUTE

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Pharmacy Practice News • September 2012

Supply Chain

Drug Tracking Registry Offers Safety, Beneﬁts A

new global drug safety registry launched this summer will elevate “track-and-trace” capabilities over radiofrequency identification (RFID) and bar coding in several ways, according to its developers Leavitt Partners and Park City Group. The registry, named ReposiTrak, is designed to pinpoint exact locations of every batch of pharmaceutical products in the supply-chain pipeline, from manufacturers to pharmacies. This would bring three practical benefits to hospital, specialty and retail pharmacies and their prescription drug suppliers. First, it could expedite recalls by reducing tracking times from weeks to minutes, so affected products could be identified quickly and removed from distribution. Already, dozens of pharmaceutical and over-the-counter drug manufacturers have listed their products in the registry. Second, the registry could “help mitigate” critical drug shortages—which multiplied from 61 in 2005 to more than 250 in 2011, according to FDA figures—by “giving a virtual view of where product is anywhere in the U.S.,” Kristina Lunner, a senior adviser to Leavitt Partners, told Pharmacy Practice News. Third, ReposiTrak could make it tougher to push counterfeit medications through the supply chain because “it has the capacity to examine inventories and know when irregularities come into the system,” noted Rich McKeown, president and CEO of Leavitt Partners, who served as chief of staff to former Health and Human Services Secretary Michael O. Leavitt, the firm’s founder. “The ability to help manage all these areas of need is a major step forward,” said Mr. McKeown. Global counterfeit drug sales were estimated to be a $75 billion problem in 2010, up 92% from 2005, according to the Center for Medicines in the Public Interest. At press time, Mr. McKeown said that pilot trials under way indicate that the registry will monitor the supply chain efficiently, effectively and economically, using the following features: • The ability to create an e-pedigree with complete backward and forward visibility; this includes foreign imports entered into the system by manufacturers (when permitted by FDA to help alleviate a shortage). FDA defines pedigree as “a statement of origin that identifies each prior sale, purchase or trade of a drug, including the date of those transactions and the names and addresses of all parties to them.” • ReposiTrak’s Universal Translator—a key simplifier for users of the registry, especially pharmacies dealing with multiple sources. “Think of it as the

United Nations,” Ms. Lunner said. It has standard identifiers for products and synchronizes information technology communications for all parties in the pipeline, regardless of the language or technology used. It accepts data in any format. • The ability to function with specialty, hospital and retail pharmacies’ existing technology. By contrast, RFID and bar coding could potentially require hardware. • No start-up or connect fees for pharmacies, just a $10 monthly maintenance fee. Pharmaceutical tracking is a sister application to food tracking by the registry. Both build on the viaLink technology used to synchronize retailers with suppliers. Supply chain participants register products with the ReposiTrak engine at every point in the shipping process; ReposiTrak can validate each lot as it is received into a location. Valid lots are certified, security signed and authorized. The registry also compares distributed quantities with quantities received by lot number, and issues alerts when information doesn’t match, is missing or isn’t authenticated. The initial implementations of the registry include a global grocery retailer that operates 1,500 pharmacies and a major grocery wholesaler that distributes pharmaceuticals to more than 1,000 pharmacies. “The initial response to ReposiTrak

from retailers, suppliers, wholesalers and other participants in the global food and drug supply chain has been very encouraging. The solution offers an easyto-implement and cost-effective way to address very real safety problems,” said Randall K. Fields, chairman and CEO of Park City Group. “In very short order, we have progressed to the point of implementation with our first customers and have several more in the pipeline.”

A ‘Simple, Comprehensive’ Tool Commenting on the ReposiTrak system, Bruce Kneeland, a pharmacy industry consultant based in Royersford, Pa., said that based on the information from Leavitt, it appears that they “have created a way to accomplish what has eluded the industry for years—a simple, comprehensive and practical way to keep track of pharmaceuticals from the [active pharmaceutical ingredient] stage to the will-call bin of the pharmacy.” Mr. Kneeland predicted, “If the system finds traction … it could help immensely in preventing drug diversion and simplifying the drug recall process.” However, he added, “good technology is not always the answer. Too often we find that political issues affect the market. It is all too rare for the best technology to win over those that have the connections.” A year-and-a-half in development, the registry will arrive on the market as Congress discusses two bills to reau-

20 No legislation or regulations Enacted legislation; rules pending

thorize the Prescription Drug User Fee Act. At press time, the House and Senate were in negotiations about how to reconcile their respective approaches (Senate bill S.3187 and House bill H.R. 5651) to requiring tighter tracking of the drug pipeline and notifications by manufacturers of potential drug shortages, said Ms. Lunner, a former vice president of government affairs for the American Pharmacists Association. “With so much FDA funding tied to the legislation, most consider this a mustpass piece of legislation. Add industry support of the bill [to] … bipartisan Congressional support, and it’s very likely the bill will pass,” she predicted. “Assuming the final bill includes a national standard, it would be beneficial because stakeholders feel the patchwork of state regulations [presents] an operational challenge,” according to Ms. Lunner. “FDA and Congress have tried before to establish track-and-trace and pedigree requirements but faced various barriers to implementation.” According to the Healthcare Distribution Management Association, 20 states had no pedigree legislation or regulation, whereas 18 had adopted final rules as of June 2012 (Figure). Moreover, two states had proposed legislation, eight had enacted it, and another two had enacted it and were developing final rules. —Al Heller

Proposed legislation

Enacted legislation

Final rules adopted

Legislation vetoed

Rules pending; no legislation

WA ME ND

MT OR

MN ID

UT CA

OH WV

KY TN

CT NJ

AR MS

MA RI

NC AZ

NH VT

DE MD

AK FL

Figure. Distributor licensing and pedigree requirements by state.a a

Current as of June 21, 2012.

Source: Healthcare Distribution Management Association.

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Pharmacy Practice News • September 2012

FDA Watch

How Strong Is Azithromycin Link to Cardiovascular Deaths?

zithromycin was associated with a small absolute increase in the risk for cardiovascular death that was most pronounced in patients with a high baseline risk for cardiovascular disease, according to a study by Tennessee researchers. The study’s findings were sufficiently striking to draw the attention of the FDA, which announced that it was reviewing the results. The retrospective cohort study included persons enrolled in the Tennessee Medicaid program who had been prescribed azithromycin between 1992 and 2006 (347,795 prescriptions); the control group included patients who received no study antibiotics (1,391,180 control periods) or took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions) or levofloxacin (193,906 prescriptions) during the same period (N Engl J Med 2012;366:1881-1889). Compared with patients who took no antibiotics, those who took azithromycin had an increased risk for cardiovascular death (hazard ratio [HR], 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (HR, 1.85; 95% CI, 1.25 to 2.75; P=0.002). Additionally, compared with patients who took amoxicillin, patients who took azithromycin had an increased risk for cardiovascular death (HR, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (HR, 2.02; 95% CI, 1.24 to 3.30; P=0.005). Compared with patients treated with amoxicillin, patients treated with azithromycin had an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk for cardiovascular death also was significantly higher among those treated with azithromycin than among those treated with ciprofloxacin, but not among those treated with levofloxacin. Lead author Wayne A. Ray, PhD, a professor of preventive medicine at Vanderbilt University School of Medicine, in Nashville, Tenn., told Pharmacy Practice News that the study “documents the absolute excess risk of cardiovascular death in patients taking azithromycin, particularly those high-risk patients with conditions that predispose to cardiovascular death.” He noted that the “study adds important information regarding the risks of azithromycin, particularly crucial for high-risk patients.”

Study Has Some Limitations Commenting on the study’s findings, C. Michael White, PharmD, a professor and the head of pharmacy practice at the University of Connecticut, in Storrs, said that “the investigators should be con-

gratulated on an important initial study into the cardiovascular complications of macrolide antibiotics.” He pointed out, however, that “the study did not adjust for severity of infectious illness, which is critical.” Thus, “it is impossible to know for sure whether azithromycin is a marker for risk of cardiovascular death in patients with more severe infections or causative in the death itself through QTc interval prolongation.”

Dr. White concluded, “Right now, the information we have is not strong enough in terms of causality to really generally impact patient care decisions.” Pending their review of the Tennessee study, the FDA issued a statement noting that the label for azithromycin had been revised earlier this year to include information about the risk for QT interval prolongation, “which appears to be low.” The statement further noted that the

drug labels for clarithromycin and erythromycin also contain information about QT interval prolongation and that the agency is “in the process of updating risk information in the drug labels for additional macrolide antibacterial drugs.” —George Ochoa Drs. Ray and White reported no relevant ﬁnancial conﬂicts of interest.

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IMPORTANT SAFETY INFORMATION FOR INTRAMUSCUL CULAR AR USE ON ONLY. LY. Proge gesterone injection in sesame oil is contraindicated in patients with current or past history of thrombophlebitis, thrombo boemb emboli olicc diso disorde rders, rs, orr ce cerebral apoplexy; liver dysfunction or disease; known or suspected malignancy of breast or genita tall organs; undiagnose osed d vagi vaginal nal bleed bleeding ing;; missed m abortion; and known sensitivity to progesterone injection in sesame oil. Since progestero one metabolites are seecre creted ted mainl i ly by b the kidneys, progesterone should be administered with caution and careful monitoring in patients with renal insufficiency. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulm monary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately. Meedication should be discontinued pending examination if there is a sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn. Because progestational drugs may cause some degree of fluid retention, conditions which might be influenced by this co condition, such as epilepsy, migraine, asthma, cardiac, or renal dysfunction, require careful observation. Patients who have a history of psychi hicc depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree. There are possible risks wh which may be associated with the use of progestin treatment, including adverse effects on carbohydrate and lipid metabolism. A decrease in glucose gl tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. For this reason, diabetic ic patients should be carefully observed while receiving such therapy. Progesterone at high doses is an antifertility drug and high doses woul uld d be expected to impair fertility until the cessation of treatment. A statistically significant association has been demonstrated between use of estrogen-progestin combination on drugs and pulmonary embolism and cerebral thrombosis and embolism. For this reason patients on progestin therapy should be carefullllyy observed. There is also evidence suggestive of an association with neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis. Adverse events associated with use of Progesterone injection in sesame oil include breakthrough bleedi ding; ng; sp spott otting; change in menstrual flow; amenorrhea; edema; change in weight (increase or decrease); changes in cervical erosion and ce cervi rvical secretions; cholestatic jaundice; breast tenderness and galactorrhea; pain, irritation, and/or redness at the injection area; ski sk n sens ensitivity reactions consisting of urticaria, pruritus, edema and generalized rash; acne, alopecia and hirsutism; rash (allergic) with and d without w pruritus; anaphylactoid reactions; mental depression; pyrexia; insomnia; nausea; and somnolence. Because laboratory results may be altered by the use of estrogenprogestin combination drugs, pathologists should be advised of progestin therapy when spec pe imenss are submitted. One Luitpold Drive | PO Box 9001 | Shirley, NY 11967 | Phone 800-645-1706 | Fax 631-924-1731

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Pharmacy Practice News • September 2012

FDA Watch

FDA Denies Being To Blame for Drug Shortages

he FDA rebutted charges that it is largely to blame for the drug shortage crisis in a July 23 letter to the House Committee on Oversight and Government Reform. The FDA was responding to the committee’s June report, “FDA’s Contribution to the Drug Shortage Crisis,” which claimed that overzealous regulatory actions by the FDA were the primary reason for the crisis. The committee’s report did not place

sole blame for the crisis on the FDA, noting other factors such as market concentration. But the FDA’s role, according to the report, could be traced to the arrival in 2009 of Obama appointee Margaret Hamburg as FDA commissioner. According to the committee, chaired by Rep. Darrell Issa (R-Calif.), the drug shortage crisis began shortly afterward, in 2010. The committee noted that the number of warning letters issued by the FDA

PROGESTERONE INJECTION, USP IN SESAME OIL FOR INTRAMUSCULAR USE ONLY

Rx Only

DESCRIPTION Progesterone injection, USP, a progestin, is a sterile solution of progesterone in a suitable vegetable oil available for intramuscular use. INDICATIONS AND USAGE This drug is indicated in amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. CONTRAINDICATIONS 1. Current or past history of thrombophlebitis, thromboembolic disorders, or cerebral apoplexy. 2. Liver dysfunction or disease. 3. Known or suspected malignancy of breast or genital organs. 4. Undiagnosed vaginal bleeding. 5. Missed abortion. 6. Known sensitivity to progesterone injection, USP. WARNINGS The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately. Medication should be discontinued pending examination if there is a sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn. PRECAUTIONS General The pretreatment physical examination should include special reference to breast and pelvic organs, as well as a Papanicolaou smear. Because progestational drugs may cause some degree of fluid retention, conditions which might be influenced by this condition, such as epilepsy, migraine, asthma, cardiac, or renal dysfunction, require careful observation. In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind, and adequate diagnostic measures undertaken. Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree. The age of the patient constitutes no absolute limiting factor although treatment with progestin may mask the onset of the climacteric. The pathologist should be advised of progestin therapy when relevant specimens are submitted. There are possible risks which may be associated with the use of progestin treatment, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving such therapy. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term intramuscular administration of Medroxyprogesterone acetate (MPA) has been shown to produce mammary tumors in beagle dogs. There is no evidence of a carcinogenic effect associated with the oral administration of MPA to rats and mice. Medroxyprogesterone acetate was not mutagenic in a battery of in vitroo or in vivoo genetic toxicity assays. Progesterone at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment. Geriatric Use: The safety and effectiveness in geriatric patients (over age 65) have not been established. Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

increased 42% from 2009 to 2010 and then climbed 156% from 2010 to 2011. In many cases, the report stated, companies that received the letters took their manufacturing offline to address the FDA criticisms. Four of the five largest U.S. manufacturers of generic injectable products have curtailed manufacturing in response to FDA action, the report claimed. In the FDA’s response, signed by Jeanne Ireland, assistant commissioner for leg-

Hepatic Insufficiency: The safety and effectiveness in patients with hepatic insufficiency have not been established. Since progesterone is metabolized by the liver, use in patients with liver dysfunction or disease is contraindicated. Drug Interactions: The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC50 < 01 μM). Ketoconazole is a known inhibitor of cytochrome P450 3A4 and these data suggest that ketoconazole or other known inhibitors of this enzyme may increase the bioavailability of progesterone. The clinical relevance of the in vitroo findings is unknown. ADVERSE REACTIONS Breakthrough bleeding; spotting; change in menstrual flow; amenorrhea; edema; change in weight (increase or decrease); changes in cervical erosion and cervical secretions; cholestatic jaundice; breast tenderness and galactorrhea; pain, irritation, and/or redness at the injection area; skin sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash; acne, alopecia and hirsutism; rash (allergic) with and without pruritus; anaphylactoid reactions; mental depression; pyrexia; insomnia; nausea; and somnolence. A statistically significant association has been demonstrated between use of estrogenprogestin combination drugs and pulmonary embolism and cerebral thrombosis and embolism. For this reason patients on progestin therapy should be carefully observed. There is also evidence suggestive of an association with neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis. The following adverse reactions have been observed in patients receiving estrogen-progestin combination drugs: Rise in blood pressure in susceptible individual, premenstrual syndrome, changes in libido, changes in appetite, cystitis-like syndrome, headache, nervousness, fatigue, backache, hirsutism, loss of scalp hair, erythema multiforme, erythema nodosum, hemorrhagic eruption, itching, and dizziness. The following laboratory results may be altered by the use of estrogen-progestin combination drugs: increased sulfobromophthalein retention and other hepatic function tests; coagulation tests: increase in prothrombin factors VII, VIII, IX, and X; metyrapone test; pregnanediol determinations; thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values. DOSAGE AND ADMINISTRATION Progesterone injection, USP is administered by intramuscular injection. It differs from other commonly used steroids in that it is irritating at the place of injection. Amenorrhea: Five to 10 mg are given for six to eight consecutive days. If there has been sufficient ovarian activity to produce a proliferative endometrium, one can expect withdrawal bleeding forty-eight to seventy-two hours after the last injection. This may be followed by spontaneous normal cycles. Functional Uterine Bleeding: Five to 10 mg are given daily for six doses. Bleeding may be expected to cease within six days. When estrogen is given as well, the administration of progesterone is begun after two weeks of estrogen therapy. If menstrual flow begins during the course of injections of progesterone, they are discontinued. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. HOW SUPPLIED Progesterone Injection USP, 50 mg/mL is available in 10 mL multiple dose vials, individually boxed. Store at 20° C to 25° C (68° F to 77° F) [See USP Controlled Room Temperature]. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Do not use Progesterone Injection after the expiration date which is printed on the vial label.

Nursing Mothers: Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the nursing infant has not been determined. Special Populations: Renal Insufficiency: The safety and effectiveness in patients with renal insufficiency have not been established. Since progesterone metabolites are excreted mainly by the kidneys, progesterone should be administered with caution and careful monitoring in this patient population.

AR154 Iss. Date 6/2012

islation, and addressed to Rep. Elijah E. Cummings (D-Md.), the committee’s ranking member, the agency asserted, “FDA is not the root cause of this serious public health problem.” The FDA stated that the number of drug shortages began to rise steadily in 2005, well before Ms. Hamburg’s appointment, and that most of the drug shortages were attributable to manufacturing production problems, such as quality-related issues and delays. The rest of the shortages were due to such factors as business decisions to discontinue products, difficulty obtaining raw materials and increased demand. The FDA claimed that the steep increase in warning letters alleged in the report was misleading because most of the letters were unrelated to drug manufacturing; they were related to the new Center for Tobacco Products. From 2008 to 2011, the level of drug manufacturing warning letters “remained relatively flat,” according to the FDA. Furthermore, according to the agency, the warning letters issued to drug manufacturers involved serious defects that posed a safety risk. Defects serious enough to require stopping production included glass shards in injectable products and fungal contamination of products, the FDA said. The committee suggested that the FDA’s field force, which performs site inspections and issues citations, is insufficiently concerned about the implications of their actions, even if the result is a shortage. But the FDA said it is committed to working with manufacturers to resolve problems and avoid shortages. The FDA reported that it has prevented or mitigated drug shortages by taking steps such as expediting reviews, identifying additional manufacturers who may be able to produce scarce drugs, helping firms qualify new sources of a raw material and allowing temporary importation of a non-U.S. product. Commenting on the committee’s charges in an interview, Erin R. Fox, PharmD, FASHP, director of the Drug Information Service at the University of Utah Hospitals & Clinics, in Salt Lake City, said, “Looking at the committee’s report, I was very surprised. There was no mention of quality and manufacturing problems, no mention of the scary things going on in factories. I’ve read the inspection forms that document what the FDA found in its inspections. The FDA wasn’t saying, ‘We found uncrossed t’s and undotted i’s, and that’s why we’re mad at you.’ In injectables, they found glass shards and mold contamination, nonsterile products.” Noting that she considered the FDA’s actions “correct,” she said, “It’s hard to comply, but high quality is first priority.” —George Ochoa

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Joint Commission

JC UPDATE continued from page 1

of surveyed organizations cited), labeling in procedures (16%), pharmacist review (15%), medication preparation (6%) and medication reconciliation (6%).

Medication Security The most common storage transgressions involve medication security and failure to properly label multidose drug vials, Dr. Rich said. For instance, surveyors frequently find mobile medication carts (including code carts) locked up but not secured in a locked room or in view of a nursing station, as required. “Just locking the cart is not sufficient,” he explained. Decontamination of mobile carts also can present a problem. Such carts must undergo thorough decontamination before being moved between patient rooms. Surveyors are particularly concerned about carts that have been used for patients with isolation precautions, Dr. Rich said. Nurses, for example, might use carts for patients with something as virulent as Clostridium difficile, then do nothing more than wipe down the unit with a disinfecting cloth. That’s not enough, he emphasized, explaining that keyboards and paper-wrapped medications cannot be adequately disinfected by a wipe down. “That can be scored as a finding under infection control … and inappropriate cleaning and lowlevel disinfection of medical equipment devices and supplies, which could be a CMS [Centers for Medicare & Medicaid Services] condition-level deficiency. You really need to worry about this one.”

One emerging issue from field surveys is a lack of eye-wash stations in areas where chemotherapy drugs are handled. Joint Commission safety standards (EC.02.02.01) require that the stations be installed where caustic or hazardous substances are handled.

One option is to use a keyboard that can be washed in a dishwasher. Another is to keep the mobile unit outside of patient rooms, although Dr. Rich noted that he recognizes the limitations this creates for facilities using bar-code drug administration. A third route is to install permanent computer workstations in patient rooms.

Medication Ordering Medication ordering slip-ups often draw the attention of surveyors, according to Dr. Rich. One common order-

ing event—cited in 16% of Joint Commission surveys—are orders that don’t meet all required parameters yet still get approved. For example, a titration order or protocol must clearly state the initial titration rate and titration parameters. If the order lacks that information, it is considered by the Joint Commission to be incomplete. Dr. Rich also emphasized that a pharmacist must review all orders before medications are removed or dispensed from floor stock or an automated

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see JC UPDATE, page 10

IT’S NO PICNIC FOR A KID WITH IBS. AND THAT’S NOT COOL.

ORDERING INFORMATION

CAN HELP CHANGE THAT.

Mobile carts must be decontaminated when moving between patient rooms— a Joint Commission requirement that can prevent the spread of Clostridium difficile and other virulent pathogens.

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Joint Commission

JC UPDATE

The Joint Commission’s Take

Medication Storage

continued from page 9

dispensing machine, with two exceptions: when a licensed independent practitioner (LIP) controls the ordering, preparation and administration of the medication and when a delay in drug administration would result in harm to the patient. Another common problem arises in diagnostic areas if a pharmacist does not review orders for noncontrast medications when there is no LIP at the patient’s bedside during drug administration (e.g., furosemide for a renal scan or lorazepam prior to a magnetic resonance imaging scan). “If you don’t have a process for sending orders to the pharmacy for review from nuclear medicine or radiology, that’s almost always going to be a problem,” Dr. Rich said. Of institutions cited, 11% are cited because orders for multiple, as-needed medications (particularly pain medications, narcotics, antiemetics, antihistamines and benzodiazepines) are not accompanied by detailed instructions about when one medication should be selected over another. “Nurses are not always given clear guidelines on selecting from multiple medications,” Dr. Rich said. “The pharmacy should review and clarify those orders.” He urged hospital pharmacies to review all of their preprinted order sets to ensure they contain clear guidelines about administering multiple drugs of the same class. Another, less common, deficiency is a lack of pharmacy preparation of IV admixtures in procedural areas, including the operating room (OR), which is not exempt even if a physician is present. “In the OR, we expect a pharmacist to have made the product, particularly if it’s something routinely used,” Dr. Rich explained. Exceptions include urgent situations and when the admixture’s stability is shorter than the usual pharmacy preparation and administration time. Dr. Rich also reviewed several emerging issues that warrant attention, including a dearth of eye wash stations in areas where chemotherapy drugs are handled; a lack of ongoing evaluation of outsourced pharmacy providers; and the new CMS interpretation of standards related to reporting of significant medication errors. He also cited the need to follow proper procedures related to the dating of prepared medication doses. (The Joint Commission requires organizations to relabel all drugs with a revised expiration date—called the “beyond use date”—once the original manufacturer’s container is opened/ punctured.) He concluded with a word of advice: “Don’t focus on the obscure issues; focus on the big ones. Those are the ones—direct-impact standards— that affect your accreditation decisions.

Medication Orders

Labeling in Procedures

Pharmacist Review

15 1

Medication Preparation

Medication Reconciliation

High-alert Medications

Medication Labeling

Percent

Figure. Top medication standards scored non-compliant in 2011.a a.

Based on 1,354 surveys

‘Don’t focus on the obscure issues; focus on the big ones. Those are the ones—directimpact standards—that affect your accreditation decisions. Work on the smaller things later.’ —Darryl S. Rich, PharmD, MBA

Work on the smaller things later.”

Education Gaps Cited Patricia Kienle, RPh, MPA, the director of accreditation and medication safety pharmacy solutions at Cardinal Health, advised health systems facing a Joint Commission survey to approach the process pragmatically. “Check if your practices match your policies,” she told Pharmacy Practice News. “If they don’t, find out why. Is it because the policy is unusable or impractical in certain areas, or is it because the staff does not understand the purpose of the policy and safety precautions it supports? Often I find there’s an educational piece missing,” she said,

noting that people say such things as, “I didn’t realize I was doing this wrong, I just thought I was being efficient and didn’t realize what the risks might be.” Ms. Kienle also postulated that these inconsistencies between policy and practice are a major reason why the same infractions pop up year after year. “Institutions may have an established policy that meets the standards, but when surveyors come around, they observe practices that don’t actually match the policies,” she said. By simply walking around and observing practice patterns, managers can see where policy and practice diverge, she added. Additionally, the Joint Commission,

ealth systems can take several steps to improve compliance with the medication management standards that were identified in the online seminar as being perennially problematic, according to a Joint Commission representative: Medication storage. Organizations need to have well-written policies governing storage, and determine that staff and physicians are following those policies. The rules should reflect the fact that medications must be stored according to the manufacturer’s recommendations and monitored so that appropriate adjustments are made per those recommendations. Organizations also need to ensure that medications are secure and that scheduled drugs are locked up according to law and regulations. In addition, multi-dose vials need to be relabeled with a revised expiration date once they are accessed for the first time. Medication orders. Organizations need to make sure they have clearly defined education policies and procedures for medication orders, and that their staff and physicians are following those procedures. An organization’s medication policies and procedures include delineation of what constitutes a complete medication order and what kinds of orders are allowed in the organization (e.g., range, titration, prn, standing orders, automatic stop orders, etc.).

as well as the other two accrediting bodies—CMS and state regulators—are focusing more than ever on procedural areas, whereas in years past their emphasis was on the inpatient care units. Most of the medication management problems Ms. Kienle witnesses occur in procedural areas, such as anesthesia areas, interventional radiology areas, dialysis units, some imaging areas and offsite clinics such as oncology clinics. “It seems that those procedural areas often haven’t been tuned in either as part of the hospital’s educational effort or maybe they just don’t think their deviation from policy is important.” A Joint Commission representative stressed that although the infractions that top the list of medication management standards are important and need to be a focus for health systems, only two of them rank high in the list of overall problem areas for hospitals. Thus, a more global approach is needed to ensure compliance with all of the areas that are covered in field surveys. Still, the Commission offered some tips that hospitals can use to steer clear of medication management citations (sidebar, page 9). —Steve Frandzel Dr. Rich and Ms. Kienle reported no relevant ﬁnancial conﬂicts of interest.

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Pharmacy Practice News • September 2012

FDA Watch

Years in the Making, REMS Approved for ER/LA Opioids

ore than three years after they were first promised, the FDAmandated risk evaluation and mitigation strategy (REMS) for extended-release (ER) and long-acting (LA) opioid analgesics are now here. Announced by the FDA on July 9, the new REMS will require the manufacturers of ER and LA opioid analgesics to provide training for health care professionals who prescribe these agents. The companies also must provide educational materials to the health care professionals and to their patients that explain how to safely use the agents. Billed as part of the Obama administration’s 2011 national prescription drug abuse plan, the new REMS affect more than 20 drug companies and involves in

excess of 30 trade-named and generic products, according to the FDA (Table). Although it is mandatory for the drug companies to provide educational training and resources, undergoing the training is voluntary on the part of prescribers. This represents a departure from a planned mandatory component of the REMS that had been discussed as part of an initial REMS proposal in July 2010. Explaining their reasoning for forgoing the mandatory component in a press release announcing the new REMS, FDA wrote, “Such a requirement [mandatory prescriber training] would require the establishment of a new system for registering prescribers of ER/LA opioid analgesics … that would duplicate the

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see OPIOIDS, page 12

Table. Opioid Products Covered By REMS Brand Name Products Drug

Brand Name(s), Manufacturer(s)

Buprenorphine transdermal system

Butrans, Purdue

Fentanyl transdermal system

Duragesic, Janssen

Hydromorphone hydrochloride extended-release capsules

Palladone, Purduea

Hydromorphone hydrochloride extended-release tablets

Exalgo, Mallinckrodt

Methadone hydrochloride tablets

Dolophine, Roxane

Morphine sulfate and naltrexone extended-release capsules

Embeda, Pfizerb

Morphine sulfate controlled-release tablets

MS Contin, Purdue

Morphine sulfate extended-release capsules

Avinza, Pfizer; Kadian, Actavis

Oxycodone hydrochloride controlled-release tablets

OxyContin, Purdue

Oxymorphone hydrochloride extended-release tablets

Opana ER, Endo

Tapentadol extended-release oral tablets

Nucynta ER, Janssen

Generic Products Drug

Sponsor(s)

Fentanyl extended-release transdermal system

Actavis, Aveva, Lavipharm, Mallinckrodt, Mylan, Noven, Watson

Methadone hydrochloride concentrate

Roxane

Methadone hydrochloride oral solution

Roxane, Vistapharm

Methadone hydrochloride tablets

Mallinckrodt, Sandoz, The Pharmanetwork

Morphine sulfate extended-release capsules

Watson

Morphine sulfate extended-release tablets

Endo, Mallinckrodt, Mylan, Nesher, Ranbaxy, Rhodes, Watson

Oxymorphone hydrochloride extended-release tablets

Actavis, Impax

a. No longer being marketed, but is still approved; b. Not currently available or marketed due to voluntary recall, but is still approved. Source: FDA

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FDA Watch

OPIOIDS continued from page 11

existing Drug Enforcement [Administration] registration system. This would be potentially burdensome ….”

Components and Timeline According to the FDA, more than 320,000 individuals prescribe ER/LA opioids annually. The agency announced a goal of 25% of prescribers trained one year following implementation of the program, 40% at two years and 60%

within three years. The FDA expects the first company-provided educational materials to be available by March 2013. An approved patient-counseling document already is available. The prescriber education resources will include information on assessing

patient need for opioid treatment; starting, modifying, managing and discontinuing opioid therapy; monitoring patients; and counseling patients and caregivers about opioid safety. In explaining why only ER and LA opioids are being required to carry

CRITICAL CARE

REMS, and not immediate-release (IR) agents, the FDA stated, “The FDA has concluded that there is a disproportionate safety problem associated with these products that must be addressed. … The amount of opioid analgesic contained in an ER tablet can be much more than the amount of opioid analgesic contained in an IR tablet because ER tablets are designed to release the opioid analgesic over a longer period of time. Improper use of any opioid can result in serious side effects, including overdose and death, and this risk is magnified with ER/LA analgesics. ” (In January 2012, the FDA approved a separate REMS for transmucosal immediate-release fentanyl [TIRF] products, which are indicated for breakthrough pain in cancer patients who are already receiving and are tolerant to opioids for underlying persistent cancer pain.)

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Stating that it understands how important continued access to ER/LA opioid analgesics is to chronic pain patients, the FDA vowed to monitor patient access and to communicate with patients “to ensure that patients get proper pain management.” The FDA also plans to conduct follow-up surveys to gauge the effectiveness of the REMS and whether it is hampering access. “The new ER/ LA opioid analgesic REMS advances the Agency’s goal of improving the safe use of ER/LA opioid analgesics while ensuring continued access to these medications for patients who need them,” the agency wrote, further noting that if “the REMS is not meeting its goals, the Agency will re-evaluate the program.” Although the REMS apply specifically to prescribers, it will be important for pharmacists to be familiar with the components of the program, according to Scott Strassels, PharmD, PhD, BCPS, an assistant professor in the Division of Pharmacy Practice at the University of Texas at Austin, and a member of the American Pain Society’s Pharmacotherapy Committee. “The REMS has a lot of potential to be of interest to pharmacists in a variety of practice settings, including hospitals and ambulatory care clinics, as a source of information to prescribers as well as patients,” he told Pharmacy Practice News. “In hospitals specifically, I can imagine pharmacists playing a role at all levels of the institution—helping set and apply policy, serving as a resource to prescribers, nurses and other hospital personnel, helping put information from the REMS into perspective (comparing one drug to another, for example), and working with patients to ensure that optimally safe and effective analgesia is provided.” —Donald M. Pizzi and Sarah Tilyou

NO SHORTAGE OF COMMITMENT.

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Pediatrics

Study Supports Tadalafil Use in Children With PAH

new study has shown that tadalafil can be a safe and effective treatment for pulmonary arterial hypertension (PAH) in children. And in a separate study, investigators have offered a detailed account of how to prepare an oral suspension of the medication. Lesley D’Albini, PharmD, BCPS, the manager of Clinical Protocols and Therapy Management at Accredo Health Group, Inc., said she was excited to see both reports because she and her colleagues had been asked to provide tadalafil to pediatric PAH patients but didn’t have guidelines on how to dose. The new findings are “a good resource and will really help physicians treat children with PAH with the correct dosing,” Dr. D’Albini told Pharmacy Practice News. “This is a big deal.” There are only a handful of therapies for PAH, an extremely rare condition marked by abnormally high blood pressure in the arteries of the lungs that can lead to right ventricular overload and failure. Current treatments include prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors (PDE-5i). Two oral PDE-5i agents, sildenafil and tadalafil (Adcirca, Eli Lilly)—used for the treatment of erectile dysfunction in men—were recently approved by the FDA for the treatment of PAH in adults; these agents improve exercise capacity by relaxing blood vessels in the lungs. Tadalafil’s effects on children, however, had not yet been formally studied, according to the authors of a new study published online in Pediatric Cardiology (2012;683-688. doi:10.1007/ s00246-012-0180-4). The investigators, from the Children’s Hospital Colorado, in Aurora, retrospectively evaluated 33 pediatric PAH patients aged 4 to 18 years who started treatment with tadalafil between March 2008 and December 2010 and were followed until March 2011. Four patients were treated with tadalafil as a firstline therapy or as initial PDE-5i therapy in combination with another targeted therapy; 29 were switched from sildenafil to tadalafil, primarily because tadalafil can be taken once daily instead of three times per day. The average dose of sildenafil was 3.4 mg/kg per day (±1.1 mg/kg per day), and of tadalafil was 1.0 mg/kg per day (±0.4 mg/kg per day). Children weighing 40 kg or more were given the adult dose of tadalafil; children weighing 20 to 39 kg were treated with one-half of the adult dose, and children weighing 19 kg or less were treated with one-fourth of the adult dose. The investigators measured the clinical effects of tadalafil through plasma brain natriuretic peptide levels, echocardiography, exercise capacity, car-

Although more pharmacokinetic studies are needed, ‘we’re certainly excited about the preliminary results.’ —David Dunbar Ivy, MD diac catheterization and World Health Organization (WHO) functional class before and after initiating therapy. The group observed statistically significant improvements in pulmonary

arterial pressure (53.2±18.3 vs. 47.4±13.7 mm Hg; P<0.05) and pulmonary vascular resistance index (12.2±7.0 vs 10.6±7.2 units/m2; P<0.05) in about half of the 29

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Pharmacy Practice News • September 2012

Patient Counseling

Interferon Takes Hit in MS Study; Patient Fallout? I

nterferon-β therapy did not produce a long-term reduction in the progression of dissability among patients with relapsing-remitting multiple sclerosis (MS), according to a study in the Joournal of the American Medical Asssociation (2012;308:247-256). Based on the results, specialty pharmacists may need to manage patients’ expectations about interferon-β’s impact on the t disease, experts suggest. Patiients who are concerned by th he widely publicized study findings also must be told not to stop complying with interferon-β β therapy—a counseling message stressed by a coauth hor of the new study. “We certainly are no ot suggesting that patients stop their h i medication,” Helen Tremlett, PhD, of the University of British Columbia in Vancouver, said in an interview with Pharmacy Practice News. “We knew before we started this study that these drugs are effective in terms of reducing relapse rates by about a third, and they also have a beneficial impact on the brain lesion load as measured by MRI [magnetic resonance imaging]. Those outcomes are still valid. This study asks a different question that couldn’t be addressed by short-term clinical trials.”

Study Details The study compared data on 868 drugtreated patients with untreated contemporary (n=829) and historical (n=959) cohorts. The main finding: Interferonβ therapy was not associated with a significantly lower hazard of reaching a disability score of 6 on the Expanded Disability Status Scale (EDSS), Dr. Tremlett and her colleagues reported. That disability is defined as the need for a cane to walk 100 m, confirmed at more than 150 days from baseline with no measurable improvement. Drilling a bit deeper, rates of reaching

‘[Patients in the study] may not have had adequate treatment time to affect their progression to disability ... [They] should continue to use interferon-β products as the medical community continues to search for even more effective ways to treat MS.” —Melody Ryan, PharmD, MPH

Chemical structure of a molecule of human interferon- , a drug used to treat multiple p sclerosis

an EDSS score of 6 were 10.8%, 5.3% and 23.1% in the interferon, untreated contemporary and historical cohorts, respectively, with median active followup times (first to last EDSS measurement) of 5.1, 4.0 and 10.8 years. Adjustment for potential confounding variables did not yield statistically significant differences between the treated group and the contemporary cohort (hazard ratio [HR], 1.30; 95% confidence interval [CI], 0.92-1.83; P=0.14) or the historical cohort (HR, 0.77; 95% CI, 0.58-1.02; P=0.07). The results did not change with further adjustment for comorbidities, socioeconomic status and propensity scores. Patients were taking one of four preparations: interferon β-1b (Betaseron [Bayer], 250 mcg subcutaneously on alternate days) and interferon β-1a (Avonex [Biogen Idec], 30 mcg intramuscularly once weekly; and Rebif [Merck Serono] 22 mcg and 44 mcg subcutaneously thrice weekly). Switches between products and breaks of less than three months between consecutive prescriptions were not considered

changess in treatment status. Alhough A evidence abou ut differences in therapeutic effectivveness among these drugs is lacking, “wee were assuming they all had the samee impact,” Dr. Tremlett said. Patients in n the control groups were not on any d disease-modifying drugs for MS. Despite the adjustment for propensity scores, “the data hint that indication bias may still be present in the data in the contemporary analysis, which makes the historical control group [for whom interferon-β therapy was not yet available] a real bonus to the study,” said Dr. Tremlett, an epidemiologist who originally trained as a pharmacist in the United Kingdom. Dr. Tremlett said she hopes pharmacists and other health professionals will counsel MS patients to have more realistic expectations about interferon-β therapy. However, the data suggest there may be subgroups of patients who experience long-term benefits. “That is where we’re going next—trying to see if we can tease out who those responders might be” to support more effective, personalized treatment, she said.

Putting Results in Perspective Jacci Bainbridge, PharmD, a professor of clinical pharmacy at the Skaggs School of Pharmacy and Pharmaceutical Sciences of the University of Colorado Denver, said that nonadherence

to therapy, a major problem among MS patients, could have influenced the results. “We don’t really know if that was accounted for in that patient population,” said Dr. Bainbridge, a clinical pharmacy specialist in the neurology clinic. She urged pharmacists to encourage their patients to remain on therapy and to follow their neurologists’ instructions. “When patients have relapses, often they don’t come back to baseline, so to have them not relapse is very important,” she said. Melody Ryan, PharmD, MPH, an associate professor in the Department of Neurology at the University of Kentucky College of Medicine, in Lexington, said that known adherence problems among MS patients suggest the possibility that these patients “may not have had adequate treatment time to affect their progression to disability. Patients should continue to use interferon-β products as the medical community continues to search for even more effective ways to treat MS.” —Susan Birk Dr. Tremlett has received speaker honoraria and/or travel expenses to speak at conferences from the Consortium of MS Centres, National MS Society, Swiss Multiple Sclerosis Society, University of British Columbia Multiple Sclerosis Research Program, Bayer Pharmaceuticals (invited speaker, honoraria declined), and Teva Pharmaceuticals (invited speaker). Dr. Ryan had no disclosures.

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Pharmacy Practice News • September 2012

Pediatrics

TADALAFIL

Procedure for Compounding Tadalafil Suspension, 5 mg/mL

continued from page 13

patients undergoing repeat catheterization, after switching to tadalafil. Among the patients treated with tadalafil as initial therapy, two WHO class 3 patients improved to class 1 or 2, and the remaining class 2 patients did not deteriorate. None of the patients added new vasodilator therapies after starting tadalafil. The side effects of tadalafil included headache, nausea, myalgia, nasal congestion, flushing and allergic reaction. Two patients discontinued the drug due to migraine or allergic reaction.

Pharmacokinetics a Next Step “We’re certainly excited about the preliminary results,” although the pharmacokinetics still have to be studied, said David Dunbar Ivy, MD, the senior author of the study and the director of the pulmonary hypertension program at the Children’s hospital. Eli Lilly is planning a multisite study to investigate the drug’s pharmacokinetics in children aged 6 months to 17 years, he said. Dr. Ivy said that he and his colleagues continue to use the drug as a first-line therapy in some patients, but he noted that, although it appears safe in older children, it has not yet been tested in neonates or infants: “The doses we used [for the study] are very empiric.” Dr. Ivy cautioned pharmacists and other health professionals treating children with PAH to be sure of the correct diagnosis and treat any underlying medical issues. Patients given tadalafil should be carefully monitored for side effects, he added. A separate article published April 1 in the American Journal of Health-System Pharmacy (2012;69:592-594) provides instructions for preparing an oral suspension of tadalafil for children or adults with PAH (box). Pharmacists from Riley Hospital for Children in Indianapolis and the University of Michigan Hospitals and Health Centers, who developed the solution, found it to be stable for at least 91 days when stored in amber plastic bottles at room temperature. Dr. D’Albini underscored the practical benefits of the new studies. “We get asked to try a lot of things off-label because [PAH] is so rare, and even more rare in children,” she said. “We have been instructing caregivers on splitting, double-splitting or triple-splitting [tadalafil] tablets, so to now have more formalized dosing instructions should really help improve patient care.” —Karen Blum Dr. Ivy disclosed that he and the University of Colorado are paid a consulting fee by United Therapeutics and Pﬁzer.

Count out 15 tadalafil 20-mg tablets.

Triturate the tablets in a glass mortar to produce a fine powder.

Mix 30 mL of Ora-Plus with 30 mL of Ora-Sweet; stir vigorously.

Levigate 30 mL of diluent into the tadalafil powder from step 2 via geometric dilution until a smooth suspension is formed.

Transfer the mixture into a 2-oz, child-resistant, amber plastic prescription bottle.

Rinse the contents of the mortar into the bottle with enough of the diluent to bring the final volume to the 60-mL mark as predetermined with a graduated cylinder.

Label the bottle “Shake Well Before Use” with an expiration date of 91 days after preparation.

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Hem/Onc Pharmacy

Pharmacy Practice News • September 2012

In Focus

FIDAXOMICIN continued from page 1

Microbiology and Infectious Diseases. The research is the first subgroup analysis involving patients with cancer of the two major clinical trials that led to the approval of fidaxomicin (Dificid, Optimer) in May 2011. The two trials, which were funded by Optimer, included 183 patients (16.6%) with a current diagnosis of cancer. In general, the researchers found, patients with cancer had a poorer response to CDAD treatment than did patients without cancer. The median time to resolution of diarrhea was 55 hours for patients without cancer

(95% confidence interval [CI], 53-58 hours) compared with 100 hours for those with a cancer diagnosis (95% CI, 71-119 hours). When the two treatments were compared among patients with cancer, those who received fidaxomicin fared significantly better than those who received vancomycin with respect to rates of clinical cure (97.3% vs. 87.5%; P=0.041), sustained response to treatment (83.6% vs. 61.3%; P=0.003) and recurrence (14.1% vs. 30%; P=0.025). As in the primary analyses, the safety profile for the two drugs was comparable. “As the first analysis of fidaxomicin in cancer patients, this is a very interesting study,” said Sara Kim, PharmD,

‘The drug is outrageously expensive, and as it stands right now, its cost is significantly too high for our facility to consider putting it on formulary.’ —Sara Kim, PharmD

97.3 9 Clinical cure 87.5

8 83.6

Sustained response to treatment

61.3

14.1 Fidaxomicin

Recurrence

Vancomycin

100

Response, %

Figure. Clostridium difficile–associated diarrhea treatment response rates.

BCOP, a clinical oncology pharmacy specialist at Mount Sinai Medical Center, in New York City. “It demonstrated improved clinical response in patients with cancer [treated with fidaxomicin], which is great.”

No Overall Survival Benefit But the analysis failed to find any overall survival benefit for cancer patients who were given fidaxomicin compared with those receiving vancomycin. Given the drug’s $2,800 price tag—significantly higher than that of either vancomycin or metronidazole, the other commonly used first-line therapy for CDAD—Dr. Kim said that it is hard to justify making the switch. “The drug is outrageously expensive, and, as it stands right now, its cost is significantly too high for our facility to consider putting it on formulary, unless it’s a lifesaving drug; but it hasn’t shown that survival benefit yet.” Oral vancomycin is itself costly at around $1,800 for a 10-day course of capsules (with some variation depending on supplier), but many hospitals— Mount Sinai included—minimize that cost by simply compounding the much less costly injectable vancomycin into an oral syringe. The price tag? About $100 for a full course of treatment (although that, too, can vary by suppliers). A 10-day treatment course of metronidazole, meanwhile, can be as low as $4. Lead researcher Oliver Cornely, MD, the medical director of the Clinical Trial Center of The University of Cologne, in Germany, said it would be a mistake to focus solely on the survival outcome. “For cancer patients with a limited life expectancy, it appears particularly tragic if [the patient is] admitted for recurrence, i.e., preventable disease.” When someone may have only six months or a year left to live, Dr. Cornely pointed out, it is difficult to quantify the benefit of living more of those limited days diarrhea-free and out of the hospital. He suggested that cost analyses should take “a comprehensive approach calculating costs of recurrence, too.” Although in clinical practice an expensive drug such as fidaxomicin usually is not considered until a patient has failed other therapies, both of the major fidaxomicin trials used the agent as first-line

‘In very sick patients— and most cancer patients would fall into this category— fidaxomicin is a reasonable first-line choice.’ —Oliver Cornely, MD

therapy. Dr. Cornely agreed with that approach, stating that for many cancer patients, the drug should indeed be considered first-line rather than salvage. “The sicker a patient [is], the more likely it is that there will be a recurrence,” he said. “In very sick patients—and most cancer patients would fall into this category—fidaxomicin is a reasonable firstline choice.” He noted that a specific trial of fidaxomicin in immunosuppressed patients is about to begin. However, Dr. Kim questioned whether the trial data applied to current clinical practice. “We can’t extrapolate from the available data that fidaxomicin also can produce the same clinical benefit in a salvage setting,” she said, adding, “I hope future studies will show this drug to be effective as a salvage therapy; that may be a different story. If they were able to show a survival benefit, that would really change things.” —Gina Shaw Dr. Cornely reported a financial relationship with Optimer. Dr. Kim reported no relevant financial conflicts of interest.

If you missed any recent issues of Pharmacy Practice News, visit www.pharmacypracticenews.com.

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www.cutispharma.com / 1-800-461-7449 18 Technology

Pharmacy Practice News • September 2012

Automation

BLACK HOLE continued from page 1

Meeting of the American Society of Health-System Pharmacists.

Nearly Complete Coverage The ADCs supply about 95% of the medications likely to be used during a procedure—a huge upgrade from the previous system, which employed percase drug trays, according to Jenna Smith, CPhT, an OR pharmacy technician who helped spearhead the technology upgrade. “Too often, the trays didn’t contain a drug that was needed during the case, and so the case might be interrupted while a nurse or the anesthesiologist left the OR to get the medications from a dispensing unit down the hall,” Ms. Smith said during the poster session. “That was a time-waster and source of frustration for the entire OR team.” The drug trays posed another problem: frequent mismatches between what the paper-based anesthesia record would say was used during the case and what was left in the tray. “Jenna would have to piece together why the mismatches were occurring,” Mr. Speth said. “If it was a narcotics discrepancy, she would have to chase down the anesthesiologist and

tor also displays the concentration and amount of each drug stored in the cart, further aiding accurate dispensing and administration. Additionally, the system prints a color-coded label for each drug dispensed, which then can be affixed to the syringe after drawing up the dose—a feature “that really helps prevent medication mix-ups,” Mr. Speth said. Nevertheless, simply citing outcomes data, however hard or soft, tells only part of the story, he stressed. “You really need to see this from the perspective of the anesthesiologists. When they realized the ADC would give them immediate access to five or 10 or even 20 vials of each drug in the OR—at the patient’s bedside—it was viewed as a major improvement over the per-case trays.”

Anesthesiologist a Fan Layne Tait, MD, a staff anesthesiologist at IUHB and one of the self-described “crash-test dummies” who helped roll out the ADC system, agreed that ready access to virtually all of the medications one could need during a procedure was by far the system’s major benefit. “It’s all there right at your fingertips,” Dr. Tait said. “There’s hardly anything you need to get from the pharmacy, other than an occasional antibiotic.”

‘It’s all there right at your fingertips. There’s hardly anything you need to get from the pharmacy, other than an occasional antibiotic.’ —Layne Tait, MD say, ‘you took out a narcotic but it wasn’t logged into the anesthesia record.’ He’d usually acknowledge it was an oversight— he forgot to record it, rather than it being [due to drug] diversion—so it wasn’t adversarial. But it was a drain on Jenna’s time because not only did she have to resolve the discrepancy, she then had to manually charge those items so that we got reimbursed for the medications.” Once the ADCs were in place, several improvements ensued: The number of controlled substance discrepancies fell from 10 per week pre-implementation to one per week, and the time required to resolve those discrepancies was cut from five to two hours per week, Mr. Speth reported. Because the carts generate charges for reimbursement when drugs are dispensed, he added, the one to two hours per day devoted to charge reconciliation was eliminated. Finally, restocking time was reduced from three to four hours per day to 1.5 hours per day. Mr. Speth added that the ADCs also improved medication safety, although those outcomes were a bit harder to document. For example, during the medication dispensing process, the cart’s computer screen lists the selected drug, “which is probably safer than selecting drugs from an open tray,” he said. The moni-

He also underscored the safety gains that accrue when nurses no longer have to leave the OR to retrieve medications not included in per-case drug trays. “If nurses are in the OR, I need them to stay in the OR—they’re important members of the surgical team. I certainly don’t want them scrambling around to find meds during a critical situation.” As for the system’s potential for reducing drug diversion, Dr. Tait and Mr. Speth both pointed out that it should make it harder for users to divert narcotics because it takes nurses out of the dispensing loop and produces a record of dispensed drugs that can be audited against the anesthesia record. “It certainly isn’t foolproof, however,” Mr. Speth noted. Asked if there are any flaws to the ADC technology, Dr. Tait cited the cabinet’s keypad response. “Sometimes you have to hit it two or three times before it responds to a command,” he said. “In this era of instant response from smart phones and tablets, the delay is noticeable.” According to Preeti Churbock, portfolio manager at McKesson’s Automation Solutions division, the latest version of the software in the company’s Anesthesia-Rx carts used at IUHB minimizes the need for a keypad. “Users wanted a quick way to remove the medication with a

simple barcode scan, so we developed this functionality,” Ms. Churbock said.

‘Horrendous Knot’ Untangled Eric Chernin, RPh, BSPharm, a pharmaceutical care specialist in the OR pharmacy at Sarasota Memorial Hospital, in Florida, said that the approach taken at IUHB “is great, given the fact that they don’t have an OR pharmacy to monitor anesthesia drug use.” Mr. Chernin said he was particularly impressed by the reduced time required to resolve narcotic discrepancies, which “can be a horrendous knot to untangle. Nobody wants them, and they may signal narcotics diversion, although I understand that wasn’t an issue at IUHB. Still, anything you can do to minimize the risk for diversion or eliminate conditions where it can occur is an impressive accomplishment.” Mr. Chernin added that he discussed implementing OR ADCs with his own anesthesiologists but met some resistance. “The most common pushback I got was a fear that the drawers or the carts would fail, and that as a result, the anesthesiologists would not be able to access the needed agents, either during the normal course of the case, or worse, during a medical emergency.” Asked about such failures, Mr. Speth said the ADCs at IUHB “have been reliable, considering their heavy use and abuse.” However, he conceded that some breakdowns have occurred. “My IT team tells me that we have had about three PC failures and one drawer failure in a little more than 18 months,” he said. “PC failure is normal and can be replaced in a couple hours by our people. The drawer failure was due to user abuse and took about the same time to fix. But at no time were drugs inaccessible to OR physicians; we have a multilevel backup plan in place.” That plan includes cart keys that are stored in a dispensing cabinet in the hallway, which can be accessed if the bedside cart in the OR locks up—an option “that we have not yet needed,” Mr. Speth stressed; using another cart from an idle room; getting the needed medication from a per-case tray left over from the hospital’s previous drug dispensing system; and “if all else fails,” obtaining medications from the pharmacy.

A Tip for Vendor Selection Mr. Speth stressed that vendor selection is key when evaluating ADC systems. “We used McKesson carts because we’re a McKesson hospital, so the carts meshed very well with our existing computer systems,” he said. “That integration piece is critical.” He cautioned, however, against focusing solely on the bits and bytes of the rollout process. “You have to start with the human element and get all of the

Hospital has implemented automated anesthesia drug carts to streamline dispensing in the OR. Photos courtesy of McKesson.

stakeholders—particularly anesthesiologists—on board.” That can be best accomplished, he suggested, with some basic psychology. “No matter what your own objective is, try to justify the program based on how it will benefit users in the OR. For my anesthesiologists, the most important benefit was rapid access to medications at the patient’s bedside. Once they realized they would have that, they really bought into the system.”

Return on Investment New technology can be an expensive proposition. If administrators push back due to cost, Mr. Speth noted, then it’s time to make a case for ADCs based on return on investment (ROI). Although total charge capture did not increase at IUHB, the process was quicker, with a resultant savings in staff time. For many hospitals, however, charges often are missed, he noted. In such instances, “you can [point out] that the increased reimbursement you’re going to achieve with this system will give you a very rapid ROI—this is truly money well spent.” If such arguments still aren’t swaying hospital management, then it may be time to cite Joint Commission requirements for storing medications in a secure manner, Mr. Speth noted. “No unauthorized staff can have access to medications, and controlled substances must be doublelocked,” he explained. “The AnesthesiaRx carts accomplish both; cart access is password-controlled and controlled substances are stored in individually locked and lidded pockets that allow access only to the item selected on the screen. So this is at least one item you don’t have to worry about during a field survey.” —David Bronstein

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www.cutispharma.com / 1-800-461-7449 20 Operations & Management

Pharmacy Practice News • September 2012

Medication Safety

INTERVENTIONS continued from page 1

two tertiary care academic institutions, the Vanderbilt University Medical Center in Nashville, Tenn., and Brigham and Women’s Hospital, in Boston, for the PILL-CVD (Pharmacist Intervention for Low Literacy in Cardiovascular Disease) Study Group. “This shows that we’re still trying to figure out how best to do this,” coauthor David W. Bates, MD, MSc, said in an interview. “Pharmacists are an expensive resource, and it’s important to use them as well as possible. We definitely thought that the approach we took was going to make a difference, and we were surprised and a bit disappointed that it did not.”

Multifaceted Intervention The approach consisted of a multifaceted intervention of pharmacist-led medication reconciliation; inpatient counseling; communication with physicians regarding clinically relevant medication discrepancies; illustrated medication reminders; pillboxes and education using the “teachback” technique for patients assessed as having low health literacy; and phone followup with patients postdischarge. The follow-up was done in a stepwise fashion, according to the researchers. The coordinators first contacted patients at home one to four days after discharge. If problems were detected, a pharmacist called. A research coordinator then followed up with patients to assess and rate any problems with medications 30 days after discharge. At baseline, pharmacists assessed patients’ understanding of medications, barriers to adherence, such as cognitive impairment, and social support, and tailored their efforts accordingly. Patients in the control group received usual care—medication reconciliation and discharge counseling by physicians and nurses. In all, approximately 10% of patients had inadequate and 8.7% had marginal health literacy, and 11.5% had some degree of cognitive impairment. “We expected a larger proportion would have low health literacy,” said Dr. Bates.

Results Not Encouraging Pharmacist intervention did not significantly reduce the per-patient number of clinically important medication errors (unadjusted incidence rate ratio [IRR], 0.92; 95% confidence interval [CI], 0.77-1.10) or ADEs (unadjusted IRR, 1.09; 95% CI, 0.86-1.39), although patients in the intervention group tended to have fewer potential ADEs (unadjusted IRR, 0.80; 95% CI, 0.611.04). The mean number of clinically important medication errors was 0.87

ISMP’s Take: Shift Focus Toward High-Alert Drugs and Causes of Errors “It looks on the surface that pharmacists didn’t make a difference in improving the medication safety of discharged patients,” said Michael R. Cohen, RPh, MS, ScD, DPS, president of the Institute for Safe Medication Practices, referring to the findings of a study on pharmacist intervention published in the July 3 issue of the Annals of Internal Medicine (see main article). But, he added, “I’m not worrying too much about it. I certainly know that pharmacists contribute a lot to patient safety.” Mr. Cohen suggested ways the study’s investigators could have improved their results. Medication errors could be reduced by focusing prevention efforts on the medications most commonly implicated in adverse drug events (ADEs) and the causes of the errors that lead to the most significant harm, he said. If efforts are focused on trying “to find out what those errors are, I think you’d see a lot more improvement,” he said. For example, Mr. Cohen said, “I would have liked to have seen more information about exactly what went wrong that led to an INR [international normalized ratio] of 14.1 [in one patient],” he said. “That’s an incredible number. I’ve never seen anything that high. That patient was absolutely at risk of bleeding. Why? Did [he or she] take an overdose of Coumadin?” According to the study, the drugs most frequently involved in ADEs and potential ADEs were cardiovascular agents, diuretics, opioids, lipid-lowering agents, nutrients (herbs, vitamins, supplements), hypoglycemic agents, anticoagulants, antidepressants, gastrointestinal agents, steroids, sedatives, gout agents, thyroid agents, analgesics (nonnarcotic), respiratory agents and antiinfective agents. “We need to focus special attention on high-alert drugs and well-known problems, and develop teaching aids,” Dr. Cohen said. “We can more easily supplement specific patient education efforts with written material that makes problems and solutions more memorable.” Toward that end, ISMP has developed a series of patient education tools on high-alert drugs. The educational tools, in checklist format, are designed for use by pharmacists to help patients remember how to take their medications safely. Patient education sheets on the following drugs are available in the tools and resources section at ISMP’s consumer Web site (www.consumermedsafety.org): enoxaparin; fentanyl patch; hydrocodone with acetaminophen; insulin aspart; insulin detemir; insulin glargine; insulin glulisine; insulin lispro; methotrexate; oxycodone with acetaminophen; and warfarin. According to Mr. Cohen, national or state regulations requiring patient education about high-alert drugs would also help efforts to reduce medication errors. “You’re not going to stop all errors that way,” he said, “but I’ll bet you would cut into them dramatically.” —S.B.

and 0.95 per patient in the intervention and control groups, respectively. These findings counter previous research by Dr. Bates and his colleagues, which showed that a pharmacist-led intervention could significantly reduce ADEs following hospitalization. In that study, ADEs occurred in only 1% of intervention patients compared with 11% of control patients ((P=0.01). Pharmacists followed up with patients by phone three to five days after discharge ((Arch Intern Med 2006;166:565-571). In the present study, 432 of 851 patients (50.8%) had one or more clinically important medication errors. Of these, 75.3% were significant, 22.9% were serious and 1.8% were life-threatening. ADEs occurred in 258 patients (30.3%) and potential ADEs occurred in 253 patients (29.7%). Approximately 46 ADEs (13%) resulted in a readmission or emergency room visit. Patients were a mean age of 60 years and had 14 years of education; 41.4% were women. Of patients, 61% were hospitalized with acute coronary syndromes only, 31% with acute heart failure only and 7% with both diagnoses. The drugs most commonly involved in ADEs were cardiovascular agents, diuretics, opioids,

lipid-lowering agents, nutrients, hypoglycemics and anticoagulants. The relatively low rate of inadequate health literacy among participants— approximately 10% compared with 26% in the medical literature—could partially explain the intervention’s failure to reduce medication errors and ADEs, the authors said. Dr. Bates also cited the inherent complexity of medication reconciliation. “It just takes a long time to do a thorough medication reconciliation, and if pharmacists are asked to do this for too many patients, they will not be able to do a good job,” he said. “It’s been very hard to implement medication reconciliation broadly. The [electronic] tools to do it have had limitations. We’re still working on how to do it well.”

Timing Is Everything Daniel C. Johnson, PharmD, BCPS, a clinical pharmacist specializing in cardiology and cardiac surgery at Vanderbilt University Medical School and a participant in the PILL-CVD study, said that the nature and timing of pharmacist interventions probably influence their effectiveness. “We really found it hard to [com-

plete] all of the interventions in faceto-face [encounters] while the patient was in the hospital,” said Dr. Johnson, who cared for some of the patients in this study. Moreover, “phone followup is definitely difficult, and so maybe some type of postdischarge, face-to-face follow-up really would be great, when patients are a little more on their feet.” Dr. Johnson noted that the study involved a follow-up call to patients by a study coordinator one to four days after discharge. Medication issues identified by the coordinator were referred to the pharmacist. “We actually captured quite a few issues in that period,” he said. “That’s a phone call that could be completed by either a health care professional or using a script [by a non– health care professional].”

Age Might Have Influenced Results According to Patrik Midlöv, MD, of the Center for Primary Health Care Research at Lund University in Malmö, Sweden, the relatively young age of patients in this study (60 years) could help explain the persistence of medication errors among those who received pharmacist intervention. A study by Dr. Midlöv and his colleagues of pharmacist involvement in medication reconciliation for patients ages 65 years and older revealed significant reductions in medication errors and drug-related readmissions ((Eur J Clin Pharmacol 2011;67:741-752). Dr. Midlöv also noted some potential methodological problems with the present study. Pharmacists communicated with the medical team to resolve medication discrepancies, and those medical teams could have had patients in both the intervention and control groups, which could have influenced the results. Additionally, the outcomes were based on patient responses to a follow-up telephone interview 30 days after discharge. “In our study we knew exactly what medications the patients took before, during and after hospital care,” he said. “In this study, however, there is a risk of recall bias.” —Susan Birk

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www.cutispharma.com / 1-800-461-7449 22 Operations & Management

Pharmacy Practice News • September 2012

Leadership in Action

Conflict Management Starts at the Top “Pharmacist, heal thyself.”

ith apologies to the immortal bard, this admonition goes a along way toward resolving one of the most common—if not most acknowledged—causes of conflict in your department: you! Sometimes our own selfish attitudes can be the source of conflict. Therefore, we need to examine our own motivations and attitudes. Are we too caught up in thinking that we are always right, simply because we are in a position of leadership? Do we sometimes dig in our heels, close our minds and determine that we are going to get our way in a disagreement? As the leader, it may be easy to think that you are supposed to always be right. After all, isn’t that your job? Well, you need to check that attitude at the door. None of us is beyond being wrong, or beyond having the wrong attitude of the heart. If this sounds a bit too familiar, it’s time to revisit a suggestion I’ve made previously: You need to have a “truth-sayer” on staff who can set you straight when

are the intimidators themselves. If you find yourself in a situation where you flew off the handle or bullied your staff, examine your own motives to see if selfish desires are at the root before you blame someone else. Watch out for reckless or aggressive words that often are spoken in haste. And have a truth-sayer close by who can call you on these potentially destructive behaviors.

You Are Ultimately the Solution Of course, the solution to avoiding these pitfalls cannot rest solely on the counsel of others; you have to ultimately be the cure for your own conflict-inducing behaviors. To help with that process,

I am not asking co-workers to be best friends, but I am expecting them to be able to work together cooperatively for the sake of a productive department in a peaceful atmosphere. you’re not seeing clearly. Such a person hopefully can remind you that, instead of lording your position over people, you need to approach your responsibilities in a sense of humble confidence, seeking wisdom from others, encouraging others and looking for the opportunities to make others shine. Honoring the people who work for you and giving them recognition at every opportunity not only encourages them but also builds community within an entire department. It creates an element of trust and an atmosphere that allows others the freedom to approach you with an alternative point of view or even the wise counsel of correction or even rebuke. Too often I see leaders who paralyze a department by the way they treat their people. They attempt to use their authority to control others. This results in people staying below the radar and not contributing due to fear of rejection or even public humiliation. I heard of an incident just this week of a good employee who left a health system after being talked down to in a public setting by someone in a high leadership position. Unfortunately, I don’t think this leader is even aware of the way he comes across to others. Such leaders often talk about eradicating intimidation in the workplace, yet often

it’s useful to turn once again to some of the principles from Ken Sande’s The Peace Maker (Grand Rapids, MI: BakerBooks; 2004). We’ve already touched on a key first step that Sande advocates— admitting that we are not infallible. As a leader, you also need to consider how your behavior affects others by asking the simple question, “Would I want to be treated the way I am treating someone else?” Another action that can bring reconciliation to a conflict is to admit your contribution to the issue and seek the forgiveness of someone else with the simple words, “I’m sorry.” However, do not say, “I’m sorry iff I did something to hurt you.” That little word “if” shifts the blame and minimizes your confession of a wrong and becomes a token apology. You also need to verbalize the specific action or words that caused hurt, frustration or embarrassment. You can even ask the offended person how you made him or her feel. Your sincere seeking of forgiveness from the offended individual has the power to bring reconciliation and peace. And you need to learn from the experience; a sincere apology is all well and good, but if it goes out of your mind and you find yourself repeating the same divisive behaviors, what have you really accomplished?

Sometimes people ask me what to do if the other person does not accept their sincere apology and they have given the situation some time for resolution. My response is that they have now placed the responsibility on the offended person to accept their apology. You have done as much as you can do. If the other person is unwilling to forgive you, then it is their weakness or stubborn pride; you have done what you can do. Hopefully, if you find yourself in such a situation, the offended person will accept your peace offering so that true reconciliation can take place.

Keep Reconciliation Local Once you’ve addressed your own contributions to conflict, it’s time to hone your skills at helping others navigate on-the-job clashes. A key principle in such peacemaking efforts is to keep the issues needing reconciliation local. That means keeping it between the two parties in conflict and discouraging gossip. If someone states that he or she is having a problem with another person or if you hear them badmouthing someone, ask them to go to that person to try and work things out, face to face. Of course, if they need help in how to approach the other person, you can give them some advice on creative ways to do that, but my preference is not to have to mediate. To help understand this strategy a bit further, think of it as being centered on the goal of gently restoring someone else. This entails having a great sensitivity toward the other person, getting your point across in a way that does not provoke the other person to defensiveness or instigate a further conflict. If I there are skill-level diifferences between the t two people or on ne may be highlyy intimidated by the other, then I may make a judgment to act as an intermediary from thee beginning.

Explore Harmfful Language I have often heard people utter very hurtful or critical words to someone and then seek k to minimize the effect of tho ose words by saying, “Hey, I was onlyy kidding.” Sorry, but that just does nott cut it. As a manager, it’s your responsibility to point out to that person thatt the initial, harmful

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Steward Health Care System, Boston, Mass. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ steward.org.

Ernest R. Anderson Jr., MS, RPh

words are what count. However, you may not succeed in resolving these types of situations if you only focus on the offender; you also have to educate the offended person how to communicate why he or she has been hurt. Telling the person to use phrases such as “let me tell you how your words made me feel” is a good start. I also have seen instances where the insecurity of an individual (including managers) results in their verbally cutting other people down to build themselves up. Of course, this rarely works and in fact has the opposite effect of reducing their credibility. To resolve these types of situations, try focusing on restoring the relationship between the two conflicting people. You are not asking co-workers to be best friends—but you should expect them to be able to work together cooperatively for the sake of a productive department in a peaceful atmosphere. I realize that many of these approaches sound straightforward, but in reality it often can be difficult to have the necessary conversations that create an effective, efficient and productive atmosphere in which people are free to make their significant contributions. The department that you manage starts with humility at the top (that’s you) and your personal openness to critique and reconciliation. The culture that you create can have positive outcomes for all.

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P(T / DV ZHOO DV WKRVH ZKR DUH UHFHLYLQJ GUXJV NQRZQ WR LQFUHDVH VHUXP SRWDVVLXP OHYHOV ADVERSE REACTIONS: Clinical Trials Experience: %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQV UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHÃ&#x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Â&#x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able 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term

Tolvaptan 15 mg/day-60 mg/day (N = 223) n (%) ( )

Placebo (N = 220) n (%)

Gastrointestinal Disorders 'U\ PRXWK

Constipation

General Disorders and Administration Site Conditions a 7KLUVW

Asthenia

Pyrexia

Metabolism and Nutrition Disorders b +\SHUJO\FHPLD

Anorexia c Renal and Urinary Disorders

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SAMSCAÂ® (tolvaptan) RU SROODNLXULD WROYDSWDQ SODFHER 7KH IROORZLQJ DGYHUVH UHDFWLRQV RFFXUUHG LQ RI K\SRQDWUHPLF SDWLHQWV WUHDWHG ZLWK 6$06&$ DQG DW D UDWH JUHDWHU WKDQ SODFHER LQ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV 1 WROYDSWDQ 1 SODFHER RU LQ RI SDWLHQWV LQ DQ XQFRQWUROOHG WULDO RI SDWLHQWV ZLWK K\SRQDWUHPLD 1 DQG DUH QRW PHQWLRQHG HOVHZKHUH LQ WKH ODEHO Blood and Lymphatic System 'LVRUGHUV 'LVVHPLQDWHG LQWUDYDVFXODU FRDJXODWLRQ &DUGLDF 'LVRUGHUV ,QWUDFDUGLDF WKURPEXV YHQWULFXODU Â¿EULOODWLRQ Investigations: Prothrombin time prolonged; Gastrointestinal Disorders: Ischemic colitis; Metabolism and Nutrition Disorders: Diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis; Nervous System: Cerebrovascular accident; Renal and Urinary Disorders: Urethral hemorrhage; Reproductive System and Breast Disorders (female): Vaginal hemorrhage; Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure; Vascular disorder: Deep vein thrombosis. DRUG INTERACTIONS: Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP 3A Inhibitors: 6$06&$ LV PHWDEROL]HG SULPDULO\ E\ &<3 $ .HWRFRQD]ROH LV D VWURQJ LQKLELWRU RI &<3 $ DQG DOVR DQ LQKLELWRU RI 3 JS &R DGPLQLVWUDWLRQ RI 6$06&$ DQG NHWRFRQD]ROH PJ GDLO\ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PJ NHWRFRQD]ROH GDLO\ RU ZLWK RWKHU VWURQJ &<3 $ LQKLELWRUV H J FODULWKURP\FLQ LWUDFRQD]ROH WHOLWKURP\FLQ VDTXLQDYLU QHOÂ¿QDYLU ULWRQDYLU DQG QHID]RGRQH DW WKH KLJKHVW ODEHOHG GRVH ZRXOG EH H[SHFWHG WR FDXVH DQ HYHQ JUHDWHU LQFUHDVH LQ WROYDSWDQ H[SRVXUH 7KXV 6$06&$ DQG VWURQJ &<3 $ LQKLELWRUV VKRXOG QRW EH FR DGPLQLVWHUHG [see Dosage and Administration (2.3) and Contraindications (4.4)]. Moderate CYP 3A Inhibitors: 7KH LPSDFW RI PRGHUDWH &<3 $ LQKLELWRUV H J HU\WKURP\FLQ Ã&#x20AC;XFRQD]ROH DSUHSLWDQW GLOWLD]HP DQG YHUDSDPLO RQ WKH H[SRVXUH WR FR DGPLQLVWHUHG WROYDSWDQ KDV QRW EHHQ DVVHVVHG $ VXEVWDQWLDO LQFUHDVH LQ WKH H[SRVXUH WR WROYDSWDQ ZRXOG EH H[SHFWHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK PRGHUDWH &<3 $ LQKLELWRUV &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PRGHUDWH &<3 $ LQKLELWRUV VKRXOG WKHUHIRUH JHQHUDOO\ EH DYRLGHG [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Grapefruit Juice: &R DGPLQLVWUDWLRQ RI JUDSHIUXLW MXLFH DQG 6$06&$ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. P-gp Inhibitors: 5HGXFWLRQ LQ WKH GRVH RI 6$06&$ PD\ EH UHTXLUHG LQ SDWLHQWV FRQFRPLWDQWO\ WUHDWHG ZLWK 3 JS LQKLELWRUV VXFK DV H J F\FORVSRULQH EDVHG RQ FOLQLFDO UHVSRQVH [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. 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Concomitant Medication: $GYLVH SDWLHQWV WR LQIRUP WKHLU SK\VLFLDQ LI WKH\ DUH WDNLQJ RUU SODQ WR WDNH DQ\ SUHVFULSWLRQ RU RYHU WKH counter drugs since there is a potential for interactions. Strong and Moderate CYP 3A inhibitors and Pg-p inhibitors: $GYLVH SDWLHQWV WR LQIRUP WKHLU SK\VLFLDQ LI WKH\ XVH VWURQJ H J NHWRFRQD]ROH LWUDFRQD]ROH FODULWKURP\FLQ WHOLWKURP\FLQ QHOÂ¿QDYLU VDTXLQDYLU LQGLQDYLU ULWRQDYLU RU PRGHUDWH &<3 $ LQKLELWRUV H J DSUHSLWDQW HU\WKURP\FLQ GLOWLD]HP YHUDSDPLO Ã&#x20AC;XFRQD]RO RU 3 JS LQKLELWRUV H J F\FORVSRULQH [see Dosage and Administration (2.3), Contraindications (4.4), Warnings and Precautions (5.5) and Drug Interactions (7.1)]. Nursing: $GYLVH SDWLHQWV QRW WR EUHDVWIHHG DQ LQIDQW LI WKH\ DUH WDNLQJ 6$06&$ >VHH 8VH ,Q 6SHFLÂ¿F 3RSXODWLRQV @ )RU PRUH LQIRUPDWLRQ DERXW 6$06&$ FDOO RU JR WR ZZZ VDPVFD FRP 0DQXIDFWXUHG E\ 2WVXND 3KDUPDFHXWLFDO &R /WG 7RN\R -DSDQ 'LVWULEXWHG DQG PDUNHWHG E\ 2WVXND $PHULFD 3KDUPDFHXWLFDO ,QF 5RFNYLOOH 0' SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

THERE’S JUST NO SUBSTITUTE

Accurate dosing Reduced compounding time Barcoded dispensing containers Pleasant strawberry flavored suspension

www.cutispharma.com / 1-800-461-7449

UNMET NEED. FILL IT.

FREE VVATER V2

CLEARANCE

Order SAMSCA® (tolvaptan)

15 mg

30 mg

NDC: 59148-020-50

NDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic and euvolemic hyponatremia

100 %

of physicians surveyed (N=57) would recommend SAMSCA to a colleague 1 In this same survey (patient cases; N=150), physicians were satisﬁed or very satisﬁed with SAMSCA 90% of the time1

Indication and important limitations • SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA. It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients

Important safety information SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients. • Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors • Co-administration with hypertonic saline is not recommended • Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium Commonly observed adverse reactions: (SAMSCA vs placebo) thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%). Reference: 1. Market Rx 2010.

For more information about SAMSCA, visit samsca.com or call 1-877-726-7220.

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. Samsca is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

March 2012

0712A-4220K