The Pharmacist’s News Source
Dedicated Team Helps To Improve Outcomes In Severe Sepsis Patients Miami Beach, Fla.—A multidisciplinary team that concentrates solely on managing severe sepsis can significantly improve patient outcomes, according to new research presented at the Society of Critical Care Medicine’s 39th Annual Critical Care Congress. The strategy improved the recognition of sepsis, reduced hospital length of stay (LOS) and lowered sepsis-associated mortality, according to lead author Audis Bethea, PharmD, BCPS, clinical pharmacy specialist, trauma surgery, Charleston Area Medical Center (CAMC), in West Virginia. The 893-bed center, which consists of three distinct hospitals, began to develop a multidisciplinary team, called the Sepsis Steering Committee, in 2005. CAMC wanted to improve its sepsis mortality rate, which ranged from 35% to 45%. “Mortality rates from sepsis can range anywhere from 20% to 60%, depending on how far the disease has progressed,” Dr. Bethea told Pharmacy Practice News. “For severely septic patients, average mortality rates can range from 30% to 50%. We were within that
see SEPSIS TEAM, page 29
When Choosing Antibiotic Regimen, Location Is Key New Study on susceptibility testing deemed practice-changing Miami Beach, Fla.—A three-drug regimen consisting of double gram-negative coverage plus methicillinresistant Staphylococcus aureus (MRSA) coverage is a must for increasing the success of proper initial empiric antibiotic selection, according to a study presented at the Society of Critical Care Medicine’s 39th Annual Critical Care Congress. What the regimen should consist of depends on the organisms that are most commonly found in each institution, according to lead investigator Jeffrey Barletta, PharmD, clinical specialist, critical care, at Spectrum Health in Grand Rapids, Mich. “Understanding the infectious epidemiology that is unique to your particular unit is crucial to this process of optimizing infection-related outcomes in critically
see MRSA TESTING, page 25
in this issue Clinical
ASHP Pearls Tips for boosting safety of HIV drug therapy, a genetic test for predicting potentially fatal drug reactions, and more.
Volume 37 • Number 3 • March 2010
Reimbursement, Shortages And REMS, Oh My! Hem/onc pharmacists take pulse of practice
Hem/Onc Pharmacy Bisphosphonates may prevent breast cancer.
BCIRG 006 study fuels debate over anthracyclines for breast cancer
Critical Care Wake-up-and-breathe protocol for ventilator weaning still lagging.
One hospital’s success with adding pharmacists to the emergency department.
Fungal sepsis remains an unrecognized danger in ICU.
Joint Commission More delays in revising medication reconciliation patient safety goal.
Operations & Mgmt
eimbursement, off-label use and drug shortages are among the issues weighing heavily on the minds of hematology/oncology pharmacists as the government ushers everchanging policies into the new decade. The pace of those changes is a problem for many clinicians. As drugs are fast-tracked, for example, evidence of efficacy often mounts faster than the FDA’s ability to recommend changes in labeling. The result? Pharmacists, whose role in drug safety and patient educa-
Leadership in Action Emotional intelligence: Do you have it?
Process Improvement “Lean” management techniques boost pharmacy efficiency.
Safe Handling of Hazardous Drugs Insert after page
tion already is virtually ignored in reimbursement calculations, face an uphill battle in recouping costs. As if that wasn’t enough, pharmacists are bracing for a slew of risk evaluation and mitigation strategies (REMS) that may soon fall onto their shoulders. In the weeks leading up to the sixth Annual Conference of the Hematology/Oncology Pharmacy Association (HOPA) in New Orleans, several leading specialists discussed these practice issues with Pharmacy Practice News.
see PRACTICE PULSE, page 12
Haiti Relief Aboard USNS Comfort Pharmacists help naval ship deliver post-earthquake care
ixing a steroid drip for a patient with a spinal cord injury and preparing hypertonic solutions to reduce intracranial swelling caused by traumatic head injury were among the potentially lifesaving services delivered by pharmacists working on board or in conjunction with the U.S. Navy hospital ship USNS Comfort during the demanding early
days of the ship’s earthquake relief mission in Haiti. Working 14-hour shifts around the clock, the phar macy staff on the USNS Comfort filled some 3,000 orders per day at the peak of demand, according to Cmdr. Michael Volstorf, MSC, RPh, director of pharmacy aboard the 1,000bed floating hospital. Although many
see USNS COMFORT, page 40
New Product Tykerb approved for combo therapy in HER2-positive breast cancer.
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Up Front 3
Pharmacy Practice News • March 2010
FDA Watch Lapatinib Gets New Indication
The five most-viewed articles last month on pharmacypracticenews.com: 1. Cytotoxic Drug Residues Still Lurking in Health Care Facilities 2. The Team as MVP in Patient Care 3. More Proof Pharmacy Enhances Care, But at a Savings? 4. Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations 5. Heart Transplant Drugs Linked to Skin Cancer Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.
‘It can’t just be the pharmacy system applying lean [techniques]— it has to be the whole institution.’
—Roger Woolf, PharmD See article, page 42
The Book Page
MCMAHONMEDICALBOOKS.COM Acute Pain Management Raymond S. Sinatra; Oscar A. de Leon-Casasola; Brian Ginsberg; Eugene R. Viscusi See page
he FDA has approved lapatinib (Tykerb, GlaxoSmithKline) in combination with letrozole (Femara, Novartis) to treat hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer in postmenopausal women for whom hormonal therapy is indicated. Approval was based on results from a double-blind, placebo-controlled study that enrolled 219 women diagnosed with postmenopausal, hormone receptor- and HER2-positive metastatic breast cancer and randomized them to receive lapatinib plus letrozole or letrozole alone. Women receiving the lapatinib plus letrozole combination experienced a 5.2-month increase in median progression-free survival compared with women treated with letrozole alone (35 vs. 13 weeks). GlaxoSmithKline sponsored the study. Lapatinib was initially approved in 2007 in combination with capecitabine (Xeloda, Roche) for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy, including an anthracycline, a taxane and trastuzumab (Herceptin, Genentech). Safety information from the new study was consistent with previous clinical studies of lapatinib in advanced breast cancer. The most commonly reported side effects of the combination were diarrhea, rash, nausea and fatigue. Treatment with lapatinib also has been associated with decreases in heart function, liver damage and lung tissue inflammation. Fetal harm may occur if it is used to treat advanced breast cancer in pregnant women. Patients should talk to their health care provider about the potential side effects, drug interactions and other medical conditions.
Renal Dosing for Bortezomib Updated
linicians should be aware that the prescribing information for bortezomib (Velcade, Millennium) pertaining to patients with hepatic impairment has been revised. The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in 51 cancer patients receiving bortezomib doses ranging from 0.5 to 1.3 mg/m2. Mild hepatic impairment did not alter dose-normalized bortezomib area under the curve (AUC) values, compared to those seen in patients with normal hepatic function, However, moderate or severe hepatic impairment increased the bortezomib AUC values by approximately 60%. Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated with the recommended bortezomib dose. Patients with moderate or severe hepatic impairment should be started on bortezomib at a reduced dose of 0.7 mg/m2 per injection during the first cycle. A subsequent dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient tolerance. Bortezomib is indicated for patients with multiple myeloma and for patients with mantle cell lymphoma who have received at least one prior therapy. —Staff
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Volume 37 • Number 3 • March 2010 • pharmacypracticenews.com
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Pharmacy Practice News • March 2010
Clinical Pearls Sparkle Again at ASHP Midyear LAS VEGAS—Yet another standing-room only crowd attended the perennially popular Clinical Pearls session at the American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting. Highlights included strategies for ensuring the safety and efficacy of HIV drug therapy, a genetic test for predicting—and preventing—potentially fatal drug reactions, and a drug regimen that can ease pain crises in patients with sickle cell anemia.
Preventing Medication Errors in HIV Patients
s the number of available antiretroviral products and combinations continues to grow, HIV therapy becomes increasingly complex, presenting challenges for clinicians treating patients in inpatient settings, according to Julie B. Dumond, PharmD, research assistant professor at University of North Carolina School of Pharmacy in Chapel Hill. In her pearl presentation, Dr. Dumond offered tips on how to deal with some of those challenges, to optimize care and prevent errors in hospitalized patients with HIV. Three primary issues to assess in patients receiving HIV therapy are the overall completeness of the patient’s regimen, the specific drug dosages prescribed, the patient’s renal and hepatic function, and how those variables may influence the regimen and dosing. “There’s no hard-and-fast rule” in HIV therapy, stressed Dr. Dumond, but generally a regimen includes at least two drugs and perhaps as many as five or six. “The typical backbone of our therapy” is nucleoside reverse transcriptase inhibitors [NRTIs],” which are used in combination with one or more drugs from other classes, such as protease inhibitors (PIs) or non-nucleotide reverse transcriptase inhibitors. She noted that generally two
NRTIs are used, but, due to resistance, a third NRTI is sometimes added to a regimen. “There are a lot of combination products that we use on an outpatient basis to improve compliance,” Dr. Dumond said. Thus, she stressed, “It’s really important when patients come in-house, where you might not have these combination products available, that the dosing is done correctly.” Particularly for treatment-experienced patients, Dr. Dumond stressed the need to ensure that the patient’s effective outpatient regimen is continued in the hospital as prescribed. “I cannot overemphasize the importance of checking and double-checking to make sure that what’s been ordered is what the patient should really be getting.” She noted that often patients at a later stage of disease have tried many different regimens and have few if any options left if their current regimen fails. “So any alteration in the drug concentration could generate resistance that may affect not only the current regimen that they’re on but also any future treatment regimens … including drugs that are still in development.” Thus, it is critically important that pharmacists question orders that don’t seem correct, and also to recognize that many medical residents are not familiar with the
Genetic Test Can Help Forestall Potentially Fatal Drug Reaction
enetic screening for the HLA-B*5701 allele can uncover patients who are likely to have a dangerous hypersensitivity to the antiretroviral agent abacavir (Ziagen, GlaxoSmithKline), reported David W. Kubiak, PharmD, during his Clinical Pearls presentation. The reaction has been associated with fatalities when abacavir was continued despite progressive symptoms, noted Dr. Kubiak, an infectious disease clinical specialist at Brigham and Women’s Hospital, in Boston. The symptoms of the reaction, which are nonspecific, include fever, rash, fatigue, myalgias and gastrointestinal disturbances. Laboratory results are nonspecific as well. Clues that the hypersensitivity reaction is occurring are onset of symptoms within six weeks of taking abacavir and worsening of symptoms with subsequent doses of the drug. Dr. Kubiak noted that the reaction historically occurred in 5% to 8% of patients initiated on abacavir, primarily whites. In most patients, he said, stopping the drug will result in prompt resolution of the symptoms. The sensitivity of the HLA-B*5701 allele test, the first
antiretrovirals they may be ordering. Dr. Dumond had some specific tips related to the PI ritonavir (Norvir, Abbott). Once thing to be alert for is that ritonavir can be confused with the NRTI Retrovir, GlaxoSmithKline’s zidovudine product. She also noted that ritonavir usually is given with another PI as a pharmacokinetic enhancer. A dosing issue to be aware of is that what had been considered “full-dose” ritonavir therapy (600 mg twice daily) is “rarely seen any longer.” Lastly, Dr. Dumond called ritonavir liquid “probably the most vile substance on the Earth” and does not recommend its routine use. The Department of Health and Human Services updated its Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents in December 2009 (http://aidsinfo.nih.gov/contentfiles/ AdultandAdolescentGL.pdf ). Dr. Dumond noted that the updated guidelines are a comprehensive resource for pharmacists with questions about these drugs. —Sarah Tilyou
Ketorolac Effective For Pain Crises In Sickle Cell Anemia
pharmacogenomic test to be used to clinically predict an adverse drug reaction, is very high, noted Dr. Kubiak. Referring to information from the government’s latest guidelines on the use of antiretroviral agents, he said that the sensitivity of HLA-B*5701 testing for predicting abacavir hypersensitivity is 100% and its specificity is 90% to 100% (http://aidsinfo.nih.gov/contentfiles/ AdultandAdolescentGL.pdf.) The guidelines, released in December 2009, recommend that all patients be screened for the HLA-B*5701 allele before starting abacavir therapy and that those who test positive for the allele should not be prescribed the drug. —S.T.
etorolac is an effective component of a regimen for treating inpatients in sickle cell crisis, said Alabama clinical pharmacist Lea S. Eiland, PharmD, in her Clinical Pearls presentation. Ketorolac’s narcotic-sparing effect, efficacy and convenience make it a good choice for a patient in a sickle cell vaso-occlusive (pain) crisis, noted Dr. Eiland, associate clinical professor of pharmacy practice, Harrison School of Pharmacy, Auburn University, in Alabama. Pain crises are the “most common reason patients [with sickle cell disease] come into the hospital,” she said, noting that at her institution they treat approximately 50 children for sickle cell pain crises each year. She stressed that
see KETOROLAC, page 6
Pharmacy Practice News • March 2010
Lipid Emulsions Tame Anesthetic Toxicity
This Beers (Criteria) Is Not for You
he Medication Appropriateness Index (MAI) is a better tool than the Beers criteria for determining whether a drug is safe for use in the elderly, according to Colorado clinical pharmacist Robert Lee Page, PharmD, FASHP. Although there is no set definition of inappropriate prescribing in the elderly, experts have proposed the following: “use of medications that introduce a significant risk of an [adverse drug event] when there exists evidence for an equally or more effective but lowerrisk alternative therapy for treating the same medical condition” (J Clin Pharm Ther 2007;32:113-121; http://www.iom. edu/Reports/1999/To-Err-is-HumanBuilding-A-Safer-Health-System.aspx). However, Dr. Page, associate professor of clinical pharmacy and physical medicine at the University of Colorado Schools of Pharmacy and Medicine, in Denver, said he considers that definition to be incomplete. It also should include overuse of drugs at higher frequencies or longer durations, underuse of drugs that are medically indicated based on guidelines and use of multiple medications, particularly with respect to drug– drug interactions. Dr. Page said that these factors should not be ignored in light of data about the increased use of medications and increased risk for drug interactions among older patients, especially those with severe, chronic diseases. Nearly
one-third of community-dwelling adults aged 65 and older take more than five prescription medications; 42% take at least one over-the-counter drug, and 49% take at least one nutritional supplement, according to a study published in JAMA (2008;300:2867-2878). Referring to data from another study published in Hospital Pharmacy (1998;33:835-840), Dr. Page cautioned, “When we increase beyond four [drugs], we have a 50% increased risk for a drug–drug interaction.” The Beers criteria do not address these drug– drug and drug–disease interactions, nor do they address over- and underuse of medications and drug duplication, according to Dr. Page. “The bottom line is that it’s just a bad drug list. All it does is give you a list of drugs and concerns.” The reason the list is used by many organizations, including the Centers for Medicare & Medicaid Services, is that it is easy to use and administer and it is one list that is easy to carry, Dr. Page noted. “But, I think one of the big problems is that it’s based on opinion,” h e said. Additionally, it lacks sufficient evidence of validity, particularly in health
systems; it is not comprehensive or well organized; and it does not consider the patient and his or her social and economic environment. “We’re in an age of patient-specific drug therapy,” noted Dr. Page, and the Beers criteria “take the patient out of the [equation].” In contrast, Dr. Page said, the MAI evaluates 10 validated measures: indication, effectiveness, dose, correct directions, practical directions, drug–drug interactions, drug–disease interactions, duplication, duration and cost, and requires some clinical judgment. So the MAI takes a little more time and effort, but it provides more practical, accurate information, according to Dr. Page. “It’s a lot more comprehensive. It has excellent interrater reliability. It also has, more importantly, been used in hospital settings,” he said, concluding, “The MAI, above all else, is a much better tool” for evaluating whether a particular drug is appropriate for a particular elderly patient. —Sarah Tilyou
KETOROLAC continued from page 4
“aggressive and early treatment of pain is essential in this population, so we hopefully don’t have to go to transfusion or further treatment of the crisis and we can easily pull them out.” In general, they treat their pediatric outpatients who are in pain crises using oral analgesics. For inpatients, they use IV fluids and IV analgesics (usually a combination of parenteral narcotics administered via patient-controlled analgesia (PCA) pumps and parenteral nonsteroidal anti-inflammatory drugs [NSAIDs]). Ketorolac is a good NSAID option in this population, said Dr. Eiland, noting that it is available in both IV and oral forms. At her institution, the regimen for pain crises is to administer IV fluids at a minimum of 1.5 times the maintenance fluid rate, IV morphine via either a pediatric-friendly PCA protocol or intermittent dosing, and scheduled IV ketorolac (0.5 mg/kg per dose every six hours for a maximum of five days). The maximum dose of IV ketorolac is 30 mg. If a patient is switched to the
oral form, the maximum dose is 10 mg, she said. She noted that with increasing numbers of children being overweight, clinicians need to pay attention to these maximums. Dr. Eiland stressed that ketorolac is only for inpatient use; it is not intended for home treatment of a pain crisis, in part due to the high incidence of adverse reactions that have been reported with the drug. Those reactions, according to ketorolac prescribing information, include gastrointestinal bleeding, ulcers, allergic reactions and, in rare cases, severe cutaneous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. In addition, “the maximum of five days of use cannot be
ntravenous lipi d e mul s i o n s (IVLE) can be used as an antidote in cases of toxicity with local anesthetic agents, according Gordon Sacks, PharmD, professor and head, Department of Pharmacy Practice, Har r i s o n S ch o o l o f Ph ar macy, Auburn University, in Alabama. Such toxicity, which can progress “from mild symptoms such as agitation or hypertension … to the severity of cardiovascular collapse,” occurs in up to 20 of every 10,000 peripheral nerve blocks and four of every 10,000 epidural blocks with agents such as bupivacaine, levobupivacaine, mepivacaine, procaine and ropivacaine (Naropin, APP Pharmaceuticals), said Dr. Sacks. The cardiac effects are related to interference in inotropic pathways involving sodium, potassium and calcium channels, as well as inhibition of adenosine triphosphate synthase. Referring to several case reports in which IVLE procedures were used to successfully rescue patients with anesthetic toxicity (Anesthesiology 2007;107:516-517; Anaesthesia 2007;
see LIPID, page 18
guaranteed at home,” she said. Another important consideration for oral ketorolac is that because the tablet cannot be cut or crushed, it should not be used in patients weighing less than 20 kg. Dr. Eiland also suggested waiting a least one month before reinitiating ketorolac if the patient has another pain crisis. She acknowledged that there are no pediatric clinical trials of ketorolac in the inpatient setting, but “it’s what we’ve been doing at our institution for the past six or seven years.” She said that “it clinically reduces narcotic use,” and despite ketorolac’s documented potential for causing adverse reactions, “we have not had problems when using it in this regimen.” Noting that some institutions use other NSAIDs, such as IV ibuprofen or cyclooxygenase-2 inhibitors, Dr. Eiland said these options are expensive. Because they have found their approach to be safe and effective, she concluded, “we’re sticking with ketorolac.” —S.T.
Pharmacy Practice News • March 2010
In Focus In gastric cancers…
Modified DCF Regimen Tames Toxicity Orlando, Fla.—Modifying the docetaxel, cisplatin and fluorouracil (mDCF) regimen given to patients with metastatic gastric and gastroesophageal junction cancers was found to significantly increase tolerability without compromising efficacy. The modified chemotherapy regimen was found to be more tolerable than traditional DCF, even when DCF was given with growth factor support, according to a study presented at the 2010 Gastrointestinal Cancers Symposium (GCS; abstract 46). DCF is a standard first-line option for metastatic gastric cancer; however, 80% of patients experience grade 3/4 nonhematologic toxicity and 30% develop neutropenia, said Manish A. Shah, MD, an attending physician in gastrointestinal oncology at Memorial Sloan-Kettering Cancer Center, New York City, who presented the Phase II multicenter study. The study included 77 patients with metastatic or unresectable gastric cancer (n=51) or gastroesophageal junction (n=26) adenocarcinoma, previously untreated for metastatic disease. Patients were randomly assigned to standard DCF with prophylactic granulocyte macrophage colony-stimulating factor G-CSF or mDCF (Table). Explaining the modifications, Dr. Shah said, “We reduced the doses of the drugs and gave them more frequently. Instead of five days of 5-FU, we gave it over 48 hours to reduce mucositis, and gave lower doses of docetaxel and cisplatin to reduce nausea and vomiting and myelosuppression.” Fifty-eight patients were evaluable for toxicity that occurred in the first three months. Grade 3/4 hematologic toxicity was seen in 11 of the 28 patients in the mDCF arm compared with 12 of the 30 patients treated with standard DCF. Grade 3/4 non-hematologic toxicity was observed in seven of the 28 patients in the mDCF arm compared with 17 of the 30 patients treated with standard DCF, Dr. Shah said. The non-hematologic toxicities were largely nausea and vomiting, fatigue, electrolyte imbalance, mucositis
Hem/Onc Coverage Coming Soon The next few issues will include highlights from the March 2010 ASCO Genitourinary Cancers Symposium, held in San Francisco, Calif. Coverage will include the latest updates on bladder, renal and prostate cancer, with new data on targeted therapy, managing early- versus late-stage disease, and more.
and thrombosis. Although toxicity was reduced with mDCF, efficacy remained comparable or greater. Response rates were 50% with the modified regimen and 33% with standard DCF. Six-month progressionfree survival (90% vs. 78%), time to treatment failure (8.6 months vs. 7.1 months) and overall survival (14.9 months vs. 12.5 months) were improved with the
modified regimen. “We showed in a randomized multicenter study that the modified DCF regimen is indeed less toxic. In fact, the standard arm had to be closed for excessive toxicity, despite the use of prophylactic G-CSF. Of 22 people who developed significant toxicity in the first three months of treatment, we had to admit 16 to the hospital,” Dr. Shah
said. “And [mDCF] is at least equally effective.” According to Richard M. Goldberg, MD, professor and chief of hematology and oncology at the University of North Carolina at Chapel Hill, “Multi-agent chemotherapy is the preferred standard of care for treating advanced gastric cancer. The modified DCF regimen used in this trial clearly is
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WARNING Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Tacrolimus Capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see brief summary of full prescribing information including boxed warning on following pages. Prograf® is a registered trademark of Astellas Pharma Inc.
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Pharmacy Practice News • March 2010
In Focus Table. DCF and mDCF Schedules Modified DCF q2wk
Parent DCF q3wk (With G-CSF) 2
400 IV push
1,000 IV continuous infusion × 2 d
750 IV continuous infusion × 5 d
Tacrolimus Capsules WARNING WARNING Increased Increased susceptibility susceptibility to to infection infection and and the the possible possible development development of of lymphoma lymphoma may may result result from from immunosuppression. immunosuppression. Only Only physicians physicians experienced experienced in in immunosuppressive immunosuppressive therapy therapy and and management management of of organ organ transplant transplant patients patients should should prescribe prescribe tacrolimus tacrolimus capsules. capsules. Patients Patients receiving receiving the the drug drug should should be be managed managed in in facilities facilities equipped equipped and and staffed staffed with with adequate adequate laboratory laboratory and and supportive supportive medical medical resources. resources. The The physician physician responsible responsible for for maintenance maintenance therapy therapy should should have have complete complete information information requisite requisite for for the the follow-up follow-up of of the the patient. patient. INDICATIONS INDICATIONS AND AND USAGE USAGE Tacrolimus Tacrolimus capsules capsules isis indicated indicated for for the the prophylaxis prophylaxis of of organ organ rejection rejection inin patients patients receiving receiving allogeneic allogeneic liver liver or or kidney kidney transplants. transplants. ItIt isis recommended recommended that that tacrolimus tacrolimus capsules capsules be be used used concomitantly concomitantly with with adrenal adrenal corticosteroids. corticosteroids. In In kidney kidney transplant transplant recipients, recipients, itit isis recommended recommended that that tacrolimus tacrolimus capsules capsules be be used used inin conjunction conjunction with with azathioprine azathioprine or or mycophenolate mycophenolate mofetil mofetil (MMF). (MMF). The The safety safety and and efficacy efficacy of of the the use use of of tacrolimus tacrolimus capsules capsules with with sirolimus sirolimus has has not not been been established. established. CONTRAINDICATIONS CONTRAINDICATIONS Tacrolimus Tacrolimus capsules capsules are are contraindicated contraindicated inin patients patients with with aa hypersensitivity hypersensitivity to to tacrolimus. tacrolimus. WARNINGS WARNINGS (See (See boxed boxed WARNING) WARNING) Post-Transplant Post-Transplant Diabetes Diabetes Mellitus Mellitus Insulin-dependent Insulin-dependent post-transplant post-transplant diabetes diabetes mellitus mellitus (PTDM) (PTDM) was was reported reported in in 20% 20% of of tacrolimus-treated tacrolimus-treated kidney kidney transplant transplant patients patients withwithout pretransplant history of diabetes mellitus in the Phase III study. out pretransplant history of diabetes mellitus in the Phase III study. The The median median time time to to onset onset of of PTDM PTDM was was 68 68 days. days. Insulin Insulin dependence dependence was was reversible reversible in in 15% 15% of of these these PTDM PTDM patients patients at at one one year year and and in in 50% 50% at at 22 years years post post transplant. transplant. Black Black and and Hispanic Hispanic kidney kidney transplant transplant patients patients were at an increased risk of development of PTDM. were at an increased risk of development of PTDM. Insulin-dependent Insulin-dependent post-transplant post-transplant diabetes diabetes mellitus mellitus was was reported reported in in 18% 18% and and 11% 11% of of tacrolimus-treated tacrolimus-treated liver liver transplant transplant patients patients and and was was reversible reversible in in 45% 45% and and 31% 31% of of these these patients patients at at 11 year year post post transplant, transplant, in in the the U.S. U.S. and and European European randomized randomized studies, studies, respectively. respectively. HyperHyperglycemia glycemia was was associated associated with with the the use use of of tacrolimus tacrolimus inin 47% 47% and and 33% 33% of of liver liver transplant transplant recipients recipients inin the the U.S. U.S. and and European European randomized randomized studies, studies, respectively, respectively, and and may may require require treatment treatment (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Nephrotoxicity Nephrotoxicity Tacrolimus Tacrolimus capsules capsules can can cause cause nephrotoxicity, nephrotoxicity, particularly particularly when when used used inin high high doses. doses. Nephrotoxicity Nephrotoxicity was was reported reported inin approximately approximately 52% 52% of of kidney kidney transplantation transplantation patients patients and and inin 40% 40% and and 36% 36% of of liver liver transplantransplantation patients receiving tacrolimus capsules in the U.S. and European tation patients receiving tacrolimus capsules in the U.S. and European randomized randomized trials, trials, respectively respectively (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). More More overt overt nephrotoxicity nephrotoxicity isis seen seen early early after after transplantation, transplantation, characterized characterized by by increasing increasing serum serum creatinine creatinine and and aa decrease decrease inin urine urine output. output. Patients Patients with with impaired renal function should be monitored closely as the dosage impaired renal function should be monitored closely as the dosage of of tacrolimus tacrolimus capsules capsules may may need need to to be be reduced. reduced. In In patients patients with with persistent persistent elevations elevations of of serum serum creatinine creatinine who who are are unresponsive unresponsive to to dosage dosage adjustadjustments, ments, consideration consideration should should be be given given to to changing changing to to another another immunoimmunosuppressive suppressive therapy. therapy. Care Care should should be be taken taken inin using using tacrolimus tacrolimus with with other other nephrotoxic nephrotoxic drugs. drugs. In In particular, particular, to to avoid avoid excess excess nephrotoxicity, nephrotoxicity, tacrolimus tacrolimus capsules capsules should should not not be be used used simultaneously simultaneously with with cyclo cyclo-sporine. sporine. Tacrolimus Tacrolimus capsules capsules or or cyclosporine cyclosporine should should be be discontinued discontinued at at least least 24 24 hours hours prior prior to to initiating initiating the the other. other. In In the the presence presence of of elevated elevated tacrolimus capsules or cyclosporine concentrations, dosing with the tacrolimus capsules or cyclosporine concentrations, dosing with the other other drug drug usually usually should should be be further further delayed. delayed. Hyperkalemia Hyperkalemia Mild Mild to to severe severe hyperkalemia hyperkalemia was was reported reported inin 31% 31% of of kidney kidney transplant transplant recipients recipients and and inin 45% 45% and and 13% 13% of of liver liver transplant transplant recipients recipients treated treated with with tacrolimus tacrolimus capsules capsules inin the the U.S. U.S. and and European European randomized randomized trials, trials, respectively, respectively, and and may may require require treatment treatment (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Serum Serum potassium potassium levels levels should should be be monitored monitored and and potassium-sparing potassium-sparing diuretics diuretics should should not not be be used used during during tacrolimus tacrolimus capsules capsules therapy therapy (see (see PRECAUTIONS). PRECAUTIONS). Neurotoxicity Neurotoxicity Tacrolimus Tacrolimus capsules capsules can can cause cause neurotoxicity, neurotoxicity, particularly particularly when when used used inin high high doses. doses. Neurotoxicity, Neurotoxicity, including including tremor, tremor, headache, headache, and and other other changes changes inin motor motor function, function, mental mental status, status, and and sensory sensory function function were were reported reported inin approximately approximately 55% 55% of of liver liver transplant transplant recipients recipients inin the the two two randomized randomized studies. studies. Tremor Tremor occurred occurred more more often often inin tacrolimus tacrolimus capsulescapsulestreated kidney transplant patients (54%) compared to cyclosporinetreated kidney transplant patients (54%) compared to cyclosporinetreated treated patients. patients. The The incidence incidence of of other other neurological neurological events events inin kidney kidney transplant transplant patients patients was was similar similar inin the the two two treatment treatment groups groups (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Tremor Tremor and and headache headache have have been been associated associated with with high high whole-blood whole-blood concentrations concentrations of of tacrolimus tacrolimus and and may may respond respond to to dosage dosage adjustment. adjustment. Seizures Seizures have have occurred occurred inin adult adult and and pediatric pediatric patients patients receiving receiving tacrolimus tacrolimus capsules capsules (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Coma Coma and and delirium delirium also also have have been been associated associated with with high high plasma plasma concentrations concentrations of of tacrolimus. tacrolimus.
Patients Patients treated treated with with tacrolimus tacrolimus have have been been reported reported to to develop develop posterior posterior reversible reversible encephalopathy encephalopathy syndrome syndrome (PRES). (PRES). Symptoms Symptoms indicating indicating PRES PRES include include headache, headache, altered altered mental mental status, status, seizures, seizures, visual visual disturbances disturbances and and hypertension. hypertension. Diagnosis Diagnosis may may be be confirmed confirmed by by radiradiological ological procedure. procedure. IfIf PRES PRES isis suspected suspected or or diagnosed, diagnosed, blood blood pressure pressure control control should should be be maintained maintained and and immediate immediate reduction reduction of of immunoimmunosuppression suppression isis advised. advised. This This syndrome syndrome isis characterized characterized by by reversal reversal of of symptoms symptoms upon upon reduction reduction or or discontinuation discontinuation of of immunosuppression. immunosuppression. Malignacy Malignacy and and Lymphoproliferative Lymphoproliferative Disorders Disorders As As inin patients patients receiving receiving other other immunosuppressants, immunosuppressants, patients patients receiving receiving tacrolimus tacrolimus capsules capsules are are at at increased increased risk risk of of developing developing lymphomas lymphomas and and other other malignancies, malignancies, particularly particularly of of the the skin. skin. The The risk risk appears appears to to be be related related to to the the intensity intensity and and duration duration of of immunosuppression immunosuppression rather rather than than to to the the use use of of any any specific specific agent. agent. AA lymphoproliferative lymphoproliferative disorder disorder (LPD) (LPD) related related to to Epstein-Barr Virus (EBV) infection has been reported in immunosupEpstein-Barr Virus (EBV) infection has been reported in immunosuppressed pressed organ organ transplant transplant recipients. recipients. The The risk risk of of LPD LPD appears appears greatest greatest inin young young children children who who are are at at risk risk for for primary primary EBV EBV infection infection while while immunoimmunosuppressed suppressed or or who who are are switched switched to to tacrolimus tacrolimus capsules capsules following following long-term immunosuppression therapy. Because of the danger long-term immunosuppression therapy. Because of the danger of of overoversuppression suppression of of the the immune immune system system which which can can increase increase susceptibility susceptibility to to infection, infection, combination combination immunosuppressant immunosuppressant therapy therapy should should be be used used with with caution. caution. Latent Latent Viral Viral Infections Infections Immunosuppressed Immunosuppressed patients patients are are at at increased increased risk risk for for opportunistic opportunistic infections, infections, including including latent latent viral viral infections. infections. These These include include BK BK virus virus associated associated nephropathy nephropathy and and JC JC virus virus associated associated progressive progressive multifocal multifocal (PML) which have been observed in patients leukoencephalopathy leukoencephalopathy (PML) which have been observed in patients receiving receiving tacrolimus. tacrolimus. These These infections infections may may lead lead to to serious, serious, including including fatal, fatal, outcomes. outcomes. PRECAUTIONS PRECAUTIONS General General Hypertension Hypertension isis aa common common adverse adverse effect effect of of tacrolimus tacrolimus therapy therapy (see (see ADVERSE ADVERSE REACTIONS). REACTIONS). Mild Mild or or moderate moderate hypertension hypertension isis more more frequently frequently reported reported than than severe severe hypertension. hypertension. Antihypertensive Antihypertensive therapy therapy may may be be required; required; the the control control of of blood blood pressure pressure can can be be accomplished accomplished with with any any of of the the common common antihypertensive antihypertensive agents. agents. Since Since tacrolimus tacrolimus may may cause cause hyperkalemia, hyperkalemia, potassium-sparing potassium-sparing diuretics diuretics should should be be avoided. avoided. While While calcium-channel calcium-channel blocking blocking agents agents can can be be effective effective inin treating treating tacrolimus-associated tacrolimus-associated hypertension, hypertension, care care should should be be taken taken since since interferinterference with tacrolimus metabolism may require a dosage reduction ence with tacrolimus metabolism may require a dosage reduction (see (see Drug Drug Interactions). Interactions). Renally Renally and and Hepatically Hepatically Impaired Impaired Patients Patients For For patients patients with with renal renal insufficiency insufficiency some some evidence evidence suggests suggests that that lower lower doses should be used. The use of tacrolimus doses should be used. The use of tacrolimus capsules capsules inin liver liver transplant transplant recipients recipients experiencing experiencing post-transplant post-transplant hepatic hepatic impairment impairment may may be be associated associated with with increased increased risk risk of of developing developing renal renal insufficiency insufficiency related related to to high high whole-blood whole-blood levels levels of of tacrolimus. tacrolimus. These These patients patients should should be be monitored monitored closely closely and and dosage dosage adjustments adjustments should should be be considered. considered. Some Some evidence evidence suggests suggests that that lower lower doses doses should should be be used used inin these these patients. patients. Myocardial Myocardial Hypertrophy Hypertrophy Myocardial Myocardial hypertrophy hypertrophy has has been been reported reported inin association association with with the the administration administration of of tacrolimus tacrolimus capsules, capsules, and and isis generally generally manifested manifested by by echocardiographically echocardiographically demonstrated demonstrated concentric concentric increases increases inin left left venventricular tricular posterior posterior wall wall and and interventricular interventricular septum septum thickness. thickness. Hypertrophy Hypertrophy has has been been observed observed inin infants, infants, children children and and adults. adults. This This condition condition appears appears reversible reversible inin most most cases cases following following dose dose reduction reduction or or discontinuance discontinuance of of therapy. therapy. In In aa group group of of 20 20 patients patients with with prepre- and and post-treatment post-treatment echocarechocardiograms diograms who who showed showed evidence evidence of of myocardial myocardial hypertrophy, hypertrophy, mean mean tacrolimus tacrolimus whole whole blood blood concentrations concentrations during during the the period period prior prior to to diagnosis diagnosis of of myocardial myocardial hypertrophy hypertrophy ranged ranged from from 11 11 to to 53 53 ng/mL ng/mL inin infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age 22 to to 15 15 years) years) and and 11 11 to to 24 24 ng/mL ng/mL inin adults adults (N=3, (N=3, age age 37 37 to to 53 53 years). years). In In patients patients who who develop develop renal renal failure failure or or clinical clinical manifestations manifestations of of ventricuventricular lar dysfunction dysfunction while while receiving receiving tacrolimus tacrolimus therapy, therapy, echocardiographic echocardiographic evalevaluation should be considered. If myocardial hypertrophy is diagnosed, uation should be considered. If myocardial hypertrophy is diagnosed, dosage dosage reduction reduction or or discontinuation discontinuation of of tacrolimus tacrolimus should should be be considered. considered. Information Information for for Patients Patients Patients Patients should should be be informed informed of of the the need need for for repeated repeated appropriate appropriate labolaboratory ratory tests tests while while they they are are receiving receiving tacrolimus tacrolimus capsules. capsules. They They should should be be given given complete complete dosage dosage instructions, instructions, advised advised of of the the potential potential risks risks during during pregnancy, pregnancy, and and informed informed of of the the increased increased risk risk of of neoplasia. neoplasia. Patients Patients should should be be informed informed that that changes changes inin dosage dosage should should not not be be undertaken undertaken without without first first consulting their physician. consulting their physician. Patients Patients should should be be informed informed that that tacrolimus tacrolimus capsules capsules can can cause cause diabetes diabetes mellitus mellitus and and should should be be advised advised of of the the need need to to see see their their physician physician ifif they they develop develop frequent frequent urination, urination, increased increased thirst thirst or or hunger. hunger. As As with with other other immunosuppressive immunosuppressive agents, agents, owing owing to to the the potential potential risk risk of of malignant malignant skin skin changes, changes, exposure exposure to to sunlight sunlight and and ultraviolet ultraviolet (UV) (UV) light light should should be be limited limited by by wearing wearing protective protective clothing clothing and and using using aa sunscreen sunscreen with with aa high high protection protection factor. factor.
‘By fine-tuning the regimen, Dr. Shah and his colleagues from multiple centers appear to have maintained the regimen’s efficacy while easing the side-effect profile.’ —Richard M. Goldberg, MD better tolerated than the original DCF program that has not been widely adopted due to patients’ difficulty tolerating it. “By fine-tuning the regimen, [the investigators] maintained the regimen’s efficacy while easing the side-effect profile,”
Laboratory Laboratory Tests Tests Serum Serum creatinine, creatinine, potassium, potassium, and and fasting fasting glucose glucose should should be be assessed assessed regularly. regularly. Routine Routine monitoring monitoring of of metbolic metbolic and and hematologic hematologic systems systems should should be be performed performed as as clinically clinically warranted. warranted. Drug Drug Interactions Interactions Due Due to to the the potential potential for for additive additive or or synergistic synergistic impairment impairment of of renal renal function, function, care care should should be be taken taken when when administering administering tacrolimus tacrolimus capsules capsules with with drugs drugs that that may may be be associated associated with with renal renal dysfunction. dysfunction. These These include, include, but but are are not not limited limited to, to, aminoglycosides, aminoglycosides, amphotericin amphotericin B, B, and cisplatin. Initial clinical experience with the co-administration and cisplatin. Initial clinical experience with the co-administration of of tacrolimus tacrolimus and and cyclosporine cyclosporine resulted resulted inin additive/synergistic additive/synergistic nephronephrotoxicity. toxicity. Patients Patients switched switched from from cyclosporine cyclosporine to to tacrolimus tacrolimus should should receive receive the the first first tacrolimus tacrolimus capsules capsules dose dose no no sooner sooner than than 24 24 hours hours after after the the last last cyclosporine cyclosporine dose. dose. Dosing Dosing may may be be further further delayed delayed inin the the presence presence of of elevated cyclosporine levels. elevated cyclosporine levels. Drugs Drugs that that May May Alter Alter Tacrolimus Tacrolimus Concentrations Concentrations Since Since tacrolimus tacrolimus isis metabolized metabolized mainly mainly by by the the CYP3A CYP3A enzyme enzyme systems, substances known to inhibit systems, substances known to inhibit these these enzymes enzymes may may decrease decrease the the metabolism metabolism or or increase increase bioavailability bioavailability of of tacrolimus tacrolimus as as indicated indicated by by increased increased whole whole blood blood or or plasma plasma concentrations. concentrations. Drugs Drugs known known to to induce induce these these enzyme enzyme systems systems may may result result inin an an increased increased metabolism metabolism of of tacrolimus tacrolimus or or decreased decreased bioavailability bioavailability as as indicated indicated by by decreased decreased whole blood or plasma concentrations. Monitoring of blood concenwhole blood or plasma concentrations. Monitoring of blood concentrations trations and and appropriate appropriate dosage dosage adjustments adjustments are are essential essential when when such such drugs drugs are are used used concomitantly. concomitantly. Drugs Drugs that that may may increase increase tacrolimus tacrolimus blood blood concentrations: concentrations: Calcium Calcium Channel Channel Blockers: Blockers: diltiazem, diltiazem, nicardipine, nicardipine, nifedipine, nifedipine, verapamil; verapamil; AntiAntifungal fungal Agents: Agents: clotrimazole, clotrimazole, fluconazole, fluconazole, itraconazole, itraconazole, ketoconazole, ketoconazole, voriconazole; voriconazole; Macrolide Macrolide Antibiotics: Antibiotics: clarithromycin, clarithromycin, erythromycin, erythromycin, troleandomycin; troleandomycin; Gastrointestinal Gastrointestinal Prokinetic Prokinetic Agents: Agents: cisapride, cisapride, metometoclopramide; Other Drugs: bromocriptine, chloramphenicol, clopramide; Other Drugs: bromocriptine, chloramphenicol, cimetidine, cimetidine, cyclosporine, cyclosporine, danazol, danazol, ethinyl ethinyl estradiol, estradiol, methylprednisolone, methylprednisolone, omeprazole, omeprazole, pretease pretease inhibitors, inhibitors, nefazodone, nefazodone, magnesium-aluminum-hydroxide. magnesium-aluminum-hydroxide. Drugs Drugs that that may may decrease decrease tacrolimus tacrolimus blood blood concentrations: concentrations: AnticonvulAnticonvulsants: sants: carbamazepine, carbamazepine, Phenobarbital, Phenobarbital, penytoin; penytoin; Antimicrobials: Antimicrobials: rifabutin, rifabutin, caspofungin, caspofungin, rifampin; rifampin; Herbal Herbal Preparations: Preparations: St. St. John’s John’s Wort; Wort; Other Other Drugs: Drugs: sirolimus sirolimus This This list list isis not not all-inclusive. all-inclusive. St. St. John’s John’s Wort Wort (Hypericum (Hypericum perforatum) perforatum) induces induces CYP3A4 CYP3A4 and and P-glycoprotein. P-glycoprotein. Since Since tacrolimus tacrolimus isis aa substrate substrate for for CYP3A4, CYP3A4, there there isis the the potential potential that that the the use use of of St. St. John’s John’s Wort Wort inin patients patients receiving receiving tacrolimus tacrolimus capsules could result in reduced tacrolimus levels. capsules could result in reduced tacrolimus levels. Interaction Interaction studies studies with with drugs drugs used used inin HIV HIV therapy therapy have have not not been been conducted. conducted. However, However, care care should should be be exercised exercised when when drugs drugs that that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., (e.g., nelfinavir, nelfinavir, ritonavir) ritonavir) are are administered administered concomitantly concomitantly with with tacrolimus. tacrolimus. Tacrolimus Tacrolimus may may affect affect the the pharmacokinetics pharmacokinetics of of other other drugs drugs (e.g., (e.g., phenytoin) phenytoin) and and increase increase their their concentration. concentration. Grapefruit Grapefruit juice juice affects affects CYP3A-mediated CYP3A-mediated metabolism metabolism and and should should be be avoided. avoided. Following Following co-administration co-administration of of tacrolimus tacrolimus and and sirolimus sirolimus (2 (2 or or 55 mg/ mg/ day) day) inin stable and CCmin stable renal renal transplant transplant patients, patients, mean mean tacrolimus tacrolimus AUC AUC0-12 0-12 and min decreased decreased approximately approximately by by 30% 30% relative relative to to tacrolimus tacrolimus alone. alone. Mean Mean tacrolimus and CCmin following co-administration co-administration of of 11 mg/day mg/day tacrolimus AUC AUC0-12 0-12 and min following of of sirolimus sirolimus decreased decreased approximately approximately 3% 3% and and 11%, 11%, respectively. respectively. The The safety safety and and efficacy efficacy of of tacrolimus tacrolimus used used inin combination combination with with sirolimus sirolimus for for the the prevention prevention of of graft graft rejection rejection has has not not been been established established and and isis not not recommended. recommended. Other Other Drug Drug Interactions Interactions Immunosuppressants Immunosuppressants may may affect affect vaccination. vaccination. Therefore, Therefore, during during treatment treatment with with tacrolimus tacrolimus capsules, capsules, vaccination vaccination may may be be less less effective. effective. The The use use of of live live vaccines vaccines should should be be avoided; avoided; live live vaccines vaccines may may include, but are not limited to measles, mumps, rubella, oral polio, BCG, include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow yellow fever, fever, and and TY TY 21a 21a typhoid. typhoid.11 At At aa given given MMF MMF dose, dose, mycophenolic mycophenolic acid acid (MPA) (MPA) exposure exposure isis higher higher with with tacrolimus tacrolimus capsules capsules co-administration co-administration than than with with cyclosporine cyclosporine co-administration co-administration due due to to the the differences differences inin the the interruption interruption of of the the entero entero-hepatic hepatic recirculation recirculation of of MPA. MPA. Clinicians Clinicians should should be be aware aware that that there there isis also also aa potential potential for for increased increased MPA MPA exposure exposure after after crossover crossover from from cyclosporine cyclosporineto totacrolimus tacrolimusininpatients patientsconcomitantly concomitantlyreceiving receivingMMF MMFor orMPA. MPA. Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, Impairment Impairment of of Fertility Fertility An An increased increased incidence incidence of of malignancy malignancy isis aa recognized recognized complication complication of of immunosuppression immunosuppression inin recipients recipients of of organ organ transplants. transplants. The The most most common common forms forms of of neoplasms neoplasms are are non-Hodgkin’s non-Hodgkin’s lymphomas lymphomas and and carcinomas carcinomas of of the the skin. skin. As As with with other other immunosuppressive immunosuppressive therapies, therapies, the the risk risk of of malignancies malignancies inin tacrolimus tacrolimus recipients recipients may may be be higher higher than than inin the the normal, normal, healthy healthy population. population. Lymphoproliferative Lymphoproliferative disorders disorders associated associated with with Epstein-Barr Epstein-Barr Virus Virus infection infection have have been been seen. seen. ItIt has has been been reported reported that that reduction reduction or or discontinuation of immunosuppression may cause the lesions discontinuation of immunosuppression may cause the lesions to to regress. regress.
Dr. Goldberg noted. “This is a much better platform to which targeted agents can be added than the original DCF regimen and the investigators should be congratulated for this important work.” —Caroline Helwick
Pharmacy Practice News • March 2010
Bisphosphonates: A Dual Benefit in Breast Cancer? San Antonio–Oral bisphosphonates can prevent the development of breast cancer in healthy women, according to two recent studies. The findings, presented at the 2009 San Antonio Breast Cancer Symposium (SABCS), add to the growing evidence
No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes. Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 - 2.5 times (mice) and 3.5 - 7.1 times (rats) the recommended clinical dose range of 0.1 - 0.2 mg/kg/day when corrected for body surface area. No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1 mg/kg (0.7 - 1.4X the recommended clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of preimplantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations. Pregnancy: Category C In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 - 1X and 1.6 - 3.3X the recommended clinical dose range (0.1 - 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1 and 3.2 mg/kg (equivalent to 0.7 - 1.4X and 2.3 - 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights. No reduction in male or female fertility was evident. There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus capsules should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus. Nursing Mothers Since tacrolimus is excreted in human milk, nursing should be avoided. Pediatric Patients Experience with tacrolimus in pediatric kidney patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using tacrolimus capsules. Two randomized trials of tacrolimus capsules in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimusbased and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus capsules to maintain blood trough concentrations of tacrolimus similar to adult patients. ADVERSE REACTION Liver Transplantation The principal adverse reactions of tacrolimus are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of tacrolimus and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Hyperkalemia and hypomagnesemia have occurred in patients receiving tacrolimus therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS). Kidney Transplantation The most common adverse reactions reported were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain and insomnia. Less Frequently Reported Adverse Reactions The following adverse events were reported in either liver and/or kidney transplant recipients who were treated with tacrolimus in clinical trials.
that bisphosphonates have anti-cancer properties. Previously, studies have shown that bisphosphonates can reduce the risk for breast cancer recurrences. “While these findings need confirmation, the idea that bisphosphonates can [prevent] breast cancer is very exciting, because about 30 million
Nervous System (see WARNINGS) Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, headache, hypertonia, incoordination, insomnia, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paresthesia, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired Special Senses Abnormal vision, amblyopia, ear pain, otitis media, tinnitus Gastrointestinal Anorexia, cholangitis, cholestatic jaundice, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, nausea, nausea and vomiting, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting Cardiovascular Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, chest pain, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital (see WARNINGS) Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis Metabolic/Nutritional Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, edema, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, peripheral edema, weight gain Endocrine (see PRECAUTIONS) Cushing’s syndrome, diabetes mellitus Hemic/Lymphatic Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia Miscellaneous Abdomen enlarged, abdominal pain, abscess, accidental injury, allergic reaction, asthenia, back pain, cellulitis, chills, fall, feeling abnormal, fever, flu syndrome, generalized edema, hernia, mobility decreased, pain, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis Respiratory Asthma, bronchitis, cough increased, dyspnea, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration
prescriptions are written for these agents each year in the United States targeting bone health. More [of the drug] could easily be used to counteract both osteoporosis and breast cancer,” said Rowan Chlebowski, MD, lead author of one of the bisphosphonate studies presented at SABCS (abstract 21).
WHI Study Dr. Chlebowski, a medical oncologist at the Los Angeles Biomedical Research
Gastrointestinal Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis,hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease Hemic/Lymphatic Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura Metabolic/Nutritional Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Nervous System Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope Respiratory Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure Skin Stevens-Johnson syndrome, toxic epidermal necrolysis Special Senses Blindness, blindness cortical, hearing loss including deafness, photophobia Urogenital Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder. There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving tacrolimus therapy (see PRECAUTIONS-Myocardial Hypertrophy). Please see current package insert for complete adverse events information. OVERDOSAGE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in the ADVERSE REACTIONS section except in one case where transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage. REFERENCE: 1 CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993;42(RR-4):1-18.
Skin Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating POST MARKETING Post Marketing Adverse Events The following adverse events have been reported from worldwide marketing experience with tacrolimus. Cardiovascular Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation
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Institute at Harbor-UCLA Medical Center, said his study focused on the association between bisphosphonates and invasive breast cancer, using data from more than 154,000 generally healthy, postmenopausal women enrolled in the Women’s Health Initiative (WHI). The analysis showed that women who took bisphosphonates (90% alendronate; Fosamax, Merck) for osteopenia or osteoporosis had 31% fewer cases of invasive breast cancer than those who did not take bisphosphonates (P<0.01). The analysis focused on 10,000 women in the WHI whose medical records included results of bone mineral density studies. Of these, 2,216 were using bisphosphonates at entry to the study. Sixtyfour of those women developed breast cancer; 50 of the cancers were estrogen receptor-positive. An age-adjusted analysis showed that women taking an oral bisphosphonate had a breast cancer rate of 3.29 per 1,000 women-years of follow-up versus a corresponding rate of 4.38 among women not taking a bisphosphonate. There were 30% fewer estrogen receptor–positive cancers (P=0.01) and 34% fewer estrogen receptor–negative cancers in bisphosphonate users (not statistically different). In contrast, the incidence of ductal carcinoma in situ (DCIS) was increased in bisphosphonate users compared with non-users (1.53 vs. 0.92 per 1,000 patientyears, respectively; P=0.002). Dr. Chlebowski speculated that this phenomenon may occur because in situ lesions are arrested by bisphosphonates and prevented from becoming invasive lesions. Additional studies are needed to clarify the findings related to DCIS. Dr. Chlebowski added that ongoing randomized trials of oral and intravenous bisphosphonates being conducted in the adjuvant setting will help shed light on whether these agents can reduce the risk for new contralateral breast cancers.
Israeli Study In a second study presented at SABCS (abstract 27), a smaller case-control trial from Israel of 4,575 postmenopausal healthy women identified a 34% reduction in the relative risk for breast cancer in women taking bisphosphonates. The study matched 2,368 cases of newly diagnosed breast cancer with a control group for age, ethnic background and residential area. Women were interviewed extensively about medical and family history as well as medication use. The self-reported data were validated by pharmacy records, said lead author Gar Rennert, MD, from the Carmel Medical Center of Clalit Health Services and the Technion-Israel Institute of Technology, in Haifa. Women who were long-term users of
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Pharmacy Practice News • March 2010
In Focus Non-bisphosphonate users
Rate per 1,000 Women-years of Follow-up
‘The jury is still out on whether there are direct anti-tumor effects for bisphosphonates that are clinically meaningful.’ —Andrew Seidman, MD
2 1 0
Figure. Comparison of rate of invasive breast cancer in Women’s Health Initiative. bisphosphonates had a 34% reduction in breast cancer incidence compared with non-users (2.5% vs. 3.7%, respectively). After adjusting for risk factors that included age, dietary consumption of fruits and vegetables, exercise, family history, ethnic group, body mass index, calcium supplementation, hormone replacement therapy use, number of pregnancies, months of breastfeeding and age at first pregnancy, the relative risk reduction in breast cancer between users and non-users was 29%. The effect on breast cancer was observed after patients took bisphosphonates for one year and remained stable over subsequent years. Dr. Rennert said that most of the breast cancers that developed in bisphosphonate users were estrogen receptor–positive, were better differentiated and had a better prognosis than the cancers that developed in the non-bisphosphonate users. Additionally, there was no increase in DCIS incidence in bisphosphonate users in this study. “This study shows an association, not a proof. Randomized clinical trials are needed,” Dr. Rennert said.
Putting It in Perspective Theresa Guise, MD, a professor at the Indiana University School of Medicine in Indianapolis, noted that osteoporosis and breast cancer are both common problems in postmenopausal women. Dr. Guise said it is encouraging that a second study in a different population found a similar protective effect against new breast cancers. “This cohort study indicates the possibility that a simple oral drug may prevent both of these common conditions,” she said. However, “this [finding] needs to be confirmed by prospective, placebo-controlled clinical trials.” Researchers have put forth several possible explanations as to why bisphosphonates may have an anti-tumor effect; one involves angiogenesis. “Bisphosphonates reduce angiogenesis and stimulate immune cells responsible for tumor cell surveillance as potential mediators,” Dr. Chlebowski said. “This association needs to be studied further.” Alison Stopeck, MD, associate professor of medicine at the Arizona Cancer Center,
University of Arizona Health Sciences Center, Tucson, offered another explanation. “Bisphosphonates, and osteoclast-targeting agents in general—including denosumab [Prolia, Amgen]—may poison the soil [i.e., the bone microenvironment] by inhibiting osteoclast activity,” Dr. Stopeck said. “By resorbing bone, osteoclasts can
release growth factors and cytokines from the bone matrix that foster tumor growth and adhesion to bone.” Andrew Seidman, MD, attending physician, Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York City, said more evidence is needed before any changes to practice
are made. Despite the two SABCS trials as well as the ABCSG-12 and the ZO-FAST trials that showed a signal for reduction in breast cancer recurrence, he said he awaits the results of larger, better-powered studies (e.g., AZURE, NSABP) to confirm whether bisphosphonates confer an anti-tumor effect as opposed to a pure bone-strengthening effect. “The jury is still out,” Dr. Seidman explained, “on whether there are direct anti-tumor effects for bisphosphonates that are clinically meaningful.” —Alice Goodman
PPN • March 2010
PRACTICE PULSE continued from page 1
Reimbursement for their patients and themselves is a perennial issue for hematology/oncology pharmacists. One stunning example of the challenges they face is the disparity in out-of-pocket costs between oral and IV chemotherapy, said Niesha Griffith, MS, RPh, FASHP, director of the pharmacy and hematology/oncology residency program at the Arthur G. James Cancer Hospital at Ohio State University in Columbus. “Intravenous chemotherapy products are usually well covered under medical benefits, but newer oral chemotherapy agents often are placed on the highest tier of the pharmacy benefit plan,” she said. “Patients on oral chemotherapy then face monthly drug costs in the thousands of dollars.” Dr. Griffith added that patients on Medicare often reach their coverage gap with their first prescription fill, and with such high out-of-pocket expenses, oral chemotherapy is unaffordable for many patients. “This raises the question—should oral products be covered like IV products?” She noted that the reimbursement concerns over oral chemotherapy have
chemotherapy drugs there are four or five checks along the line. None of that is reimbursed.” Reimbursement issues also affect pharmacists who provide end-of-life care, and expense can be a consideration when oncology patients are transitioning to a hospice program, said Bridget C. Fowler, PharmD, clinical pharmacy manager at the Dana-Farber C a n c e r I n s t i t u t e Department of Pharmacy in Boston. “Hospice only has so many dollars a day, and some medications may be exorbitantly expensive, so we need to be mindful of how that affects our clinical recommendations. Sometimes we may have to recommend different medications,” she said. The situation becomes even more complex when patients receive palliative chemotherapy, itself an evolving issue in oncology pharmacy. “With chemotherapy, there’s a question of whether it is intended for lengthening life or alleviating symptoms,” said Dr. Fowler. “[Issues] like that dovetail into the decision about when it’s appropriate to refer a patient to hospice, and there may be a delay in hospice admission until weeks or days before death because of hesitance to choose one [purpose] or the other.
‘The common theme for reimbursement is that all you are really covering is the cost of the drug, and sometimes not even that.’ —Niesha Griffith, MS, RPh, FASHP
another layer, that of reimbursement for pharmacists for patient education. “When a patient is in the clinic for IV treatment, we do the education during the infusion. But with oral treatment, we’re turning things over to the patient and we might not see them for another month,” she said. “There’s a lot that’s not being paid for with oral chemo, which usually requires 30 to 60 minutes of education.” Oral chemotherapy is just one example, however. “The common theme for reimbursement is that all you are really covering is the cost of the drug, and sometimes not even that,” said Ms. Griffith, who is HOPA’s past legislative chair. “[The Centers for Medicare & Medicaid Services] has not recognized the role of the pharmacist, the education that takes place with the patient, the clinical decision-making process, the overhead costs of the pharmacy or all of the safety checks—and with
“We want what is clinically best, but Medicare hospice reimbursement is not set up for [lengthy chemotherapy], and hospice programs cannot continue to provide care without getting paid,” she added.
Off-Label Use Reimbursement for off-label use is another hot topic, said Amy Hatfield Seung, PharmD, BCOP, program director of oncology pharmacy practice residency in the Department of Pharmacy at Johns Hopkins Hospital in Baltimore. She points to the monoclonal antibody ofatumumab (Arzerra, GlaxoSmithKline), which is approved for use in treating chronic lymphocytic leukemia (CLL). The drug attaches to a molecule called CD20, which is found on the surface of B cells, the type of cell that becomes cancerous in patients with CLL. “This new drug is being touted as
Hem/Onc Pharmacy 13
Pharmacy Practice News • March 2010
In Focus potentially being useful for CD20 in patients with non-Hodgkin’s lymphoma, but there already is a CD20 antibody on the market for that, rituximab [Rituxan, Genentech and Biogen IDEC],” Dr. Seung said. “Ofatumumab is now only being studied as an alternative agent. We’re trying to decide whether to add it to the formulary, and for now, we have to make sure patients get insurance approval before committing to it.” “A lot of places simply write off the costs of off-label use. It takes resources to track claims or take them to a second denial,” said Ms. Griffith. But there are creative ways to recoup costs. “Sometimes the drug companies will reimburse you with free replacements. Other times we enlist their help. Right now we’re trying to get drug companies to help us get paid to the tune of more than $1.5 million.” With new research appearing in the literature every day, the battle for reimbursement is hardly a detriment to off-label use. “So many drugs are being studied in so many types of cancer. Doctors know if a drug is being studied in a trial, and if it’s successful, they want to use it even if it’s off-label,” said Ms. Griffith. The most important factor in deciding to use a drug off-label is whether there are data establishing its safety and efficacy, said Leila R. Mohassel, PharmD, BCPS, BCOP, clinical pharmacy specialist in hematology/oncology at Inova Fairfax Hospital in Falls Church, Va. “Is there sufficient evidence? If there is, then cost should be secondary,” she said. “But sometimes prescribers want to try things that don’t have as much data and the drug involved is expensive. Those are the situations where you struggle with what you want to do.”
‘It really depends on where the FDA lands [with REMS], but in my experience as an oncology pharmacist, sometimes what is well intended can be a huge challenge to overcome.’ —Bridget C. Fowler, PharmD would be a lot more significant than it was,” said Ms. Griffith. “However, the problem with shortages is that there’s no notice. You don’t know why there is a shortage or how long it will last. The drug companies are not obliged to tell the FDA. Unfortunately, a lot of these drugs don’t have an alternative.” That leaves pharmacists and prescribers scrambling to ensure treatment, she said.
programs may differ depending on the drug being tracked. “The main concern is that the FDA doesn’t have a template for REMS, and they leave it up to the drug companies to determine what REMS programs should consist of and what the requirements would be,” said Ms. Griffith. “The FDA has provided a general framework, but we really want standardization. Right now, the REMS programs could have one
‘Doctors know if a drug is being studied in a trial, and if it’s successful, they want to use it even if it’s off-label.’ —Amy Hatfield Seung, PharmD, BCOP
Drug Shortages Several drug shortages in recent years have left hematology/oncology pharmacists with lingering concerns. A survey of 145 HOPA members last year indicated that although less than 8% of respondents reported having to “change treatment due to drug unavailability,” such changes were needed more frequently with the following medications: acyclovir (Zovirax, GlaxoSmithKline, 17.9%), dexrazoxane (Zinecard, Pfizer, 12.3%), leucovorin (31.7%) and ondansetron (Zofran, GlaxoSmithKline, 16.2%). According to the survey, less than 4% reported having to actually stop treatment or hold drug therapy until the drug shortage was alleviated. But again, there were important exceptions: Such interruptions were more common for dexrazoxane (13%), leucovorin (15.5%) and mitomycin (Mutamycin, BristolMyers Squibb, 23.2%). “We thought the patient care impact
Ms. Griffith added that to make matters worse, the FDA isn’t always aware of the shortages. “There was one case when a gentleman on our legislative committee sent me an e-mail saying he had notified the FDA about a cancer drug shortage, and the FDA basically said, ‘Thanks for the heads up.’”
set of requirements for erythropoietin drugs and another for opioid drugs. Do you know how many opioids are prescribed in a chemo center every day? The drug companies have been back and forth with the FDA because they know this will be an issue when it hits the physician’s office or clinic.”
Impact of REMS Still a Huge Question
‘A Logistical Nightmare’
As hematology/oncology pharmacists grapple with ongoing issues regarding reimbursement and shortages, REMS programs loom on the horizon. Because of its role in dispensing drugs, the pharmacy is a natural hub for the extensive patient and provider tracking that the programs will require, which means that the lion’s share of the work most likely will fall to pharmacists. To complicate the matter further, REMS
The looming REMS programs are “a logistical nightmare,” said Dr. Fowler. “It really depends on where the FDA lands, but in my experience as an oncology pharmacist, sometimes what is well intended can be a huge challenge to overcome.” Dr. Fowler said her concern stems from the amount of paperwork REMS programs would require. “The intent is safety, and that requires a lot of monitoring,” she said. “Each patient and provider would have to be registered,
and pharmacists will have to collect information, verify the registrations and prescriptions. It will be interesting to see how these programs are approached and how it affects patient care.” According to Dr. Seung, the impact of the REMS initiative will be broad and deep. “REMS programs are going to affect virtually all oncology pharmacists,” she said. “These programs will be applied to oral and subcutaneous agents, treatment agents and supportive agents like antibiotics.” Another significant concern is the time it will take to monitor so many drugs when many clinics and hospitals are facing hiring freezes and already juggling tasks among their existing staff, she noted. Overall, the pharmacist’s place in hematology/oncology practice will accommodate changes in treatment and policy, Dr. Seung said. “Our role is always evolving.”
HOPA President Encouraged By Progress HOPA president Phil Johnson, MS, RPh, said that all of these practice issues pose significant challenges. But he said he was encouraged by the positive impact HOPA has been able to make on hematology/oncology pharmacy practice. “We had lots of legislative and policy victories in the past year, which built on other successes we’ve had since HOPA’s inception,” Mr. Johnson said. He cited, as an example, HOPA’s efforts to provide more control over the board-certification process for pharmacists seeking advanced training in hematology/oncology. This process has traditionally been coordinated by the American College of Clinical Pharmacy (ACCP), as part of its larger role in offering advanced practice training and credentialing for a wide range of specialties. “All stakeholders agreed that the hematology/oncology portion of that process could be handled more efficiently by a group such as HOPA, because we have a more targeted focus on this practice area,” Mr. Johnson said. “ACCP and ASHP supported that change and we all agree that it is to the benefit of oncology practitioners.” Mr. Johnson also pointed to the continued growth of HOPA as an organization. “Each year, the number of abstracts detailing original research presented at our annual meeting grows, as does meeting attendance and membership. “That’s very encouraging,” he said. “Am I concerned about some of the practice issues outlined here? Of course. But I am confident that our leadership is looking very carefully at these issues and will continue to serve the needs of members and the specialty.” —Terri D’Arrigo
Pharmacy Practice News • March 2010
BCIRG Trial Spotlights Anthracycline Role in Breast Cancer T
he third and final interim analysis of the Phase III BCIRG (Breast Cancer International Research Group) 006 study has rekindled debate over whether anthracycline-based trastuzumab (Herceptin, Genentech) regimens should be continued in patients with human epidermal growth factor receptor 2 (HER2)positive breast cancer. Triggering the concern are data showing up to a fivefold increase in congestive heart failure (CHF) seen in the anthracycline-based arm of the trial, according to Dennis Slamon, MD, co-chair of the study, who presented the results at the 2009 San Antonio Breast Cancer Symposium (SABCS, abstract 62). The new results dovetail with data presented at the 29th annual SABCS in 2006. When those data (abstract 52) were presented, Dr. Slamon, director of clinical and translational research at the University of California, Los Angeles Jonsson Comprehensive Cancer Center, questioned whether anthracycline-based regimens should remain a viable treatment option for most patients with HER2positive disease. “If we are now causing more problems than we are solving with [such] regimens, we have to rethink what we are doing,” he said. At the 2009 SABCS, after presenting the latest BCIRG 006 results and reviewing the toxicity data, Dr. Slamon expressed similar concerns and concluded that the benefits of anthracyclines appear to be restricted to higher-risk patients—specifically, those with topoisomerase II amplification. But several breast cancer experts say they are not yet ready to completely abandon anthracyclines. Laura Boehnke Michaud, PharmD, manager of clinical pharmacy services at the University of Texas M.D. Anderson Cancer Center in Houston, acknowledged that cardiac toxicity is higher with the chemotherapeutic agents. “In absolute terms, however, it is still extremely low [less than 2% in the anthracycline arm],” she said. “Those results have to be balanced with the added [survival] benefit seen in the trastuzumab-plus-anthracycline arm.”
Study Detailed BCIRG 006 randomized 3,222 patients with documented HER2-positive early breast cancer to one of three treatment arms: a control arm (AC-T) of anthracycline (doxorubicin) and cyclophosphamide therapy followed by docetaxel (Taxotere, Sanofi-aventis); an experimental arm of the anthracycline-based AC-T regimen followed by one year of trastuzumab (AC-TH); and another experimental arm of trastuzumab coupled with non-anthracycline (docetaxel/carboplatin) chemotherapy (TCH).
Patients were enrolled from April 2001 to March 2004. Median age was approximately 53 years; about 60% of the patients had a mastectomy, approximately 68% had radiotherapy, and about 51% had hormone therapy. Twenty-nine percent of all patients were node-negative; about 38% had one to three nodes involved; about 23% had four to 10 nodes involved; and approximately 10% had more than 10 nodes involved. The primary end point of the study was disease-free survival (DFS). At the first planned analysis in 2005, DFS was 84% for AC-TH (P<0.0001 compared with the AC-T control arm), 80% for TCH (P=0.0002) and 73% for AC-T. In the updated five-year data reported at the 2009 SABCS, DFS was 84% for ACTH (P<0.001), 81% for TCH (P=0.04) and 75% for AC-T, Dr. Slamon reported.
trol (P=0.0003 for AC-TH and P=0.013 for TCH). In high-risk patients with four or more positive nodes, five-year DFS was 73%, 72% and 61%, respectively, which was highly significant for AC-TH and TCH arms versus AC-T (P=0.002 for AC-TH and TCH arms). OS in those patients with four or more positive nodes was 84%, 83% and 76%, respectively. Only the AC-TH arm was significantly superior to the AC-T group (P=0.02). The non-anthracycline TCH regimen had a more favorable toxicity profile than AC-TH. Both nonhematologic and hematologic toxicities occurred significantly less frequently with TCH, including grade 3 and 4 arthralgia, myalgia, hand– foot syndrome, stomatitis, vomiting, neutropenia and leukopenia. Cardiac toxicity was more frequent in the experimental AC-TH anthracycline
‘It takes seven to 10 years to know the true benefit of these [breast cancer] therapies, and it is premature to discard the anthracyclines.’
—Laura Boehnke Michaud, PharmD
The total number of DFS events in each arm was 257 (AC-TH), 185 (TCH) and 214 (AC-T). The difference between those first two groups was not statistically different, Dr. Slamon noted, although it was slightly numerically superior for the AC-TH arm. The 2009 final analysis also included the secondary end point of overall survival (OS). According to Dr. Slamon, 92%, 91% and 87% of patients were alive at five years in the AC-TH, TCH and AC-T arms, respectively. The number of deaths due to any cause was 94 in the AC-TH arm, 113 in the TCH arm, and 141 in the AC-T arm. Again, the difference in OS between the two experimental arms was not statistically significant, but favored the AC-TH arm. For node-negative disease, five-year DFS was 93%, 90% and 85% in the ACTH, TCH and AC-T arms, respectively. The difference was statistically significant favoring the AC-TH arm over the AC-T arm (P=0.02), with a trend favoring TCH compared with AC-T. Five-year OS in node-negative patients was 97%, 96% and 93% in the AC-TH, TCH and AC-T arms, respectively. In patients with higher-risk, node-positive disease, five-year DFS was 80%, 78% and 71%, respectively. Both experimental arms were significantly superior to con-
arm, with a four- to fivefold increase in CHF compared with the TCH arm. Although mean left ventricular ejection fraction (LVEF) declined at the beginning of treatment, patients treated with TCH recovered to normal at five years, whereas LVEF in patients randomized to the other two arms has not yet returned to normal. “Our interpretation of the study data is that trastuzumab provides similar DFS and OS with an anthracycline and a nonanthracycline regimen in low- and highrisk patients,” Dr. Slamon said. “Acute and chronic toxicity favors the non-anthracycline regimen. [But] the advantage of slightly fewer events with the anthracycline regimen plus trastuzumab comes at a cost of cardiotoxicity and leukemia.”
Experts Divided Clifford Hudis, MD, chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City, had a different view. “There were six acute myelogenous leukemia/ myelodysplastic syndrome events with AC-T, only one with AC-TH, and one with TCH. By lumping AC-T and AC-TH [together], one might be overstating the risk since both trastuzumab-containing arms had but one case each,” he said. Andrew Seidman, MD, an attending
physician at the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, also said that Dr. Slamon’s fears over cardiac events and leukemias are overblown. “Numerically speaking many more women are dying of breast cancer on the TCH arm than are dying of heart failure or secondary leukemia with AC-TH,” Dr. Seidman said. Other experts are less willing to downplay anthracycline toxicity. “The longterm risks for CHF and leukemia are real,” said Stephen Jones, MD, medical director at US Oncology, Baylor-Sammons Cancer Center in Houston. “We are at a point where patients deserve to know there are alternatives to standard anthracyclinebased therapy.” Dr. Michaud cautioned against overreacting to the cardiotoxicity data in the BCIRG study, in part because the type of toxicity documented “may be somewhat reversible and manageable,” she said. Still, “long-term detailed information on patient outcomes related to cardiac dysfunction in the BCIRG trial is not yet available.” Regarding the issue of whether highrisk patients drove the benefit of anthracyclines in the BCIRG study, she said, “We should be skeptical of subgroup analyses. As you slice and dice the information, it weakens the findings.” “The bottom line is that the two DFS curves in BCIRG were not superimposable,” Dr. Michaud said. “The 3% absolute difference in DFS has been considered clinically meaningful in trials with other drugs—for example, the ATAC [Arimidex, Tamoxifen, Alone or in Combination] trial with anastrozole versus tamoxifen— and a similar emphasis should be placed on the differences here.” If the two DFS curves were in fact superimposable, she added, “there would be good reason to use the less toxic agent.” However, “based on previous neoadjuvant studies with anthracyclines, it could take seven to 10 years to know the true benefit of these therapies. So it may be premature to discard the anthracyclines based soley on five-year data from a single study.”
More Data Needed Joanna Schwartz, PharmD, BCOP, assistant professor in the Department of Pharmacy Practice at Albany College of Pharmacy and Health Sciences, Vermont Campus, Colchester, also stressed that the BCIRG 006 follow-up “is not sufficient enough at this time to reach the definitive conclusion that anthracyclines can be abandoned.” However, “it is certainly possible,” Dr. Schwartz said, “that [the BCIRG] results will be used to tailor the use of anthracyclines in the near future.” —Alice Goodman
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Pharmacy Practice News • March 2010
With Few Successors, Succinylcholine Lingers, Warts and All New Orleans—In more than 50 years on the market, the depolarizing muscle relaxant succinylcholine has had its share of ups and downs. From wonder drug to “black box” warnings, few pharmaceutical agents have enjoyed such widespread use while spawning as much controversy. At the 2009 annual meeting of the American Society of Anesthesiologists (ASA), two clinicians took up the battle over whether ‘sux’ should be withdrawn or should remain a widely used induction agent. Arguing for withdrawal of the drug was James E. Caldwell, MB, ChB, professor of anesthesia at the University of California, San Francisco, who asked his audience to suspend disbelief as he took them down an imaginary road to a point when succinylcholine had not yet been approved, beginning with preclinical studies, which he said the drug would “fly through.” Phase I and II studies would follow, comprising a small number of volunteers and patients receiving 0.5-3.0 mg/ kg doses of the agent. “You find it to be a wonderful drug in small populations,” he said. “It’s got fast onset and rapid recovery, and is unlike anything you’ve ever had before.” Occasional bradycardia and small, dose-related increases in creatinine kinase are observed in these studies, although neither is significant. Muscle pain is problematic for a small subset of patients, although easily treated with ibuprofen. A few unexplained problems, perhaps, “but nothing that would stop this unique drug from proceeding to Phase III clinical studies, where it would be tested in 1,200 to 1,500 patients,” Dr. Caldwell noted. “So what do you have after these studies?” he asked. “Succinylcholine has minimal prolongation in chronic systemic disease. It’s a little slower in the elderly, but the longest recovery observed is 25 minutes. The biggest question mark is with prolonged infusion, where the block seems to get longer and recovery slower.”
Postmarketing Swoon Given these promising results, the pharmaceutical company files a new drug application with the FDA. A subcommittee of experts reviews the data and gives unanimous recommendation to the full committee, which also gives succinylcholine its blessing. The only requirement is that prolonged infusions be studied more in Phase IV trials. When the drug hits the open market, it is an unqualified success. “Everybody uses and loves succinylcholine,” Dr. Caldwell said. “But remember, the drug
was really only tested in 1,500 patients.” In succinylcholine’s first year on the market, clinicians administer a halfmillion doses—and reports of various major adverse events begin to trickle in. Otherwise healthy children die suddenly after receiving the agent; cardiac arrest occurs in adult burn patients and those with neurologic disease. Acute rhabdomyolytic failure also is reported, as is malignant hyperthermia. A few patients develop jaw contracture, and there is one case of anaphylaxis.
Minor to moderate adverse events include jaw tightening and bradycardia in children, increased intraocular and intracranial pressures, and prolonged block lasting as long as four hours.
option only in selected cases, and not for rapid-sequence induction, Dr. Mellinghoff said. “Moreover, we risk laryngeal morbidity in a substantial number of our patients when we intubate without neuromuscular blockade.” New drugs may also obviate the need for succinylcholine, the most promising of which is gantacurium chloride (Avera Pharmaceuticals), a nondepolarizing short-acting neuromuscular blocker. Dr. Mellinghoff participated in a multicenter trial that studied intubation scores 60 seconds after administration of gantacurium. “In more than 90% of patients, intubation scores were good to excellent at 60 seconds,” he said. No adverse effects were observed, he added, although mild, transient flushing occurred in 25% of patients. “And so, while there may be promising developments on the horizon with new drugs, it is still too early to draw any firm conclusions, because large clinical trials have not yet been published,” Dr. Mellinghoff said. The final succinylcholine successor
‘Taking away a potentially lifesaving drug that has no real alternative in a time when there are unparalleled drug shortages would be a mistake.’
—Julie Golembiewski, PharmD
The FDA asks for a summary report, and has no choice but to withdraw succinylcholine. “You can’t allow a drug with this profile to stay clinically available,” Dr. Caldwell said. “Remember rapacuronium [Raplan, Organon]? Within a year of its release [in 1999], there were reports of severe bronchospasm. That drug was subsequently withdrawn. Succinylcholine might make it to the marketplace, but it would not survive its first year.”
Little Choice In contrast, Hermann Mellinghoff, MD, senior lecturer at the University of Cologne in Germany, argued that few viable alternatives to succinylcholine are currently available. “Succinylcholine still has its place in rapid-sequence induction, for conditions of full stomach, in cesarean sections and especially in ultrashort procedures,” he said. One possible alternative to succinylcholine is intubation without a muscle relaxant, which has been examined in several trials (Can J Anesth 2003;50: 108-115; Anaesthesia 1999;54:1037-1040; Anesthesiology 2003;98:1049-1056). These studies demonstrated that intubation without a muscle relaxant is an
discussed was sugammadex (Bridion, Schering-Plough) to reverse rocuronium-induced neuromuscular blockade. Dr. Mellinghoff acknowledged that the pharmacologic profile of sugammadex is “revolutionary,” yet the price of the drug currently is prohibitive, he said. “A small ampoule of the drug [2 mL] costs 100 euros [approximately $150US],” he said, “which adds up quickly in a 70-kg patient.” Schering recommends doses of 2 mg/kg for light blockade, 4 mg/kg for deep blockade and 16 mg/kg for immediate reversal after administration of up to 1.2 mg/kg of rocuronium (Zemuron, Schering).
Sux Not Dead Yet Session moderator Aaron F. Kopman, MD, clinical professor of anesthesiology at Weill Cornell Medical College, in New York City, said the demise of succinylcholine has been greatly exaggerated. “Ultimately, while succinylcholine clearly has serious potential side effects, it has probably saved many more lives than it has terminated,” Dr. Kopman, chair of the ASA’s neuromuscular transmission subcommittee, said. “I have a syringe of the drug already drawn up on my anesthesia machine
for virtually every case I do. For rapid control of the airway with quick recovery, it has no equal in North America, and perhaps in the rest of the world.” Dr. Kopman agreed that industrialstrength doses of rocuronium plus sugammadex can, in theory, duplicate the onset and offset profile of succinylcholine. “However, economic constraints will probably prevent almost all anesthetists from having sugammadex routinely available at a moment’s notice,” he said. Although someday there may be a nondepolarizing replacement for succinylcholine, Dr. Kopman said the FDA’s recent actions regarding sugammadex make him skeptical that such an agent is on the horizon. “Why would a pharmaceutical company spend hundreds of millions of dollars to develop what is, in effect, a niche drug that the FDA may never approve? Big Pharma wants a drug that will either improve your sex life or that millions of people will need to take on a daily basis. A drug that may generate sales of under $100 million a year is viewed as a poor bet.”
A Pharmacist’s Perspective Julie Golembiewski, PharmD, a member of the Pharmacy Practice News editorial advisory board who has published extensively in the area of medication use and safety in the operating room, said she agreed with Dr. Caldwell’s contention that succinylcholine would face significant hurdles in obtaining FDA approval in the current regulatory environment. “In fact, any new drug in development today faces a very different road to approval versus 50 years ago,” Dr. Golembiewski said. “Add to that the current economic climate and the end result is an extremely limited potential for an alternative agent.” She added that succinylcholine “has unique properties that remain unrivaled. Yes, it has side effects that can be very serious. But these effects are well known.” Dr. Golembiewski cited, as an example, several MedWatch reports as well as published case studies culled from half a century of use. “What hasn’t been well reported are the lives succinylcholine saved and that should not be ignored. This is true for anesthesia care providers in private practice and possibly even more so for those in training.” All medications have benefits and risks, Dr. Golembiewski added. “Taking away a potentially lifesaving drug that has no real alternative in a time when there are unparalleled drug shortages would be a mistake. I would think that anesthesia care providers would make it a point to know the risks of succinylcholine and administer it wisely.” —Michael Vlessides
Pharmacy Practice News • March 2010
continued from page 6
When Are Prophylactic Antibiotics Needed in Acute Pancreatitis?
ontradictory results from various studies and disagreement among guideline committees muddy the picture for clinicians deciding whether to provide antibiotic prophylaxis to patients with acute pancreatitis. Abbie Erickson, PharmD, clinical pharmacy specialist in emergency medicine at Brigham and Women’s Hospital, in Boston, recommends reserving prophylaxis for a select group of patients. Despite evidence from studies showing no significant differences in infection or mortality (Gastroenterology 2004;126:997-1004; Ann Surg 2007;245:674-683; Am J Gastroenterol 2008;103:104-110), clinicians provide antibiotics 70% to 90% of the time, according to Dr. Erickson. “There are a lot of hospitals that are still practicing that way. It’s a difficult decision and it’s hard not to give antibiotics when your patient looks infected.” However, she said that at this point “higher levels of evidence are needed.” Additionally, she cautioned that there are risks associated with prophylaxis. These
include selection of resistant organisms, development of fungal infections, adverse drug reactions and drug interactions. She said “there are some rare scenarios in which prophylaxis may be warranted,” such as when patients have several signs and symptoms of infection and positive cultures in combination with hemodynamic instability or organ failure.” However, in general she recommended against prophylaxis. Dr. Erickson said that it’s important to “keep in mind that infection takes days or weeks to develop,” so patients early on in their presentation “are very unlikely to be infected.” Additionally, she pointed out that fever and leukocytosis are symptoms of acute pancreatitis with or without infection so these symptoms do not necessarily indicate infection. —Sarah Tilyou
Colistin Combinations Good for Gram-Negatives
olistin is an effective treatment for gram-negative infections, but only when used in combination, not as monotherapy, according to David S. Burgess, PharmD, FCCP, clinical professor and head of the Pharmacotherapy Division, University of Texas at Austin. Multidrug resistance in gram-negative organisms has “increased dramatically” over the last decade. Dr. Burgess called it “a major worldwide public health problem” that “is becoming a bigger issue because of the lack of new drugs in development.” Treatment options for gram-negative infections are limited. Dr. Burgess said gram-negative organisms—primarily Pseudomonas aeruginosa, Klebsiella pneumoniae, and “the big one that we deal with at a lot of institutions, Acinetobacter”—are becoming resistant to at least three classes of drugs. For example, Acinetobacter is resistant to carbapenems, fluoroquinolones and aminoglycosides. Only two drugs seem to work against Acinetobacter, Dr. Burgess noted: polymyxin [or colistin] and tigecycline [Tygacil, Wyeth]. But both agents have their drawbacks. In the case of tigecycline, he
noted, some resistance in Acinetobacterinfected patients has been seen. As for colistin, the drug can be very effective, killing the bacteria “extremely rapidly,” Dr. Burgess said. But if it is used as monotherapy, “gramnegative organisms can develop resistance to it rather easily.” Fortunately, as gram-negative organisms develop colistin resistance, “they becomes more susceptible to other drugs,” he noted. Thus, “colistin should be used in combination with another agent.” Dr. Burgess said the best combination has yet to be determined, but he listed several options—colistin plus rifampin, colistin plus β-lactams, colistin plus macrolides, and colistin plus tetracyclines—that have been evaluated and appear to work. However, “more clinical studies must be performed to determine the best regimen.” —S.T.
Clozapine Is Still a Viable Antipsychotic Option
lozapine is still a very effective antipsychotic agent despite some of its side effects and monitoring concerns, according to Ericka L. Breden, PharmD, clinical pharmacy specialist in psychiatry, Virginia Commonwealth University Health System, Richmond. “As pharmacists, we play a very large role in monitoring and dispensing this medication” because there is a lot of confusion surrounding it, Dr. Breden noted. Clozapine can be confused with the generic names clonazepam, clo-
nidine, as well as the brand names Colazal (Salix) and Klonopin (Roche), he cautioned, and there are some physicians who are unaware that it is still used. Those drawbacks notwithstanding, clozapine still can be a very effective therapy for some patients, Dr. Breden told attendees at the Clinical Pearls session. She said that clozapine, a stage 3 recommended agent that can be used in patients who have failed two trials of a first- or second-generation agent,
62:516-518; Anesthesiology 2006;105; 217-218; Anaesthesia 2006;61:800801), Dr. Sacks noted that, typically, patients are given a bolus dose (1.2-2 mL/kg) of 20% IVLE followed by a continuous infusion of 0.2-0.5 mL/kg per minute for one to two hours. These case reports indicate that this approach is “safe and effective,” noted Dr. Sacks, but he cautioned that because of possible adverse effects (e.g., allergic reactions), as well as unknown effects of IVLE on other lipophilic medications, such as amiodarone, clinicians should only “use intravenous lipid emulsions after standard [advanced cardiac life support] measures have failed.” Dr. Sacks said www.lipidrescue. org offers additional information on the use of lipids for cardiac resuscitation as well as kits for treating patients in the emergency department. However, “before I would recommend using the kit, I would try to give some educational seminars to the nursing staff and the physicians about how it works and how to use it, and specifically … when not to use it.” —S.T.
has some advantages over some of the other available medications. For example, discontinuation rates have been shown to be lower in clozapine-treated patients than in patients treated with other antipsychotics. In Phase II of the National Institute of Mental Health–sponsored CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial, rates of discontinuation due to any cause were lower with clozapine than with the second-generation agents quetiapine
Pharmacy Practice News • March 2010
ASHP Pearls (Seroquel, AstraZeneca; P=0.01), risperidone (P<0.02) and olanzapine (Zyprexa, Eli Lilly; P=0.12; NS) (Am J Psychiatry 2006;163:600-610). When the CATIE investigators looked at discontinuation due to lack of efficacy, they found that approximately 11% of patients discontinued clozapine due to lack of efficacy, while 35% discontinued olanzapine (P<0.02) and 43% discontinued quetiapine (P=0.004) or risperidone (P=0.003) for the same reason. Suicide also was lower among clozapine-treated patients than olanzapinetreated patients in the International Suicide Prevention Trial (Arch Gen Psychiatry 2003;60:82-91). There was a statistically significant reduction in suicide attempts, 6.9% among clozapine-treated patients versus 11.2% among olanzapine-treated patients (P=0.03). For pharmacists who receive orders for clozapine, Dr. Breden said there are several important steps to take. “You need to make sure that the patient has been actually taking the medicine. If it’s been over 48 hours, you need to strongly encourage your physicians to start at either 12.5 or 25 mg once daily and titrate up to the home dose from there.” Before dispensing clozapine, she added, pharmacists have to verify that the necessary blood work has been completed and that the patient’s white blood cell count and absolute neutrophil count are within normal limits because of concerns about agranulocytosis. In addition, the pharmacy needs to verify which clozapine product they have available and “register the patient with the appropriate registry.”
Dr. Breden noted that there are five products available: Clozaril, the original product from Novartis; FazaClo, the orally disintegrating product from Alamo; and three generic versions, from Mylan, Caraco and Teva (Ivax). All of the products require a registration process in which patient-specific information (initials, social security number, race, gender, zip code), physician and pharmacy DEA numbers, as well as recent blood and laboratory results, are recorded. Each product has a different code, which the pharmacist will receive once the registration is completed. This code is crucial for dispensing, Dr. Breden stressed. If the patient is continuing treatment, as long as the required blood work and patient compliance are verified, the drug can be dispensed and the manufacturer may take up to 72 hours to provide the pharmacy with the code. However, she cautioned, “if the patient has never ever taken the drug,” then the drug can “absolutely not” be dispensed without the code. When asked about tapering clozapine, Dr. Breden said, “ideally, I hope no one has to come off clozapine because it is one of the best medications for schizophrenia.” But in cases where discontinuation is necessary, she cautioned against abrupt discontinuation. “Generally, we try to do a minimum of two weeks [of tapering], but ideally a couple of months. And you want to make sure that their new antipsychotic is therapeutic before you take them off [clozapine].” —Sarah Tilyou
We Want Your Pearls Do you have an interesting practice pearl you’d like to share? If so, send it to email@example.com. Pearls should: • Focus on a clinical or operational problem at your institution, with tips (“tricks of the trade”) on how to manage the problem via an innovative system or strategy
No dextran or modified dextran No test dose • No black box warning In pre-dialysis CKD anemia
for so many reasons
IMPORTANT SAFETY INFORMATION: Venofer® (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Hypersensitivity reactions have been reported with IV iron products. Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving IV iron. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered. In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer ® administration, were taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension.
• Offer insights that are not widely known, understood or published ™
• Explain why the pearl should be implemented on a widespread basis
Millions prescribed. Millions treated.
• Not exceed 500 words in length Please see brief summary of full prescribing information on following pages..
Readers whose Practice Pearls are accepted for publication will be paid a $100 honorarium.
Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2009 American Regent, Inc. Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com
Leading anemia management.™
Pharmacy Practice News • March 2010
Still Asleep at the (Ventilator) Switch? Miami Beach, Fla.—Despite growing recognition that daily interruption of sedation saves lives and reduces coma as well as the duration of mechanical ventilation and time spent in the intensive care unit, the adoption of the “wake up and breathe” protocol at hospitals remains slow and inconsistent. The latest indication of lethargy? A new study showing that less than half of eligible patients are being placed on the sedation-weaning regimen. The results
dovetail with a 2008 survey sent to Society of Critical Care Medicine (SCCM) members showing a similar hesitancy. Simon Lam, PharmD, co-investigator of the new study and a clinical pharmacist at the Cleveland Clinic, in Ohio, said he was not surprised by the results. Because of individual patient and prescriber variation, “we certainly didn’t expect 100% adherence,” he told Pharmacy Practice News. The study was based on a retrospec-
tive chart review of patients admitted to the Cleveland Clinic’s ICU during a twomonth period in 2008. All of the patients were mechanically ventilated and given a continuous infusion of sedative and/ or analgesic. Patients were not considered eligible for the weaning protocol if they were given a fraction of inspired oxygen of 0.7 or greater, positive end expiratory pressure of 12 cm H2O or greater, neuromuscular blocking agents or specialized mechanical ventilation
Reference: 1. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S, for the United States Iron Sucrose (Venofer®) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005;68:2846-2856. 2. Data on file. American Regent, Inc., Shirley, NY.
(Table 2 continued)
Brief Summary (See Package Insert For Full Prescribing Information) Therapeutic Class: Hematinic CLINICAL INDICATIONS AND USAGE Venofer® (iron sucrose injection, USP) is indicated in the treatment of iron deficiency anemia in the following patients: • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin CONTRAINDICATIONS The use of Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. WARNINGS Hypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS and ADVERSE REACTIONS. PRECAUTIONS General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload. Patients receiving Venofer® require periodic monitoring of hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum iron values may be reliably obtained 48 hours after IV dosing. See DOSAGE AND ADMINISTRATION and OVERDOSAGE. Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving Venofer®. No life-threatening hypersensitivity reactions were observed in the clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening hypersensitivity reactions in patients receiving Venofer. See ADVERSE REACTIONS. Hypotension: Hypotension has been reported frequently in hemodialysis dependent chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose administered. Caution should be taken to administer Venofer® according to recommended guidelines. See DOSAGE AND ADMINISTRATION. Carcinogenesis, Mutagenesis, and Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer®. Venofer® was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Venofer® at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Venofer®. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Venofer® is excreted in milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Venofer® is administered to a nursing woman. Pediatric Use: Safety and effectiveness of Venofer® in pediatric patients have not been established. In a country where Venofer® is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer®, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugs could be established. Geriatric Use: The five pivotal clinical trials did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Adverse Events observed in all treated populations The frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis dependent and 75 peritoneal dialysis dependent-CKD patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent-CKD patients for a total of 1,496 patients. In addition, over 2,000 patients treated with Venofer® have been reported in the medical literature. Treatment-emergent adverse events reported by 2% of treated patients with NDD-CKD in the randomized clinical trials, whether or not related to Venofer® administration, are listed by indication in Table 2. Table 2. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Clinical Indication (Multidose Safety Population) NDD-CKD Oral Iron Adverse Events Venofer® (Preferred Term) (N=139) (N=139) % % Subjects with any adverse event 76.3 73.4 Ear and Labyrinth Disorders Ear Pain 2.2 0.7 Eye Disorders Conjunctivitis 0 0 Gastrointestinal Disorders Abdominal pain NOS* 1.4 2.9 Constipation 4.3 12.9 Diarrhea NOS 7.2 10.1 Dysgeusia 7.9 0 Nausea 8.6 12.2 Vomiting NOS 5.0 8.6 General Disorders and Administration Site Conditions Asthenia 0.7 2.2 Chest pain 1.4 0 Edema NOS 6.5 6.5 Fatigue 3.6 5.8 Feeling abnormal 0 0 Infusion site burning 3.6 0 Injection site extravasation 2.2 0 Injection site pain 2.2 0 Peripheral edema 7.2 5.0 Pyrexia 0.7 0.7 Infections and Infestations Catheter site infection 0 0 Nasopharyngitis 0.7 2.2 Peritoneal infection 0 0 Sinusitis NOS 0.7 0.7 Upper respiratory tract infection NOS 0.7 1.4 Urinary tract infection NOS 0.7 5.0 Injury, Poisoning and Procedural Complications Graft complication 1.4 0 Investigations Cardiac murmur NOS 2.2 2.2 Fecal occult blood positive 1.4 3.6 Metabolism and Nutrition Disorders Fluid overload 1.4 0.7 Gout 2.9 1.4 Hyperglycemia NOS 2.9 0 Hypoglycemia NOS 0.7 0.7 Musculoskeletal and Connective Tissue Disorders Arthralgia 1.4 2.2 Arthritis NOS 0 0
Treatment-emergent adverse events reported in 2% of patients by dose group are shown in Table 3. Table 3. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)
Adverse Events (Preferred Term) Subjects with any adverse event Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain NOS* Constipation Diarrhea NOS Dysgeusia Nausea Vomiting NOS General Disorders and Administration Site Conditions Asthenia Chest pain Edema NOS Fatigue Feeling abnormal Infusion site burning Injection site pain Peripheral edema Pyrexia Infections and Infestations Catheter site infection Nasopharyngitis Peritoneal infection Sinusitis NOS Upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications Graft complication Investigations Cardiac murmur NOS Fecal occult blood positive Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia NOS Hypoglycemia NOS Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp Myalgia
NDD-CKD 200 mg 500 mg (N=109) (N=30) % % 75.2 80.0 0.9
1.8 3.7 6.4 9.2 9.2 5.5
0 6.7 10.0 3.3 6.7 3.3
0.9 0.9 7.3 4.6 0 3.7 2.8 5.5 0.9
0 3.3 3.3 0 0 3.3 0 13.3 0
0 0.9 0 0 0.9
0 0 0 3.3 0
1.8 1.8 3.7 0.9
0 6.7 0 0
0.9 1.8 0 2.8
3.3 3.3 3.3 6.7
(Table 3 continued)
NDD-CKD Venofer® Oral Iron (N=139) (N=139) % %
Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Back pain Muscle cramp Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Hypoesthesia Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Dyspnea exacerbated Nasal congestion Pharyngitis Rhinitis allergic NOS Skin and Subcutaneous Tissue Disorders Pruritus Rash NOS Vascular Disorders Hypertension NOS Hypotension NOS *NOS=Not otherwise specified
2.2 0.7 3.6 4.3
3.6 0.7 0 0
6.5 2.9 0.7
1.4 0.7 0.7
2.2 3.6 2.2 1.4 0 0.7
0.7 0.7 0.7 2.2 0 2.2
NDD-CKD 200 mg 500 mg (N=109) (N=30) % %
Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Pharyngitis Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension NOS Hypotension NOS
0.9 1.8 0
6.7 10.0 0
‘At least anecdotally, we frequently hear from clinicians in ICUs across the country who are using the [ABC] protocol that they are having great success with it.’
*NOS=Not otherwise specified
Drug related adverse events reported by 2% of Venofer® (iron sucrose injection, USP) treated patients are shown by dose group in Table 4. Table 4. Most Common Adverse Events Related to Study Drug Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)
NDD-CKD Adverse Events (Preferred Term) Subjects with any adverse event Gastrointestinal Disorders Diarrhea NOS* Dysgeusia Nausea General Disorders and Administration Site Conditions Infusion site burning Injection site pain Peripheral edema Nervous System Disorders Dizziness Headache Vascular Disorders Hypotension NOS
200 mg (N=109) % 23.9
500 mg (N=30) % 20.0
0 7.3 2.8
0 3.3 0
3.7 2.8 1.8
0 0 6.7
—Timothy Girard, MD
*NOS=Not otherwise specified Adverse Events Observed in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD) Patients In the pivotal study of 182 NDD-CKD patients, 91 were exposed to Venofer®. Adverse events, whether or not related to Venofer®, reported by 5% of the Venofer® exposed patients were as follows: dysgeusia (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related adverse reaction was reported (hypotension and shortness of breath not requiring hospitalization in a Venofer® patient). Two patients experienced possible hypersensitivity/allergic reactions (local edema/hypotension) during the study. Of the 5 patients who prematurely discontinued the treatment phase of the study due to adverse events (2 oral iron group and 3 Venofer® group), three Venofer® patients had events that were considered drug-related (hypotension, dyspnea and nausea). Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. Serious episodes of hypotension occurred in 2 patients treated with Venofer® at a dose of 500 mg. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration. OVERDOSAGE leading to hemosiderosis. Periodic monitoring Dosages of Venofer® (iron sucrose injection, USP) in excess of iron needs may lead to accumulation of iron in storage sites of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation. Venofer® should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines . Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia. Symptoms associated with overdosage or infusing Venofer® too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution as recommended or at a slower rate may also alleviate symptoms. Preclinical Data: Single IV doses of Venofer® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation, hypoactivity, pale eyes, and bleeding in the gastrointestinal tract and lungs. DOSAGE AND ADMINISTRATION The dosage of Venofer® is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron. Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over sequential sessions, to achieve a favorable hemoglobin response and to replenish iron stores (ferritin, TSAT). Administration: Venofer® must only be administered intravenously either by slow injection or by infusion. Recommended Adult Dosage: Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer®, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated. (See CLINICAL TRIALS, Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients sections.) HOW SUPPLIED Venofer® is supplied in 5 mL and 10 mL single dose vials. Each 5 mL vial contains 100 mg elemental iron (20 mg/mL) and each 10 mL vial contains 200 mg elemental iron (20 mg/mL). Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F). [See the USP controlled room temperature]. Do not freeze. Sterile NDC-0517-2340-01 100 mg/5 mL Single Dose Vial Individually Boxed NDC-0517-2310-01 200 mg/10 mL Single Dose Vial Individually Boxed NDC-0517-2340-10 100 mg/5 mL Single Dose Vial Packages of 10 NDC-0517-2310-05 200 mg/10 mL Single Dose Vial Packages of 5 NDC-0517-2340-25 100 mg/5 mL Single Dose Vial Packages of 25 NDC-0517-2310-10 200 mg/10 mL Single Dose Vial Packages of 10 Rx Only REFERENCE:  National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis. 37: S182-S238, (suppl 1) 2001. BS2340 Rev. 10/08 Venofer® is manufactured under license from Vifor (International) Inc., Switzerland.
(e.g., oscillation). Forty-one patients were evaluated, resulting in 154 individual patient-day episodes. Although 70.1% of the patient episodes were eligible for a spontaneous awakening trial (SAT), the procedure was performed only 40.7% of the time, the researchers found. Fear of hypoxia was the most common reason cited by nurses for not performing a SAT, Dr. Lam said.
VENJA Rev 10/2008 © 2008 American Regent, Inc
Of the patients who did receive a SAT, 86.4% were re-initiated with sedation. Among those patients, 31.6% of the time the re-initiation was done for a protocol-specified reason. The average dose on the re-initiation was 108.9% of the prior dose, instead of the 50% dose specified in the weaning protocol; only 26.3% of the re-initiations were at the 50% level (Figure). Dr. Lam stressed that although the results show that clinicians are falling far short of the goals set forth in the “wake up and breathe” protocol, the results were not outside the norm. “Upon discussion with other institutions and evaluation of existing data, we found that our rate of SAT performed was similar to that of other centers,” he said.
A Lack of Follow-up Study Timothy Girard, MD, lead researcher of the randomized, multicenter Awakening and Breathing Controlled (ABC) trial that was published in 2008 and demonstrated striking benefits from use of the protocol (Lancet;371:126-134), said that he is not surprised at the slow
Pharmacy Practice News • March 2010
Critical Care SAT given per protocol
Sedation re-initiated per protocol
years from the time a clinical trial is published before its findings are put into practice. “I certainly hope this won’t be the case for the ABC trial results, but it’s now been 10 years since Kress and colleagues published their trial, and [only] 40% to 50% of ICUs say they are doing daily interruption of sedatives,” he said. Dr. Girard said there is a reason to hope that the protocol will soon gain new traction: The long-term results of the ABC trial are under review, and publication is expected by midyear.
Correct re-initiation dose given
rate of adoption documented in the Cleveland Clinic study. Part of the problem, Dr. Girard said, is the lack of additional studies confirming his results. “I am not aware of any new trials published in the last year examining our wake-upand-breathe protocol,” said Dr. Girard, a critical care physician at the Vanderbilt University School of Medicine, in Nashville, Tenn. Nevertheless, “at least anecdotally, we frequently hear from clinicians in ICUs across the country who are using the protocol that they are having great success with it.” In Dr. Girard’s ABC trial, eligible patients underwent daily interruption of sedatives coupled with spontaneous breathing trials to determine if patients were ready to be weaned from mechanical ventilation. Compared with a control group, ICU patients who received the protocol at four community and university hospitals experienced three more ventilator-free days in the ICU, were discharged four days earlier and had significantly fewer days in coma. Mortality benefits were also striking: Patients who underwent the sedationweaning protocol were 32% less likely to die than were patients in the control group, Dr. Girard reported (Pharmacy Practice News, March 2009). Dr. Girard’s ABC trial was not the first time the wake-up-and-breathe protocol was shown to be worthwhile. Kress et al first reported success with a variation of the protocol 10 years ago (N Engl J Med 2000;342:1471-1477). Additionally, a daily interruption of sedation strategy actually has been part of SCCM’s practice guidelines since 2002. Despite this, only 40% of SCCM members reported having such a strategy in place in the 2008 survey (J Crit Care 2009;24:66-73). Reasons for lack of use included no physician order (35%), lack of nursing support (11%) and fear of over-sedation (7%). Resistance to use included a lack of nursing acceptance (22%), concern about risk for patient-initiated device removal (19%) and inducement of either respiratory compromise (26%) or patient discomfort (13%). One of the major concerns about turning off patient sedation in the ICU is that it might lead to adverse psychological outcomes. But according to Dr. Girard, “we found no difference between [awakened and nonawakened patients] with regard to post-traumatic stress disorder symptoms, depression symptoms, functional status or cognitive outcomes. So, the short-term improvements in time spent off the ventilator and time to ICU and hospital discharge, as well as the long-term survival benefit, did not come at the cost of long-term psychological problems.” That the protocol is being performed in less than half of all eligible patients is “unfortunate but not unexpected,” Dr. Girard said, noting that it often takes
40 31.6 30
20 10 0
Figure. Reaching wake-up-and-breathe protocol goals. SAT, spontaneous awakening trial
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Pharmacy Practice News • March 2010
Pharmacy and Emergency Department Collaboration:
A Novel Approach SHAWN ROGGIE, PHARMD, BCPS Senior Clinical Pharmacy Specialist, Emergency Medicine Baystate Medical Center Springfield, Massachusetts
JOHN SANTORO, MD
ANN MAYNARD, RN
Vice Chair and Chief of Emergency Services Baystate Medical Center Springfield, Massachusetts
Director, Emergency Services Baystate Medical Center Springfield, Massachusetts
AARON MICHELUCCI, PHARMD Assistant Director Clinical Pharmacy Services Baystate Medical Center Springfield, Massachusetts
harmacists are becoming increasingly involved in emergency departments (EDs) throughout the country. By their nature, EDs have continual turnover of patients, with cases arising throughout the day that might
benefit from a pharmacist’s expertise. Many institutions now dedicate a clinical pharmacy specialist (CPS) to work in the ED, a move that has proved to be an effective model for improving patient outcomes. However, because of budget
involvement may include: • participating in resuscitation efforts; • providing consultative services that foster evidence-based medication selection; • providing drug information consultation to physicians and nurses; • monitoring for therapeutic responses; and
• continually assessing for and managing adverse drug reactions. According to ASHP, there are 5 accredited emergency medicine specialty pharmacy-practice residencies in the country. The small number of programs makes it difficult to find and hire residency-trained individuals. Additionally, there is an ongoing national shortage of pharmacists, making it difficult sometimes
Table 1. Provider Surveya
Our facility has a dedicated CPS in the ED from 7 AM to 3:30 PM, 5 days per week. The CPS has been practicing in this role since November 2006. During this time, the CPS has attended ED operations meetings, worked with managers and staff on medication safety issues, and worked on direct patient care cases. Customer service evaluations have indicated that this has been an effective way for the pharmacy department
see NOVEL APPROACH, page 27
Table 2. Nursing Surveya
Pre-Intervention Post-Intervention Survey Survey (March 2009) (October 2009)
to fill an open position within a pharmacy department. According to pharmacymanpower.com, there was an aggregate demand index of 3.66 in November 2009, indicating a strong demand for pharmacists. It is challenging for many in pharmacy department leadership to find ways to provide a high level of service to the ED with the current staff available at the institution.
Hypothesis and Specific Aims
constraints, few institutions have placed a CPS in the ED to cover all hours.
Several studies have shown that having a dedicated CPS in the ED reduces errors, saves money, and is well received by other clinical staff.1-3 In a pre-/post-study that examined the rate of medication errors in the ED, Brown et al found that there was a statistically significant difference in the rate of errors if a pharmacist checked the orders.1 The rate of error was 16.09 per 100 orders written in the control group and 5.38 per 100 orders written in the intervention group (P=0.0001). In another study, Lada and Delgado documented 2,150 pharmacist interventions in a hospital’s ED over a 4-month period.2 The investigators then conducted a costavoidance analysis and found that during this time, $1,029,776 in extra cost was avoided. A study surveying nursing and medical staff indicated that they valued the role of the CPS in the ED.3 In a consensus statement published by the American Society of Health-System Pharmacists (ASHP), the society recommended that every pharmacy department should provide the ED with the pharmacy services required to ensure safe and effective patient care.4 Services must be tailored to match the institution’s needs and resources, but potential
SEAN ILLIG, PHARMD Inpatient Pharmacy Supervisor Baystate Medical Center Springfield, Massachusetts
Pre-Intervention Post-Intervention Survey Survey (March 2009) (October 2009)
Aggregate of pharmacy services
Aggregate of pharmacy services
Perception of the main pharmacy
Perception of the main pharmacy
Perception of the clinical pharmacy specialist
Perception of the 1.37 clinical pharmacy specialist
Desire to see an increase in pharmacy services
Desire to see an increase in pharmacy services
Scores based on Likert scale ranging from 1 (strongly agree) to 5 (strongly disagree).
Scores based on Likert scale ranging from 1 (strongly agree) to 5 (strongly disagree).
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Safe Handling Of Hazardous Drugs: Reviewing Standards for Worker Protection LUCI A. POWER, MS, RPH
MARTHA POLOVICH, MN, RN, AOCN
Senior Pharmacy Consultant Power Enterprises San Francisco, California
Associate Director Clinical Practice Duke Oncology Network Durham, North Carolina
010 marks 3 decades of concern
for health care workers exposed
to cytotoxic and other hazardous
drugs. As a new generation of health care workers joins those already engaged in patient care, it is essential that they understand the occupational risks associated with the handling of hazardous drugs and the need for training in proper techniques for all handling activities to reduce occupational exposure to such drugs.
Continuing research in this area, promoted by the National Institute for Occupational Safety and Health (NIOSH), demonstrates ongoing exposure. Studies conducted at prominent health care facilities show surface contamination in many areas, not just pharmacy. Additionally, biological sampling of exposed staff indicates damage to key chromosomes. Hazardous drugs, which include antineoplastic agents, antiviral agents, biological modifiers, hormones, and others agents, provide therapeutic benefit to patients but studies have shown that healthy workers exposed to these drugs may experience adverse effects.1-4 Potential health risks for workers who compound and administer these agents include adverse reproductive outcomes and cancer.5 This review emphasizes new information about this well-recognized issue. It focuses on NIOSHâ€™s activities as well as the 2008 revision of United States Pharmacopeia
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(USP) Chapter <797>, which mandates compliance with environmental, engineering, and training standards for worker protection.
Routes of Occupational Exposure Many studies have documented both surface and worker contamination from hazardous drugs.613 Standard work practices for handling injectable drugs in vials and syringes generate powder and liquid aerosols. These drug residues may contaminate the air and surfaces in the work area.6-8,14,15 It also has been shown that many hazardous drug vials are delivered from the manufacturer with drug residue on the outside of the vials, creating yet another opportunity for contamination.16 Certain hazardous drugs have been shown to vaporize at room temperature, resulting in drug contamination in the air.17-19
P H A R M AC Y P R AC T I C E N E WS â€˘ M A R C H 2 0 1 0
Workers may breathe contaminated air or touch contaminated surfaces and absorb hazardous drugs. Drug uptake also may occur through the ingestion of contaminated food or drink that is improperly located in or near drug-handling areas. Additionally, the transfer of contaminated residues from hands to mouth may result in the ingestion of hazardous drugs. Needlesticks with hazardous-drug contaminated needles or cuts from glass fragments of vials or ampules also may trigger exposure by injection.
Guidelines for the Safe Handling of Hazardous Drugs Since 1980, numerous organizations have issued guidelines for the safe handling of hazardous drugs. The Occupational Safety and Health Administration (OSHA) issued guidelines in 1986,20 updated them in 1995,21 and made them available online in 1999.22 The American Society of Health-System Pharmacists (ASHP) published guidelines on the safe handling of cytotoxic agents as Technical Assistance Bulletins in 1985 and 1990, and new guidelines on hazardous drugs in 2006.23-25 In an attempt to influence nursing practice and protect its members from exposure, the Oncology Nursing Society (ONS) published guidelines for safe handling and also developed an extensive educational program based on “Chemotherapy and Biotherapy Guidelines and Recommendations for Practice.”26-28
Continuing Exposure Adverse health effects and chances for exposure have been demonstrated among health care workers for more than 2 decades. Studies of surface and worker contamination conducted in the late 1990s and the early years of the next decade continued to document exposure.6-8,10,14,15 Some possible reasons for the problem include new workers’ lack of awareness of the issue, a lack of vigilance in work practices, poor adherence to the use of personal protective equipment (PPE),29-32 and other potential sources of contamination that have yet to be discovered.33 In 2000, NIOSH convened a working group of interested individuals to examine the issue of occupational exposure of health care workers to hazardous drugs. The Hazardous Drug Safe Handling Working Group was composed of representatives from government (OSHA, NIOSH, and FDA), industry, pharmaceutical manufacturers, academia, membership organizations (eg, American Nurses Association [ANA], ASHP, and ONS), and union leaders whose members handle hazardous drugs. The Working Group assessed existing information and formulated a plan to increase affected workers’ awareness of the risks and to reduce those risks. In 2004, as a result of the efforts of the Working Group, NIOSH issued “Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings.”34 This NIOSH Alert is similar to the OSHA documents in that it is a guidance document without enforcement authority. However, OSHA may enforce the recommendations in
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the NIOSH Alert and the OSHA Technical Manuals under the general duty clause of the Occupational Safety and Health (OSH) Act, which sets safety and health standards for US workers. Employers subject to the OSH Act have a general duty to provide work and a workplace free from recognized, serious hazards.35 NIOSH actively continues to increase awareness of this issue by maintaining 2 Safety and Health Topic pages online: “Hazardous Drug Exposures in Health Care”36 and “Occupational Exposure to Antineoplastic Agents.”37 These pages provide links to extensive background information, the latest studies, updates on related activities, and NIOSH publications. In 2007, the USP released Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations,” which became effective in 2008.38 This revision of the 2004 standard includes a section specific to the compounding of hazardous drugs and is coordinated with much of the 2004 NIOSH Alert. More importantly, USP Chapter <797> is an enforceable standard and establishes many of the NIOSH recommendations as requirements. The standards set by USP Chapter <797> are applicable in all settings in which sterile doses of hazardous drugs are compounded, not just hospitals and clinics. To assess the impact of the 2004 NIOSH Alert on hazardous drugs,34 NIOSH designed a large, multifacility study to provide a comprehensive evaluation of the workplace and the potential sources of exposure. The prepublication results of this study were presented at the Safe Handling of Hazardous Drugs in the Clinical Environment Symposium in Massachusetts in October 2009 and at the ASHP Midyear Clinical Meeting in Las Vegas in December 2009.39,40 The study included surface sampling in pharmacy and nursing areas; self-maintained exposure diaries for health care workers in the study; and urine and blood sampling. Consistent with previous studies, contaminated surfaces were detected in all study sites. The findings of the study included a correlation between the size and spatial design of the compounding area and the amount of surface contamination. Preliminary reports support the USP Chapter <797> design standard that requires an appropriate buffer area around the primary engineering control (PEC).38 The site with a smaller, less delineated compounding area had greater surface contamination. At the Massachusetts and Las Vegas meetings, members of the Massachusetts General Hospital (MGH) Hazardous Drug Safety Task Force also presented the findings of an extensive, longitudinal study designed to assess contamination from receipt of the hazardous drug (loading dock) to hazardous waste transport (loading dock).41,42 The MGH Task Force identified a “chain of custody” for hazardous drugs and found surface contamination in most of the study areas along this chain, including on elevator buttons. According to the MGH investigators, another round of surface wipes will be conducted to assess interventions prior to publication of the study results.
Table 1. Comparison of 2004 NIOSH and 1990 ASHP Definitions NIOSH
Carcinogenicity in animal models, in the patient population, or both as reported by the International Agency for Research on Cancer
Teratogenicity or developmental toxicity
Teratogenicity in animal studies or in treated patients
Fertility impairment in animal studies or in treated patients
Organ toxicity at low doses
Evidence of serious organ or other toxicity at low doses in animal models or treated patients
Genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems)
Structure and toxicity profile of new drugs that mimic existing drugs determined hazardous by the above criteria ASHP, American Society of Health-System Pharmacists; NIOSH, National Institute for Occupational Safety and Health Originally published in reference 23 © 2006, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission. (RO908)
These reports are not surprising but they are alarming. Additional concern was generated by a substudy within the NIOSH research.43 Investigators at the University of Maryland evaluated chromosomal effects of the hazardous drugs studied to determine specific effects in the health care workers involved in the study. Therapy-related malignancies (myelodysplastic syndrome [MDS] and acute myeloid leukemia [AML]) are known to be associated with signature lesions in chromosomes 5, 7, and 11 based on fluorescent in situ hybridization (FISH). In the prepublication data, the DNA of exposed workers in this study showed a statistically significant increased frequency of damage to chromosome 5 or 7 (P=0.01) and an increased frequency of damage to chromosome 5 alone (P=0.01). The published conclusions of the researchers will provide additional evidence of valid concerns regarding occupational exposure to hazardous drugs.
Defining Hazardous Drugs A number of drug types that are potent and toxic to patients have the potential to cause adverse effects in persons exposed to them occupationally. Although the cytotoxic potential of the alkylating agents is of primary concern, there are multiple mechanisms by which drugs exhibit hazardous effects. In 1990, ASHP attempted to categorize these drugs in its “Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs,”24 for the first time using the term “hazardous drug” in reference to drugs that involve risks from occupational exposure. The terminology was selected to be inclusive of the types of drugs with safety concerns and to be compatible with the then newly developed OSHA Hazard Communication Standard (HCS).44,45 The HCS is
intended to ensure that employers and workers who are at risk for exposure to hazardous chemicals in the workplace are informed of the specific hazardous chemicals, their associated health and safety hazards, and the appropriate protective measures to be taken. The HCS defines a “hazardous chemical” as any chemical that poses a physical or health hazard. It further defines a “health hazard” as any chemical for which statistically significant evidence from at least one study conducted in accordance with established scientific principles is available to indicate that it may cause acute or chronic health effects in exposed employees. The HCS further notes that the term “health hazard” includes chemicals that are carcinogens, toxic or highly toxic agents, reproductive toxins, irritants, corrosives, sensitizers, and agents that produce target organ effects. ASHP has used similar criteria to define hazardous drugs.23,24 Data on the side effects of a drug are collected during both the premarket investigational phase of the drug and clinical use. These data reasonably may be used to infer “health hazards” in workers occupationally exposed to the drug. As such, ASHP proposed the following criteria to define hazardous drugs24: • genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems); • carcinogenicity in animal models, in the patient population, or both, as reported by the International Agency for Research on Cancer (IARC); • teratogenicity or fertility impairment in animal studies or in treated patients; and • evidence of serious organ or other toxicity at low doses in animal models or treated patients. ASHP’s criteria for hazardous drugs were revised by NIOSH for the 2004 Hazardous Drug Alert.
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USP Chapter <797> has adopted the following definition of hazardous drugs, which supports both the HCS and the NIOSH Alert definitions: Drugs are classified as hazardous if studies in animals or humans indicate that exposures to them have a potential to cause cancer, developmental or reproductive toxicity, or harm to organs.38 NIOSH has adopted a mechanism both to review its hazardous drug criteria and to judge newly FDA-approved drugs against these criteria on a regular basis. In 2007, a group of experts met to review the drugs that have been approved by the FDA since 2004 to evaluate which ones should be considered hazardous. Sixty-two drugs from many different therapeutic categories met at least one criterion of the hazardous definition in the preliminary analysis by NIOSH.46 The final list will be published when it is approved by the Office of Management and Budget (T. Connor, personal communication, July 10, 2008). Once published, the complete list may include nearly 200 pharmacologic agents available in the United States that are deemed hazardous to health care workers. The current NIOSH list of drugs that should be considered hazardous can be found in Appendix A of the NIOSH Alert.47 Table 1 compares the 2004 NIOSH and 1990 ASHP definitions of hazardous drugs.
Recommendations Recommendations for the safe handling of hazardous drugs have been available since the early 1980s. As more research has been conducted and more groups have been involved, the recommendations have been coordinated in an attempt to provide uniformity. Each group, however, has a somewhat different focus. The NIOSH Alert and OSHA Technical Manuals are broad guidelines; the ONS “Chemotherapy and Biotherapy Guidelines” focus on administration and patient safety information; ASHP addresses pharmacists’ concerns; and USP Chapter <797> deals exclusively with sterile compounding. All guidelines agree that to reduce exposure to hazardous drugs in the occupational setting, a comprehensive safety program must be developed that deals with all aspects of drug handling—from selection and receipt of the product to storage, compounding, administration, spill control, and waste management. Key components of such a program are administrative controls, environmental and engineering controls, work practice controls, and PPE. These components are based on principles of industrial hygiene that have been successfully used to mitigate risks from other occupational exposures.48
ADMINISTRATIVE CONTROLS Administrative controls include policies, procedures, staff education and training, validation of competency, and medical surveillance. All aspects of hazardous drug handling must be identified, staff performance expectations clearly defined, methods for validating staff competency determined, and processes for the ongoing monitoring of adherence to policies judiciously established. USP Chapter <797> emphasizes administrative
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controls for the safe compounding of hazardous drugs by mandating conditions that protect health care workers and other personnel in preparation and storage areas. Further requirements include extensive training of all personnel who handle hazardous drugs in the storage, handling, and disposal of such drugs. USP Chapter <797> reinforces the OSHA and NIOSH recommendations by requiring training before the preparation or handling of hazardous compounded sterile preparations, and by mandating that the effectiveness of training be verified by testing specific hazardous drug preparation techniques. Ongoing training must be documented at least annually. The components of the training program are specified to include didactic overview of hazardous drugs and their mutagenic, teratogenic, and carcinogenic properties. The training program must address each new hazardous drug that enters the marketplace. Training in work practices also must include the following: aseptic manipulation; negative-pressure technique; correct use of safety equipment; containment, cleanup, and disposal procedures for breakages and spills; and treatment of personnel for contact and inhalation exposure. OSHA and NIOSH include medical surveillance in their safety program recommendations. Medical surveillance involves collecting and interpreting data to detect changes in the health status of working populations potentially exposed to hazardous substances. In 2007, NIOSH released “Workplace Solution: Medical Surveillance for Health Care Workers Exposed to Hazardous Drugs,” which provides direction for establishing such a program and the elements that should be included.49 USP Chapter <797> requires that all compounding personnel with reproductive capability confirm in writing that they understand the risks associated with handling hazardous drugs. Although USP Chapter <797> mandates this only for personnel responsible for compounding, prudent practice dictates that the requirement should extend to all personnel who handle hazardous drugs.
The recent revision to USP Chapter <797> contains extensive mandates to improve the environment in which sterile doses of hazardous drugs are compounded. These directives are designed to increase safety for patients by reducing the potential for the microbial contamination of sterile dosage forms, and to improve worker safety by addressing design concerns in traditional, positive-pressure compounding environments. Table 2 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for the environment in which hazardous drugs are compounded. Hazardous drugs must be stored separately from other inventory in a manner to prevent contamination and exposure of personnel. Because of the concerns of volatilization at room temperature, storage is preferably within a containment area such as a negativepressure room with sufficient exhaust ventilation and
Table 2. Comparison of the NIOSH, ASHP, and USP Chapter <797> Recommendations for the Hazardous Drug Compounding Environment NIOSH
USP Chapter <797>
Store hazardous drugs separately from other drugs in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.
Segregate hazardous drug inventory and store in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.
Hazardous drugs shall be stored separately from other inventory, preferably within a containment area such as a negative-pressure room.
Prepare hazardous drugs in an area that is devoted to that purpose alone and is restricted to authorized personnel.
Hazardous drugs should be compounded in a controlled area where access is limited to authorized personnel trained in handling requirements.
Hazardous drugs shall be prepared in a PEC, which shall be placed in an ISO class 7 area that is physically separated from other preparation areas.
Where feasible, exhaust 100% of the filtered air to the outside.
Because of the hazardous nature of these preparations, a contained environment where air pressure is negative relative to that of the surrounding areas or that is protected by an air lock or anteroom is preferred.
Storage: area should have exhaust ventilation of at least 12 air changes per hour. Compounding: optimally at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas.
ASHP, American Society of Health-System Pharmacists; ISO, International Organization for Standardization; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; USP, United States Pharmacopeia Based on references 23, 34, and 38.
at least 12 air changes per hour (ACPH) to dilute and remove airborne contaminants. An International Organization for Standardization (ISO) class 5 primary engineering control (PEC) is required for hazardous drug compounding to prevent microbial contamination of sterile preparations and to protect workers and the environment by preventing the escape of hazardous drug aerosols or residue. Appropriate PECs for compounding sterile hazardous drug preparations include class II biological safety cabinets (BSCs) and compounding aseptic containment isolators (CACIs) meeting or exceeding the standards set forth in USP Chapter <797>. Isolators are recommended as a PEC in both the NIOSH Alert and the ASHP hazardous drug guidelines. The USP Chapter <797> revision sets performance standards for isolators used to compound sterile preparations, for compounding aseptic isolators (CAIs), and for isolators used to compound sterile hazardous drug preparations (CACIs). To meet the criteria of USP Chapter <797>, an isolator must provide isolation from the room and maintain ISO class 5 air quality within the cabinet during dynamic operating conditions. CAI and CACI air quality must be documented by particle counts during compounding operations and during material transfer in
and out of the isolator. Recovery time to ISO class 5 air in the main chamber must be documented after material is transferred into and out of the main chamber. Work practices must be developed to reduce disruption of the air quality in the isolator and to minimize recovery time. A CACI meeting all of these conditions, as detailed in USP Chapter <797>, is exempt from the requirement of placing the CACI in an ISO class 7 buffer area. For hazardous drug compounding, however, the compounding area must maintain negative pressure and have a minimum of 12 ACPH. A class II BSC has an open front and depends on an air barrier to prevent hazardous drug contamination from escaping the cabinet.50 This air barrier can be compromised by worker technique, allowing escape of the contaminated air.51 The design of this type of cabinet is questionable for product protection because the air barrier is composed of air coming from the buffer area around the BSC. As air is pulled into the BSC, poor air quality in the buffer area may compromise the ISO class 5 compounding environment within the class II BSC. A class II BSC or CACI not meeting the conditions listed in USP Chapter <797> must be placed in an area that is physically separated from other compounding areas and has air quality of ISO class 7. Optimally, this
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Table 3. Comparison of NIOSH, ASHP, and USP Chapter <797> Recommendations for Primary Engineering Controls NIOSH
USP Chapter <797>
Primary engineering controls
• Aseptic containment ventilation control class II BSC-type B2 is preferred. • Class III BSC or CACI.
• Class II BSC-type B2 with outside exhaust is preferred. • Total exhaust is required if the hazardous drug is known to be volatile. • Class III BSC or CACI.
• BSC or CACI that meets or exceeds the standards for CACI in USP Chapter <797>.
• Do not use a ventilated cabinet that recirculates air inside the cabinet or exhausts air back into the room environment if a drug is volatile.
• Without special design considerations, class II BSCs are not recommended in traditional, positive-pressure clean rooms.
• BSCs and CACIs optimally should be 100% vented to the outside air through HEPA filtration.
ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; HEPA, high-efficiency particulate air; NIOSH, National Institute for Occupational Safety and Health; USP, United States Pharmacopeia Based on references 23, 34, and 38.
area should be at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas, thus providing inward airflow to contain airborne drug. Optimally, a PEC used for compounding sterile hazardous drug preparations should be 100% vented to the outside air through high-efficiency particulate air (HEPA) filtration. All environments in which sterile preparations are compounded must be provided with HEPA-filtered air from outside the environment. The PEC may not be the sole source of HEPA-filtered air and it may not provide more than 50% of the ACPH in that environment. The ISO class 7 buffer area and ante-area must be supplied with HEPAfiltered air providing a total of at least 30 ACPH. Table 3 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for hazardous drug PECs.
WORK PRACTICE CONTROLS Work practices must be designed to minimize the generation of hazardous drug contamination and maximize the containment of inadvertent contamination that occurs during routine handling or in the event of a spill. The compounding techniques described by Wilson and Solimando continue to be the standard for any procedure in which needles and syringes are used to manipulate sterile dosage forms of hazardous drugs.52 These techniques, when performed accurately, minimize the escape of drugs from vials and ampules. Many adjunct devices have been developed to reduce the generation of contamination during the compounding process. Vented needles with 0.2-micron hydrophobic filters were designed to reduce the powder and liquid drug residues that escape from vials through standard vented needles. Dispensing pins with small spikes and hydrophobic filters were introduced
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to make the compounding process more efficient. One study documents the effectiveness of one of these devices, but the investigators used only a visual inspection process because no sensitive drug assays were available at the time of the study.53 Since then, sensitive, drug-specific assays have been developed that provide a means to validate work practice controls at different work sites. The persistent presence of contamination in hospitals and pharmacies generated interest in an adjunct device, generically named by NIOSH in the 2004 Alert as a “closed-system drug-transfer device” (CSTD). NIOSH defines a CSTD as a drug-transfer device that mechanically prevents the transfer of environmental contaminants into the system and the escape of hazardous concentrations of drug or vapor from the system.34 These systems provide some of the benefits of the earlier devices, but with the added protection that they can be locked into place on the drug vial. CSTD components also provide protection during the administration of IV push and IV infusion doses, which had not been available previously. Numerous studies using markers for hazardous drugs have demonstrated the effectiveness of a CSTD in reducing hazardous drug contamination in the workplace.6,14,15 At clinical practice sites representing inpatient and outpatient compounding and administration, the implementation of a CSTD reduced surface contamination significantly compared with standard practice.6,14,15, USP Chapter <797> similarly defines CSTDs as “vialtransfer systems that allow no venting or exposure of hazardous substance to the environment.” USP Chapter <797> further states that CSTDs must be used within the ISO class 5 environment of a BSC or CACI. In facilities that prepare a low volume of hazardous drugs, the use of 2 tiers of containment (eg, a CSTD within a BSC
Table 4. Comparison of NIOSH, OSHA, ASHP, And USP Chapter <797> Recommendations for PPE
USP Chapter <797>
• Use double gloving for all activities involving hazardous drugs.
• Wear double gloves for all activities involving hazardous drugs. • Guidelines for the safe handling of hazardous drugs recommend the use of gowns for compounding in the BSC, administration, spill control, and waste management to protect the worker from contamination by fugitive drug generated during the handling process.
• Hazardous drugs shall be handled with caution at all times with the use of appropriate chemotherapy gloves during receiving, distributing, stocking, taking inventory, preparing for administration, and disposal.
OSHA: • Protective equipment, including PPE for eyes, face, head, and extremities, protective clothing, respiratory devices, and protective shields and barriers shall be provided, used, and maintained in a sanitary and reliable condition wherever it is necessary by reason of hazards of processes or environment, chemical hazards, radiological hazards, or mechanical irritants encountered in a manner capable of causing injury or impairment in the function of any part of the body through absorption, inhalation, or physical contact.
Receiving and storage
• Wear chemotherapy gloves, protective clothing, and eye protection when opening containers to unpack hazardous drugs.
• Gloves must be worn at all times when drug packaging, cartons, and vials are handled, including during the performance of inventory control procedures and the gathering of hazardous drugs.
• Wear PPE (including double gloves and protective gowns) while reconstituting and admixing drugs. • Make sure that gloves are labeled as chemotherapy gloves. • Use disposable gowns made of polyethylene-coated polypropylene material (which is nonlinting and nonabsorbent).
• Select disposable gowns of material tested to be protective against the hazardous drugs to be used. • Coated gowns must not be worn for longer than 3 hours during compounding and must be changed immediately when damaged or contaminated. • Gowns worn as barrier protection in the compounding of hazardous drugs must never be worn outside the immediate preparation area.
• Wear PPE (including double gloves, goggles, and protective gowns) for all activities associated with drug administration.
• Gowns worn during administration should be changed when the patient care area is left and immediately if contaminated.
Sterile compounding: • Shoe covers, head and facial hair covers (eg, beard covers in addition to face masks), and face masks; a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck; sterile powder-free gloves. Hazardous drug compounding: • Appropriate PPE shall be worn during compounding in a BSC or CACI and during the use of CSTDs. PPE should include gowns, face masks, eye protection, hair covers, shoe covers or dedicated shoes, double gloving with sterile chemotherapy-type gloves, and compliance with manufacturers’ recommendations when a CACI is used.
ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; CSTD, closed-system drug-transfer device; OSHA, Occupational Safety and Health Administration; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; PPE, personal protective equipment; USP, United States Pharmacopeia Based on references 22, 23, 34, and 38.
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or a CACI that is located in a nonâ€“negative-pressure room) is acceptable. The NIOSH Alert specifies that CSTDs should be used only within a ventilated cabinet. Neither USP Chapter <797> nor NIOSH has developed performance standards for any device marketed as a CSTD. Because the configurations of available CSTDs vary from that of the tested device, it is unclear how effective these devices are in reducing environmental contamination resulting from the compounding and administration of hazardous drugs. Any device marketed as a CSTD should be clinically tested.
PERSONAL PROTECTIVE EQUIPMENT In addition to environmental and engineering controls, PPE is required to provide a barrier between the health care worker and the hazardous drug during episodes of potential contact. This is especially important during administration, spill control, handling of drug waste, and handling of patient waste because no PECs are in place for these activities. All PPE should be selected for effectiveness. Glove and gown materials should be able to withstand permeation by a selection of hazardous drugs.54-56 Several hazardous drugs require nonaqueous diluents for patient use and may permeate PPE more readily than others. The American Society for Testing and Materials has developed a standard for testing chemotherapy gloves.57 There is no standard for chemotherapy gowns, but recommendations have been made based on several studies.55,56 See Table 4 for a comparison of PPE recommendations. During sterile compounding, barrier garments must be worn to prevent the shedding of human skin and hair cells and the deposition of mucus or respiratory residue into the compounding area. USP Chapter <797> specifies that compounding garb must include the following: dedicated shoes or shoe covers, face masks, head and facial hair covers (eg, beard covers in addition to face masks), a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck, and sterile powder-free gloves. Appropriate PPE must be worn when the sterile compounding of hazardous drugs is performed in a BSC or CACI and when CSTDs are used. PPE includes coated gowns, masks or respirators, eye protection, hair covers, shoe covers, and double gloving with sterile hazardous drugâ€“tested gloves.
New Technologies Technological advances include robotic automation that can compound sterile doses of hazardous and nonhazardous drugs. By replacing the human compounder, these robots reduce the occupational exposure of health care workers during the compounding process. Robotic units provide contained ISO class 5 environments and use techniques to reduce the generation of hazardous drug residues during compounding. Robots operate with sophisticated mechanics and software and provide a degree of accuracy and patient safety not available with manual compounding. CytoCare
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from Health Robotics, IntelliFill Chemo from ForHealth Technologies, Inc, and RIVA (Robotic IV Administration) from Intelligent Hospital Systems all provide robotic solutions to the compounding of sterile preparations of hazardous drugs. Like most technology, these robots are not perfect. They require human staff to load and clean them. Hazardous drug contamination may be generated in the compounding environment and transferred to the final product. Cleaning of the compounding environments requires both disinfection as well as decontamination of hazardous drug residues. No particular cleaner has been shown to effectively deactivate all known hazardous drugs,11 so routine cleaning and spill control are still challenges to the health care personnel working with these robots. The robots help only with the compounding process, leaving the workers administering hazardous drugs without protection. Spill control and waste handling also remain issues for human workers to address.
Conclusion Despite almost 3 decades of data on the adverse health effects of occupational exposure to hazardous drugs, skepticism about the risks continues, as evidenced by the lack of programmatic controls for reducing exposure. NIOSH has renewed its dedication to this health risk by continuing to promote worker awareness of safety. USP Chapter <797> has elevated many of the NIOSH recommendations to a standard, ensuring both awareness and compliance with at least the compounding segment of safety program controls. Each new generation of health care workers needs to be educated about the risks of handling hazardous drugs and the importance of training in the proper techniques to reduce their exposure. Employers and employees must implement all aspects of hazardous drug safety programs to reduce occupational exposure and its potential adverse effects.
Ng LM, Jaffe N. Possible hazards of handling antineoplastic drugs. Pediatrics. 1970;46(4):648-649.
2. Crudi CB, Stephens BL, Maier P. Possible occupational hazards associated with the preparation/administration of antineoplastic agents. NITA. 1982;5(4):264-265. 3. Baker ES, Connor TH. Monitoring occupational exposure to cancer chemotherapy drugs. Am J Health Syst Pharm. 1996;53(22):2713-2723. 4. Sessink PJ, Bos RP. Drugs hazardous to healthcare workers. Evaluation of methods for monitoring occupational exposure to cytostatic drugs. Drug Saf. 1999;20(4):347-359. 5. Martin S. The adverse health effect of occupational exposure to hazardous drugs. Community Oncol. 2005;2(5):397-400. 6. Wick C, Slawson MH, Jorgenson JA, Tyler LS. Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. Am J Health Syst Pharm. 2003;60(22):2314-2320. 7.
Nygren O, Lundgren C. Determination of platinum in workroom air and in blood and urine from nursing staff attending patients receiving cisplatin chemotherapy. Int Arch Occup Environ Health. 1997;70(3):209-214.
8. Pethran A, Schierl R, Hauff K, Grimm CH, Boos KS, Nowak D. Uptake of antineoplastic agents in pharmacy and hospital personnel. Part I: monitoring of urinary concentrations. Int Arch Occup Environ Health. 2003;76(1):5-10. 9. Sessink PJ, Van de Kerkhof MCA, Anzion RB, Noordhoek J, Bos RP. Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians: is skin absorption an important exposure route? Arch Environ Health. 1994;49(3):165-169. 10. Sessink PJ, Boer KA, Scheefhals AP, Anzion RB, Bos RP. Occupational exposure to antineoplastic agents at several departments in a hospital. Environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch Occup Environ Health. 1992;64(2):105-112. 11. Dorr RT, Alberts DS. Topical absorption and inactivation of cytotoxic anticancer agents in vitro. Cancer. 1992;70(4 suppl):983-987. 12. Ensslin AS, Huber R, Pethran A, et al. Biological monitoring of hospital pharmacy personnel occupationally exposed to cytostatic drugs: urinary excretion and cytogenetics studies. Int Arch Occup Environ Health. 1997;70(3):205-208. 13. Sessink PJ, Wittenhorst BCJ, Anzion RB, Bos RP. Exposure of pharmacy technicians to antineoplastic agents: reevaluation after additional protective measures. Arch Environ Health. 1997;52(3):240-244. 14. Vandenbroucke J, Robays H. How to protect environment and employees against cytotoxic agents, the UZ Ghent experience. J Oncol Pharm Pract. 2001;6(4):146-152. 15. Harrison BR, Peters BG, Bing MR. Comparison of surface contamination with cyclophosphamide and fluorouracil using a closed-system drug transfer device versus standard preparation techniques. Am J Health Syst Pharm. 2006;63(18):1736-1744. 16. Connor TH, Sessink PJ, Harrison BR, et al. Surface contamination of chemotherapy drug vials and evaluation of new vial-cleaning techniques: results of three studies. Am J Health Syst Pharm. 2005;62(5):475-484. 17. Connor TH, Shults M, Fraser MP. Determination of the vaporization of solutions of mutagenic antineoplastic agents at 23 and 37 degrees C using a desiccator technique. Mutat Res. 2000;470(1):85-92. 18. Opiolka S, Schmidt KG, Kiffmeyer TK, Schoppe G. Determination of vapor pressure of cytotoxic drugs and its effects on occupational safety. J Oncol Pharm Pract. 2000;6:15. Abstract. 19. Kiffmeyer TK, Kube C, Opiolka S, Schmidt KG, Schoppe G, Sessink PJ. Vapour pressures, evaporation behaviour and airborne concentrations of hazardous drugs: implications for occupational safety. Pharm J. 2002;268:331-337. 20. Yodaiken RE, Bennett D. OSHA work-practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Occupational Safety and Health Administration. Am J Hosp Pharm. 1986;43(5):1193-1204. 21. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (OSHA Instruction CPL 2-2.20B CH-4). Washington, DC: Directorate of Technical Support, Occupational Safety and Health Administration; 1995:chap 21.
assistance bulletin on handling cytotoxic drugs in hospitals. Am J Hosp Pharm. 1985;42(1):131-137. 26. Brown KA, Esper P, Kelleher LO, O’Neil JEB, Polovich M, White JM, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 2001. 27. Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Press; 2005. 28. Mahon SM, Casperson DS, Yackzan S, et al. Safe handling practices of cytotoxic drugs: the results of a chapter survey. Oncol Nurs Forum. 1994;21(7):1157-1165. 29. Martin S, Larson E. Chemotherapy-handling practices of outpatient and office-based oncology nurses. Oncol Nurs Forum. 2003;30(4):575-581. 30. Nieweg R, de Boer M, Dubbleman R, et al. Safe handling of antineoplastic drugs. Results of a survey. Cancer Nurs. 1994;17(6):501-511. 31. Valanis B, McNeil V, Driscoll K. Staff members’ compliance with their facility’s antineoplastic drug handling policy. Oncol Nurs Forum. 1991;18(3):571-576. 32. Valanis B, Vollmer WM, Labuhn K, Glass A, Corelle C. Antineoplastic drug handling protection after OSHA guidelines. Comparison by profession, handling activity, and work site. J Occup Med. 1992;34(2):149-155. 33. Connor TH, Anderson RW, Sessink PJ, Broadfield L, Power LA. Surface contamination with antineoplastic agents in six cancer treatment centers in Canada and the United States. Am J Health Syst Pharm. 1999;56(14):1427-1432. 34. National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. DHHS (NIOSH) Publication No. 2004165. Washington, DC: NIOSH; 2004. http://www.cdc.gov/niosh/ docs/2004-165/. Accessed February 16, 2010. 35. Code of Federal Regulations. Title 29—Labor. Subtitle B—Regulations Relating to Labor. Chapter XVII—Occupational Safety and Health Administration, Department of Labor. Part 1910—Occupational Safety and Health Standards. Subpart A—General. Article 1910.2—Definitions. Washington, DC: US Government Printing Office; 2004. http://ecfr.gpoaccess.gov/cgi/t/text/textidx?c=ecfr&tpl=/ecfrbrowse/Title29/29cfr1910_main_02.tpl. Accessed February 16, 2010. 36. National Institute for Occupational Safety and Health. NIOSH safety and health topic: hazardous drug exposures in health care. http://www.cdc.gov/niosh/topics/hazdrug. Accessed February 16, 2010. 37. National Institute for Occupational Safety and Health. NIOSH safety and health topic: occupational exposure to antineoplastic products. http://www.cdc.gov/niosh/topics/antineoplastic/. Accessed February 16, 2010. 38. US Pharmacopeial Convention. Chapter <797> Pharmaceutical compounding—sterile preparations. In: The United States Pharmacopeia, 31st rev, and The National Formulary, 26th ed. Rockville, MD: US Pharmacopeial Convention; 2008. 39. Connor TH. NIOSH Multi-Center Study of Hazardous Drug Exposure. 2009. Presented at the Safe Handling of Hazardous Drugs in the Clinical Environment Symposium. Bedford, MA.
22. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (TED 01-00-015 [TED 1-0.15A] Sec VI Chap 2); 1999. http://www. osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html. Accessed February 16, 2010.
40. Connor TH. NIOSH Study Of Health Care Workers in Three Sites: Study Design & Results. 2009. Presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting, Las Vegas, NV.
23. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2006;63(12):1172-1191.
41. Demonaco HJ. Report on the Massachusetts General Hospital Hazardous Drug Study. 2009. Presented at the Safe Handling of Hazardous Drugs in the Clinical Environment Symposium. Bedford, MA.
24. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47(5):1033-1049. 25. American Society of Hospital Pharmacists. ASHP technical
42. Ahmed S. Massachusetts General Hospital (MGH) study of hazardous drug (HD) work practices: Study design and results. 2009. Presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting, Las Vegas, NV.
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43. McDiarmid MA. NIOSH Study of Healthcare Workers Handling Anti-Cancer Agents: Chromosomal Effects. 2009. Presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting, Las Vegas, NV. 44. Occupational Safety and Health Administration. Hazard Communication-59:6126-6184. http://www.osha.gov/pls/oshaweb/owadisp. show_document?p_table=federal_register&p_id=13349. Accessed February 16, 2010. 45. Occupational Safety and Health Administration. Hazard Communication Standard 1910.1200. http://www.osha.gov/pls/oshaweb/ owadisp.show_document?p_table=STANDARDS&p_id=10099. Accessed February 16, 2010. 46. National Institute for Occupational Safety and Health. Draft document for public review and comment: process for updating the list of hazardous drugs (Appendix A) for the NIOSH Alert on Hazardous Drugs. NIOSH Docket #105. http://www.cdc.gov/niosh/review/ public/105/default.html. Accessed February 16, 2010. 47. National Institute for Occupational Safety and Health. NIOSH Publication No. 2004-165: Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. Appendix A. drugs considered hazardous. http://www. cdc.gov/niosh/docs/2004-165/2004-165d.html#o. Accessed February 16, 2010. 48. US Department of Labor. 1998. OSHA 3143. Informational booklet on industrial hygiene. http://www.osha.gov/Publications/ OSHA3143/OSHA3143.htm. Accessed February 16, 2010. 49. National Institute for Occupational Safety and Health. Medical surveillance for healthcare workers exposed to hazardous drugs. NIOSH Publication No. 2007-117. http://www.cdc.gov/niosh/docs/ wp-solutions/2007-117/. Accessed February 16, 2010. 50. NSF International. NSF/ANSI 49-2007: NSF 49 Class II (Laminar
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Flow) Biosafety Cabinetry. Ann Arbor, MI: NSF International; 2007. 51. Clark RP, Goff MR. The potassium iodide method for determining protection factors in open-fronted microbiological safety cabinets. J Appl Bacteriol. 1981;51(3):439-460. 52. Wilson JP, Solimando DA Jr. Aseptic technique as a safety precaution in the preparation of antineoplastic agents. Hosp Pharm. 1981;16(11):575-576, 579-581. 53. Hoy RH, Stump LM. Effect of an air venting filter device on aerosol production from vials. Am J Health Syst Pharm. 1984;41(2):324-326. 54. Connor TH. Permeability of nitrile rubber, latex, polyurethane, and neoprene gloves to 18 antineoplastic drugs. Am J Health Syst Pharm. 1999;56(23):2450-2453. 55. Harrison BR, Kloos MD. Penetration and splash protection of six disposable gown materials against fifteen antineoplastic drugs. J Oncol Pharm Pract. 1999;5(2):61-66. 56. Connor TH. An evaluation of the permeability of disposable polypropylene-based protective gowns to a battery of cancer chemotherapy drugs. Appl Occup Environ Hyg. 1993;8:785-789. 57. American Society for Testing and Materials. D 6978-05 standard practice for assessment of resistance of medical gloves to permeation by chemotherapy drugs. West Conshohocken, PA: American Society for Testing and Materials; 2005.
Suggested Reading Polovich M, Whitford JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Press; 2009.
Pharmacy Practice News • March 2010
Fungal Septic Shock in the ICU Defies Simple Solution Miami Beach, Fla.—Fungal sepsis remains underrecognized and undertreated in the intensive care unit, according to a study by Canadian researchers, who suggest that pharmacists should raise their level of clinical suspicion for the highly lethal condition.
empirical selection of antifungal agents. In the 10-year retrospective study, Dr. McIntyre’s team reviewed 54 consecutive cases of yeast-associated septic shock identified from more than 8,000 ICU admissions (61% male, mean age 67 years; mean APACHE score
‘If certain risk factors are present, such as long-term antibiotic or corticosteroid therapy, or immunosuppression of any variety, that patient deserves a second look and a higher suspicion for fungal infection.’
—Mark McIntyre, PharmD
“In the absence of rapid and appropriate antifungal therapy, mortality rates from fungal sepsis septic shock can be extremely high, yet clinical suspicion tends to be lower and response tends to be delayed,” said lead author Mark McIntyre, PharmD, who presented the results of the study (abstract 479) at the Society of Critical Care Medicine’s 39th Annual Critical Care Congress. “Physicians in critical care typically rely on broad-spectrum antibacterial therapy for patients with sepsis, but seldom will they consider early antifungal therapy,” said Dr. McIntyre, a clinical pharmacist in the Emergency and Critical Care Departments at Mt. Sinai Hospital in Toronto. If cultures come back positive for fungal infection, Dr. McIntyre added, it’s often too late for effective therapy. The authors also found, as have many other centers, an epidemiologic shift toward non-albicans Candida. The increasing incidence of non-albicans species, some of which are less susceptible or intrinsically resistant to the antifungal drug fluconazole, complicates
of 29). Candida albicans represented 50% of isolated yeast, with a trend toward increasing non-albicans species over time. The mortality rate was 96%, which Dr. McIntyre called “extraordinarily high, and likely a result of the high acuity of the patient cohort.” The initial antimicrobial therapy was appropriate in only 52% of patients, and the average time to effective therapy for those treated was 52 hours. Twentyeight percent did not receive antifungal treatment before death. Fluconazole was the agent used most commonly (42%), followed by amphotericin B (39%) and caspofungin (20%). Use of caspofungin (Cancidas, Merck) increased markedly (largely replacing fluconazole), and represented 50% of initial antifungal therapy during the last two years of the study. Comorbidities included immunosuppression (52%), leukemia-lymphoma (43%), chronic renal disease (29%) and diabetes mellitus (28%). Dr. McIntyre acknowledged that the study’s limitations prevent clinicians from drawing firm conclusions about the relationship between treatment delay
fied all patients who were admitted to the SICU between January 2006 and July 2008 who had positive blood or pulmonary bacteria cultures isolated. They then determined what were the most common organisms in the SICU as well as their susceptibility patterns to commonly used empiric antibiotics, including aztreonam (Azactam, BristolMyers Squibb), cefepime, levofloxacin (Levaquin, Ortho-McNeil), imipenem (Primaxin, Merck), piperacillin/tazobactam, aminoglycosides and vancomycin. The researchers then calculated success rates for each individual antibiotic alone as well as various combinations of double gram-negative coverage with and without vancomycin. The drug regimens were deemed to be a success if
continued from page 1
ill patients, especially as the incidence of multidrug-resistant bacteria is increasing,” Dr. Barletta said. The goal of the study, he noted, was to evaluate infectious epidemiology in his center’s surgical intensive care unit (SICU) and determine the antimicrobial regimen best suited for empiric therapy based on calculated success rates. “We were observing more MRSA and more multidrug–resistant organisms, so we wanted to see whether the regimens we have been using were still appropriate, given that pattern of susceptibility,” Dr. Barletta said. The researchers retrospectively identi-
and mortality rates. But they underscore the need for pharmacists and their physician colleagues to be particularly vigilant for underlying fungal etiology among ICU patients with septic shock. “If certain risk factors are present, such as long-term antibiotic or corticosteroid therapy, or immunosuppression of any variety, that patient deserves a second look and a higher suspicion for fungal infection,” Dr. McIntyre said. “If we just put this on our radar as something we need to think of, we can at least bring it up with our clinical colleagues and make them aware of it.” Such a team approach to antimicrobial stewardship is the preferred strategy to managing fungal and other potentially severe infections, and is recommended in clinical practice guidelines from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology. For smaller hospitals with limited resources, the same precepts hold: Good relationships with physician partners are key, as are surveillance and the ability to assess your patients appropriately and quickly, Dr. McIntyre said. “The history you take from a medical and medication perspective can be really useful even before a patient gets to the floor.”
More Study Needed The study’s conclusions are appropriate based on the data presented, commented Marshall Lyon III, MD, an infectious disease specialist and assis-
tant professor of medicine at Emory University in Atlanta. However, he cautions that there is scant evidence to link delays in antifungal treatment with an increase in mortality rates among this patient cohort. Previous research, including empiric therapy trials, “have failed to find a mortality benefit among people who present with septic shock in the ICU and who receive early antifungal therapy,” Dr. Lyon said. “There are many causes of septic shock, and they all present similarly,” whether bacterial or fungal. The minority of cases is caused by fungi, he added, which makes it hard to know if earlier treatment would improve outcomes in the overall cohort of sepsis patients. (One ongoing randomized, prospective trial is looking at the efficacy of caspofungin as pre-emptive therapy against invasive candidiasis in a critical care setting: http://clinicaltrials.gov/ct2/show/NCT00520234.) Although there is no notable clinical downside to prescribing antifungal therapy along with antibacterial drugs while awaiting culture results, the most recent IDSA guidelines recommend against using fluconazole in critically ill patients, favoring instead one of the echinocandins (e.g., caspofungin, micafungin [Mycamine, Astellas], anidulafungin [Eraxis, Pfizer]), which are also more costly. Both Drs. McIntyre and Lyon agree that the study further emphasizes the need for non–culture-based diagnostics that will enable quick identification of fungal etiology. —Steve Frandzel
‘Each institution should really understand what their own infectious epidemiology is in individual units. That information should be used to … optimize initial empiric antibiotic selection.’ —Jeffrey Barletta, PharmD
the organism was susceptible to at least one of the antibiotics in the regimen, Dr. Barletta explained. During the three-month study, 608 bacterial isolates were assessed in 455 patients. The most common organisms identified were Pseudomonas (16.4%), methicillin-sensitive S. aureus (15.1%) and Enterobacter (11.7%).
Dr. Barletta and his team found that to optimize their first choice for antibiotics, three drugs were necessary— two to cover gram-negative organisms and one for empiric MRSA coverage. With single-drug coverage, the calculated success rate was 53% for aztreonam, 64% for aminoglycosides, 78%
see MRSA TESTING, page 26
Pharmacy Practice News • March 2010
MRSA TESTING continued from page 25
for cefepime, 82% for piperacillin/ tazobactam, 83% for imipenem and 84% for levofloxacin. The calculated success rate with double gram-negative coverage was significantly higher and ranged from 84% to 89% (P<0.05 for all combinations). There were no differences between individual two-drug regimens. The addition of vancomycin to double gram-negative coverage increased the calculated success rate to greater than 94% (P<0.05 vs. double gram-negative coverage without vancomycin), Dr. Barletta reported.
the antibiogram, looking at what their organisms are and how resistant they are, over a period of time,” she said. “Some recommend reviewing this information every six months and others every year. The real issue is making sure you have enough isolates from a specific unit to make recommendations for empiric therapy on. Too few isolates and the information may not be reliable. But if you have enough isolates over a shorter time frame, then you would have reliable-enough information to make changes to your recommended empiric therapies.”
Dr. Cappelletty added that the next step is to see whether empiric antibiotic selection that is individualized to each center will improve outcomes.
“This is a very difficult question to answer when you go across the broad range of types of infections. We intuitively think that if we have the right drugs on board at the outset, we should have better outcomes,” she said. “But knowing what you need to do at your own institution to cover your organisms is a good start, and it’s a new mindset for many physicians, because resistance is growing at such an alarming rate that single drug coverage just isn’t doing it any longer.” —Fran Lowry
Tailored Epidemiology “The main take-home message here is that each institution should really understand what their own infectious epidemiology is in individual units,” Dr. Barletta told Pharmacy Practice News. “That information should be used to guide therapy to try to optimize initial empiric antibiotic selection.” When taking that approach, he added, an adequate sample size is necessary. “Preferably, a two- to three-year period would be required to gain a basic understanding of the bacteria present and their respective susceptibilities.” Diane Cappelletty, PharmD, associate professor at the University of Toledo College of Pharmacy, in Ohio, said that the study findings should help hospitals implement changes in clinical practice. “Each microbiology department, as they do their identification and susceptibility testing, can go back and do
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Pens are for single-patient use only and should not be shared among patients. Please see Important Safety Information on adjacent page and accompanying Brief Summary of full Prescribing Information.
Pharmacy Practice News • March 2010
NOVEL APPROACH continued from page 22
to service the ED. However, the benefit seems to wane when the CPS is not in the institution. Because the CPS coverage at our hospital is not available in a 24-hour per day, 7-day per week manner, we wanted to see if some of the benefits of pharmacy services in the ED could be obtained by providing intensive training to our staff pharmacists in this area. We hypothesized that involving 4 key staff pharmacists in the ED during selected
shifts would improve the relationship between the departments. The greatest gain should be seen on off-shifts when the CPS is not present. Training of pharmacists took place between April and August 2009. Because this was classified as a quality improvement project (QIP), institutional review board (IRB) approval was not sought.
Methods The CPS, along with the leadership team in the pharmacy, selected 4 pharmacists to complete the
training after they expressed interest in the program. Those selected had a wide range of clinical experience. One of the 4 had completed a postgraduate year-1 (PGY-1) pharmacy practice residency. Prior to any intervention, the CPS distributed surveys to 76 ED providers (attending physicians, resident physicians, and ED physician assistants) and 133 nurses to assess satisfaction with the pharmacy department. The response rates were 32% and 26%, respectively. A Likert scale, ranging from 1 (strongly agree) to 5 (strongly disagree), was
Indication Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control of hyperglycemia. Humalog should be used with longer-acting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.
Important Safety Information Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients. Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of action. Therefore, when used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an insulin pump). Glucose monitoring is recommended for all patients with diabetes. The safety and effectiveness of Humalog in patients less than 3 years of age have not been established. There are no adequate and well-controlled clinical studies of the use of Humalog in pregnant or nursing women. Starting or changing insulin therapy should be done cautiously and only under medical supervision. Hypoglycemia Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia can happen suddenly, and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening. Other Side Effects Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and hypersensitivity. Systemic allergy is less common, but may be life-threatening. Because of the difference in action of Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those who are fasting, have autonomic neuropathy or renal impairment, are using potassium-lowering drugs, or taking drugs sensitive to serum potassium level). For additional safety proﬁle and other important prescribing considerations, see accompanying Brief Summary of full Prescribing Information. Please see full user manual that accompanies the pen. Humalog® is a registered trademark of Eli Lilly and Company and is available by prescription only. Humalog® KwikPen™ is a trademark of Eli Lilly and Company and is available by prescription only. Humulin® is a registered trademark of Eli Lilly and Company.
1109 PRINTED IN USA
©2009, LILLY USA, LLC. ALL RIGHTS RESERVED.
used. Questions also were asked to assess the typical shift that the staff member worked, and the area of the ED where the staff worked the majority of their shifts. Pharmacy staff was then assigned to work in the ED with the CPS on sporadic days when scheduling permitted. During the assigned day, the staff pharmacist spent the entire shift (8 hours) with the CPS. Each pharmacist completed 4 days in the ED. Areas of instruction included initiation and titration guidelines for vasopressors
see NOVEL APPROACH, page 28
Pharmacy Practice News • March 2010
NOVEL APPROACH continued from page 27
and vasodilators, toxicology/antidotes, infectious disease topics, management of acute heart failure, rapid sequence intubation, and various operational topics. The final day was set up to allow the staff pharmacist to function on his or her own with pager back-up from the CPS. After the 4 pharmacists completed the intervention in the ED, another survey was distributed to the ED providers and nursing staff to assess
whether any change in perception or level of service took place. Training was completed in August 2009 and final surveys were distributed in October to 78 ED providers and 134 nurses. The response rates were 32% and 18%, respectively.
Results Tables 1 and 2 provide the results of the surveys distributed to ED providers and nurses. Questions were divided to ascertain the perception of the pharmacy department as a whole, the perception of the main
pharmacy services, the perception of the CPS, and a desire to see an increase of direct pharmacy coverage in the ED. Questions were asked using a Likert scale (as in the preintervention assessment), with a lower score indicating a more favorable response or an increased desire to see more extensive pharmacy services in the ED. Because statistical analysis was not performed, we did not find any specific differences in the pre/postintervention surveys. However, there were some anecdotal successes. One of the most
HUMALOG® INSULIN LISPRO INJECTION (rDNA ORIGIN) BRIEF SUMMARY: Consult package insert for complete prescribing information. INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used without a longer-acting insulin when used in combination therapy with sulfonylurea agents. Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients with type 2 diabetes. CONTRAINDICATIONS: Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or any of its excipients. WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an external insulin pump). External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin. Patients should carefully read and follow the external insulin pump manufacturer’s instructions and the “PATIENT INFORMATION” leaﬂet before using Humalog. Physicians should carefully evaluate information on external insulin pump use in the Humalog physician package insert and in the external insulin pump manufacturer’s instructions. If unexplained hyperglycemia or ketosis occurs during external insulin pump use, prompt identiﬁcation and correction of the cause is necessary. The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION). Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using an external insulin pump. Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the need for a change in dosage. PRECAUTIONS: General—Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins. As with all insulin preparations, the time course of Humalog action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress. Hypoglycemia—As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensiﬁed diabetes control. Renal Impairment—The requirements for insulin may be reduced in patients with renal impairment. Hepatic Impairment—Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary. Allergy—Local Allergy—As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Systemic Allergy—Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life-threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving Humulin R® (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053). Antibody Production—In large clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy. Usage of Humalog in External Insulin Pumps—The infusion set (reservoir syringe, tubing, and catheter), Disetronic® D-TRON®2,3 or D-TRONplus®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external insulin pump should not be exposed to temperatures above 37°C (98.6°F). In the D-TRON ®2,3 or D-TRONplus ®2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be selected every 48 hours or less. When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and Storage). Information for Patients—Patients should be informed of the potential risks and advantages of Humalog and alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia, and periodic assessment for diabetes complications. Patients should be advised to inform their physician if they are pregnant or intend to become pregnant. Refer patients to the “PATIENT INFORMATION” leaﬂet for timing of Humalog dosing (<_15 minutes before or immediately after a meal), storing insulin, and common adverse effects. For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the “PATIENT INFORMATION” leaﬂet that accompanies the drug product and the User Manual that accompanies the delivery device. They should also reread these materials each time the prescription is renewed. Patients should be instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose of needles. Patients should be advised not to share their Pens with others. For Patients Using External Insulin Pumps: Patients using an external infusion pump should be trained in intensive insulin therapy and in the function of their external insulin pump and pump accessories. Humalog was tested in the MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyﬁn®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir), and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 insulin pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. The infusion set (reservoir syringe, tubing, catheter), D-TRON®2,3 or D-TRONplus ®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced, and a new infusion site selected every 48 hours or less. Humalog in the external pump should not be exposed to temperatures above 37°C (98.6°F). A Humalog 3 mL cartridge used in the D-TRON ®2,3 or D-TRONplus ®2,3 pump should be discarded after 7 days, even if it still contains Humalog. Infusion sites that are erythematous, pruritic, or thickened should be reported to medical personnel, and a new site selected. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. Laboratory Tests—As with all insulins, the therapeutic response to Humalog should be monitored by periodic blood glucose tests. Periodic measurement of hemoglobin A1C is recommended for the monitoring of long-term glycemic control. Drug Interactions—Insulin requirements may be increased by medications with hyperglycemic activity, such as corticosteroids, isoniazid, certain lipid-lowering drugs (eg, niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy (see CLINICAL PHARMACOLOGY). Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (eg, octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients. Mixing of Insulins—Care should be taken when mixing all insulins as a change in peak action may occur. The American Diabetes Association warns in its Position Statement on Insulin Administration, “On mixing, physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological response to the insulin mixture may differ from that of the injection of the insulins separately.” Mixing Humalog with Humulin® N or Humulin® U does not decrease the absorption rate or the total bioavailability of Humalog. Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect compared with regular human insulin. Pregnancy—Teratogenic Effects—Pregnancy Category B—Reproduction studies with insulin lispro have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to Humalog. There are, however, no adequate and well-controlled studies with Humalog in pregnant women. Because
animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the ﬁrst trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted. Nursing Mothers—It is unknown whether Humalog is excreted in signiﬁcant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both. Pediatric Use—In a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf life may be reduced (see DOSAGE AND ADMINISTRATION). Geriatric Use—Of the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were 65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed. ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a difference in frequency of adverse events between the 2 treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Whole—allergic reactions (see PRECAUTIONS). Skin and Appendages—injection site reaction, lipodystrophy, pruritus, rash. Other—hypoglycemia (see WARNINGS and PRECAUTIONS). OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent premeal hyperglycemia. When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longer-acting insulin being given may need to be adjusted when using Humalog. The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin preparations, the time course of action of Humalog may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques. Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30, and Humulin® R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted Humalog may remain in patient use for 28 days when stored at 5°C (41°F) and for 14 days when stored at 30°C (86°F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump. Parenteral drug products should be inspected visually before use whenever the solution and the container permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be reﬁlled with insulin. External Insulin Pumps—Humalog was tested in MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyﬁn®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. HOW SUPPLIED: Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each presentation containing 100 units insulin lispro per mL [U-100]): 10 mL vials NDC 0002-7510-01 (VL-7510) 3 mL vials NDC 0002-7510-17 (VL-7533) NDC 0002-7516-59 (VL-7516) 5 x 3 mL cartridges 3 5 x 3 mL preﬁlled insulin delivery devices (Pen) NDC 0002-8725-59 (HP-8725) 5 x 3 mL preﬁlled insulin delivery devices (Humalog® KwikPen™ ) NDC 0002-8799-59 (HP-8799)
1 2 3
MiniMed® and Polyﬁn® are registered trademarks of MiniMed, Inc. Disetronic®, H-TRONplus®, D-TRON®, and Rapid® are registered trademarks of Roche Diagnostics GMBH. 3 mL cartridge is for use in Eli Lilly and Company’s HumaPen® MEMOIR™ and HumaPen® LUXURA™ HD insulin delivery devices, Owen Mumford, Ltd.’s Autopen ® 3 mL insulin delivery device, and Disetronic D-TRON ® and D-TRONplus ® pumps. Autopen® is a registered trademark of Owen Mumford, Ltd. HumaPen®, HumaPen® MEMOIR™ and HumaPen® LUXURA™ HD are trademarks of Eli Lilly and Company. Other product and company names may be the trademarks of their respective owners.
Storage —Unopened Humalog should be stored in a refrigerator (2° to 8°C [36° to 46°F]), but not in the freezer. Do not use Humalog if it has been frozen. Unrefrigerated (below 30°C [86°F]) 12 vials, cartridges, Pens, and KwikPens must be used within 28 days or be discarded, even if they still contain Humalog. Protect from direct heat and light. Use in an External Insulin Pump—A Humalog 3mL cartridge used in the D-TRON®2,3 or D-TRONplus®2,3 should be discarded after 7 days, even if it still contains Humalog. Infusion sets, D-TRON ®2,3 and D-TRONplus ®2,3 cartridge adapters, and Humalog in the external insulin pump reservoir should be discarded every 48 hours or less. Literature revised December 7, 2009 KwikPens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA. Pens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France. Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Hospira, Inc., Lake Forest, IL 60045, USA or Lilly France, F-67640 Fegersheim, France. Cartridges manufactured by Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA. www.humalog.com Copyright © 1996, 2008, Eli Lilly and Company. All rights reserved.
notable occurred on a holiday weekend. A patient with a rattlesnake bite was airlifted to the hospital. Rattlesnakes are very rare in Massachusetts, so the treatment of a bite requires unique knowledge and skill. When the call came to the pharmacy to assist the ED with antivenin, one of the pharmacists who had recently completed her training went to the trauma bay and helped with the preparation and administration of the medication.
Discussion Because this project was not approved by an IRB, the results need to be interpreted with caution. Statistical analysis was not performed on our survey results, so it is unclear whether or not any improvements were made. Also, based on our preintervention survey results, provider and nursing satisfaction was very good, even before our project began. This also may have made it difficult to show any dramatic improvements postintervention. It is apparent that pharmacy departments have some unique challenges to meet when servicing EDs. With budget constraints and a lack of residency-trained pharmacists,
see NOVEL APPROACH, page 39
Comment on Study
r. Roggie and colleagues have accurately described some of the challenges of providing around-theclock clinical pharmacy services to emergency departments (EDs). They have evaluated an interesting concept of briefly exposing inpatient pharmacists to the ED to increase their understanding of therapeutic and administrative issues in this environment. Their intent was that this exposure would translate into better service to ED nurses and providers in the absence of a dedicated clinical pharmacy specialist (CPS) during off-shift hours.
Although there was no apparent difference in the perception of ED nurses or providers after the intervention in this study, the authors have anecdotally reported instances of improved team work and better patient care. It seems obvious that inpatient pharmacists should be given a thorough orientation to all areas of the hospital with critically ill patients because during evenings, overnights, and weekends they often are the only pharmacists available to provide services. However, although the incorporation of inpatient pharmacists is necessary, it is no substitute for a dedicated CPS. Asad (Sid) Patanwala, PharmD Clinical Assistant Professor Critical Care/Emergency Medicine The University of Arizona Tuczon, AZ
Pharmacy Practice News â€˘ March 2010
SEPSIS TEAM continued from page 1
average, but we wanted to be better.â€? The Sepsis Steering Committee created a standardized sepsis screening tool and order set, which included an automatic consult with clinical pharmacy services at the bedside. A triage nurse initiates the screening tool when a patient presents to the emergency department. Patients who meet sepsis criteria are then treated according to a protocol that includes collection of blood and other laboratory parameters, and administration of fluids, pending diagnosis by a physician. Once a diagnosis of severe sepsis is made, a severe sepsis order set is implemented, which includes a sepsis panel, radiographic testing, consultation with the clinical pharmacy service (on call 24/7) and therapeutic interventions. The measures are based on sepsis â€œbundlesâ€? recommended by the Institute for Healthcare Improvement (IHI). According to the IHI, the bundles are designed to reduce severe sepsis mortality by 25%.
Having clinical pharmacy at the forefront of developing and implementing a plan for such a severe disease state â€œwas pretty much outside the box,â€? he added.
A â€˜Strikingâ€™ Study Gets Kudos For Coordinated Care Asked to comment on the study, Ishak Lat, PharmD, clinical coordinator of critical care, University of Chicago Hospitals, in Illinois, said it addresses a very important topic, especially because sepsis is so prevalent. â€œWhat was particularly striking [at CAMC] was the coordination of so many multidisciplinary
â€˜For severely septic patients, average mortality rates can range from 30% to 50%. We were within that average, but we wanted to be better.â€™
â€”Audis Bethea, PharmD, BCPS
personnel working together in concert to improve care,â€? Dr. Lat said. Having a dedicated sepsis team that deals just with sepsis is an excellent innovation, he added. â€œThey donâ€™t have sepsis mixed in with everything else. It is a distinct group that has the oppor-
tunity to be exposed to the problem of sepsis on a daily basis. This repeated exposure gives them greater expertise. The more you do the same task over and over again, the better you become.â€? â€”Fran Lowry
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Study Detailed Dr. Bethea and colleagues reviewed data collected since implementation of the management program began in two of CAMCâ€™s three hospitals. Between January 2007 and July 2009, 1,732 patients were admitted to CAMC for severe sepsis or septic shock; all were included for analysis in the study. The researchers were able to make some significant inroads with respect to patient outcomes. Clinician recognition of severe sepsis, for example, increased from an average of 42 cases in 2007 to 77 cases per month in 2009 (P<0.0001). At baseline, mortality was 39.5%, dropping to 15.2% by the end of the study (abstract 118), for an overall reduction of 38% (P<0.0001). LOS decreased by 1.8 days, from 12 to 10.2 days (P<0.0217). â€œWe did this study to determine whether our interventions were having the intended results,â€? Dr. Bethea said. â€œSo these data are very encouraging; they clearly show that we significantly improved patient outcomes.â€? He added that having the sepsis management tools in place around-theclock was a key factor in the programâ€™s success. â€œThere is an automatic, standing order for clinical pharmacy services to be consulted when a patient is suspected of having sepsis,â€? Dr. Bethea said. â€œSo whether itâ€™s 10 oâ€™clock in the morning or 4 oâ€™clock in the morning, we respond to the bedside and develop a plan for pharmacotherapeutic management as well as anything else that may be clinically applicable, such as sedation analgesia, acid-based management, those types of issues.â€?
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Pharmacy Practice News • March 2010
Medication Safety Adverse reaction risk may be overstated
Tyramine-Rich Foods and Rasagiline Not Always a Bad Mix Las Vegas—The caution to completely swear off tyramine-rich foods while taking the selective monoamine oxidase (MAO)-B inhibitor rasagiline is no longer valid, according to data from a study presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting. The new data have prompted changes in the labeling for rasagiline (Azilect, Teva). “Rasagiline is a medication that, I think it’s fair to say, many clinicians would like to use more often but [have hesitated] because of a food and drug interaction listed on the package labeling,” noted Jack J. Chen, PharmD, a post hoc study collaborator who presented the results of the recent tyramine challenge study during the meeting (abstract 4-092). This interaction, which has been thought to cause potentially dangerous increases in blood pressure, also is known as the “cheese reaction” because of the high levels of tyramine in certain aged cheeses. However, the new data indicate that the reaction is unlikely to occur even in patients consuming a meal high in tyramine. The randomized, placebo-controlled, Phase I study was conducted by Tamar Goren, PhD, and colleagues from Teva Pharmaceuticals at a research site in The Netherlands, and originally presented at the American Academy of Neurology 2009 annual meeting. During the study, 149 patients entered a run-in challenge with escalating doses of tyramine (25-800 mg) for up to 10 days. This run-in challenge phase was followed by 14 to 30 days of either the selective MAO-B inhibitors rasagiline (doses of 1-6 mg/d) or selegiline (5 mg twice daily), or the nonselective MAO inhibitor phenelzine (Nardil, Pfizer; 15 mg three times per day). The next phase was a tyramine rechallenge, with escalating doses for up to 11 days. During both of the challenge phases, the tyramine dose was increased until a pressor response was elicited, defined as an increase in systolic blood pressure of at least 30 mm Hg for three consecutive measurements taken at five-minute intervals. Dr. Chen, associate professor of neurology in the Schools of Medicine and Pharmacy at Loma Linda University, in California, noted that for doses of rasagiline (1-2 mg/d) and selegiline (5 mg twice daily), a median dose of 200 mg tyramine was required to elicit a pressor response compared with a median of 25 mg of tyramine for phenelzine. Thus, he explained, at therapeutic doses of rasagiline (1 mg), “it takes, on average, about 200 mg of pharmaceutical-grade
Table. Tyramine-Rich Meal Food
Portion Size, oz
Dietary Tyramine, mg
Red wine (Pinot Noir)
cheese, aged meat and red wine (Table), he said, “You would have to consume all of this in one sitting and that would equal 55 mg of dietary tyramine.” He further noted that tyramine from food is 50% to 70% less bioavailable than pharmaceutical tyramine (J Clin Pharmacol 2003;43:604-609). Thus, 55 mg of dietary tyramine is equivalent to approximately 30 mg of pharmaceutical tyramine, which “gives a greater margin of safety,” he said. Dr. Chen noted that the results of the study were submitted to the FDA.
‘It’s really not a clinical concern. You should let your patients and your colleagues … know that they should not worry about the cheese reaction [in patients taking rasagiline].’ —Jack J. Chen, PharmD
tyramine to induce a cheese reaction.” Describing a tyramine-rich meal as
one that would contain several typical tyramine-containing foods, such as
Reflecting this new information, the FDA, in December, approved new labeling for the product that reduces the dietary restrictions related to tyramine. Rather than a total restriction from tyramine-rich foods, the label now reads, “Dietary tyramine restriction is not ordinarily required with recommended doses.” However, it still cautions that “certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts (i.e., >150 mg) of tyramine and could potentially cause a hypersensitive ‘cheese’ reaction in patients taking Azilect even at the recommended dose due to mild increased sensitivity to tyramine.” The revised prescribing information also removes contraindications to sympathomimetic amines such as phenylephrine, pseudoephedrine, phenylpropanolamine and ephedrine, which can be found in cold medicines and weight reduction products. In a press release announcing the labeling change and describing the study results, Teva Pharmaceuticals wrote “nonselective MAO inhibitors may interfere with the breakdown and elimination of tyramine in the body, which can induce hypersensitivity reactions.” The company noted that the findings of this postmarketing study support the selectivity of rasagiline at the approved doses (0.5 and 1 mg). However, the company cautioned that “selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.” The researchers found that selectivity was significantly reduced “at doses greater than 2 mg per day.” However, those doses are not used in clinical practice, said Dr. Chen, who concluded that “it’s really not a clinical concern. You should let your patients and your colleagues and clinicians know that they should not worry about the cheese reaction.” —Sarah Tilyou
Important Safety Information WARNING: FOR SHORT-TERM HOSPITAL USE ONLY ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have registered in and met all of the requirements for the ENTEREG Access Support & Education (E.A.S.E.â„˘) Program may use ENTEREG. taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG
treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic pain. In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of alvimopan, including studies of patients undergoing bowel resection surgery who received alvimopan 12 mg twice daily for up to 7 days. A causal relationship with alvimopan has not been established
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Make ENTEREG Part of Your Preop and Postop Routine Clinical studies showed ENTEREG reduced mean time to GI recovery by up to 1 day (11 to 26 hours) vs placebo1 —Improved time to GI recovery was beyond a standardized, accelerated postoperative care pathway1
receiving more than 3 doses of an opioid within the week prior to surgery. These patients may be more sensitive to ENTEREG and may experience GI side effects (eg, abdominal pain, nausea and vomiting, diarrhea) ENTEREG is not recommended for use in patients with severe hepatic impairment, end-stage renal disease, or in patients undergoing surgery for correction of complete bowel obstruction E.A.S.E. Program Please see Brief Summary of Prescribing Information following this ad.
To enroll in the E.A.S.E. Program, the hospital must acknowledge that: —Hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use —Patients will not receive more than 15 doses of ENTEREG —ENTEREG will not be dispensed to patients after they have been discharged from the hospital
Pharmacy Practice News • March 2010
Medication Reconciliation Revisions Delayed A
meeting to finalize a simplified and streamlined version of the Joint Commission’s medication reconciliation National Patient Safety Goal (NPSG) has been postponed until later this month. Maureen Carr, project director of the Joint Commission’s Division of Standards and Survey Methods, declined to discuss specifics of the new revisions, saying they were still being developed in preparation for approval by the Joint Commission’s Standards and Survey
Procedures Committee. That meeting was originally scheduled for last month, but was postponed for “logistical reasons,” Ms. Carr said. If approved by the board committee, the new goal will be sent out to the field for comment before being promulgated. NPSG No. 8, issued in late December 2008, outlined requirements to “completely reconcile” medication lists that accompany patients as they travel from home through various levels of hospi-
tal care and then back into their communities. Almost immediately after the safety goal was issued, however, hospitals and other organizations complained that it was too detailed and would be burdensome to implement. In February 2009, the Joint Commission decided that although surveyors would continue to evaluate organizations according to the requirements, survey scores would not be factored into an organization’s accreditation decision, be made part of
[see Warnings and Precautions (5.1 and 5.2)]
in vitro In vitro in vitro
[see Clinical Pharmacology (12.3) of full prescribing information]
[see Clinical Pharmacology (12.3) of full prescribing information].
see Clinical Pharmacology (12.3)]
[See Warnings and Precautions (5.4) and Dosage and Administration (2.2) and Clinical Pharmacology (12.3) of full prescribing information]
[see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) of full prescribing information]
[see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) of full prescribing information]
Reference: 1. ENTEREG Prescribing Information. Exton, PA: Adolor Corporation; 2009. ENTEREG is a registered trademark and E.A.S.E. is a trademark of Adolor Corporation. © 2009 Adolor Corporation. All rights reserved. Printed in USA. ETG249R0 December 2009
requirements for improvement or be included in an accreditation report until after new revisions had been made. Although the timing of the revision is still in flux, the overall goal has not changed, according to Ms. Carr. “We are still looking at streamlining the goal,” she said. “We heard feedback from the field that the revisions to be put in place for 2009 were way too prescriptive and were an impediment for a number of organizations. So we are trying to focus more on the objective and leave the details up to the organization.” Bona E. Benjamin, RPh, director of Medication Use Quality Improvement at the American Society of Health-System Pharmacists’ (ASHP) Practice Development Division, said the revised goal likely would be reduced and simplified. “For example, the number of elements of performance for the goal may decrease. We also might see requirements eliminated if they are sufficiently covered in the medication management standards,” Ms. Benjamin said. ASHP recently reviewed and commented on the goal as a member of the Joint Commission’s Professional Technical Advisory Committees. Ms. Benjamin welcomed the fact that the Joint Commission had placed a moratorium on the old goal. “Changes are needed that allow organizations to accomplish the intent of the goal—accurate information on current medications whenever needed—and that also allow the Joint Commission to determine that the goal is met, without burdensome procedural requirements,” she told Pharmacy Practice News.
Technicians to the Rescue Inadequate medication reconciliation may account for nearly half of medication errors and as many as onefifth of adverse drug events (see Pharmacy Practice News January 2010, p. 40). Many hospitals and organizations already have successfully implemented some aspects of medication reconciliation, which should help them meet the new goal. Kathy L. Doub, RPh, pharmacy manager at Medical Park Hospital, a 22-bed facility in Winston Salem, N.C., that specializes in elective surgery, created a medication reconciliation program by reassigning a pharmacist to the hospital’s preanesthesia visit area to review admission medications while the patient was awake. More than one-third of the medication lists were found to contain discrepancies, but the pharmacist was able to resolve discrepancies nearly two-thirds of the time by simply talking with the patients, reducing the need to call providers. Although Medical Park Hospital is a small facility, it is part of the Novant
Pharmacy Practice News • March 2010
Joint Commission ‘Changes are needed that allow organizations to accomplish the intent of the goal—accurate information on current medications whenever needed—and that also allow the Joint Commission to determine that the goal is met, without burdensome procedural requirements.’ —Bona E. Benjamin, RPh Health System of 12 hospitals in three states with more than 3,000 beds. Some larger hospitals in the system have started placing medication reconciliation technicians in the emergency department because of the volume of patients,
a process Ms. Doub said was working “pretty well.” Although pharmacists are more likely to spot clinical issues than are technicians, she noted it might be difficult for many institutions to take their approach.
“I am glad the Joint Commission has backed off the requirement for now,” Ms. Doub said. “If your model dictates that you have to increase staffing in your facility, then it may be challenging to justify in these hard economic times. Medication
reconciliation is an important patient safety goal to pursue, and giving everyone a little more time to figure out how they will do it is a good thing.” An additional benefit to reconciliation came in “decreasing the time required at the back end if you can get it right on the front end,” she continued. “The value is in order entry and turnaround time. If you can come up with a plan, you’ll find in addition to increasing patient safety that you’ll also increase employee satisfaction because it’s just so much easier to do order entry.” —Ted Agres
FDA: Generic Morphine Approval Will Resolve Drug Shortage
he FDA has approved a generic formulation of 100 mg/5 mL (20 mg/mL) morphine sulfate oral solution from Roxane Laboratories, which will allow the agency to follow through on an initiative to pull unapproved opioid pain products from the market. On March 31, 2009, as part of its ongoing Unapproved Drugs Initiative, the FDA sent warning letters to the makers of 14 unapproved opioid products, citing possible enforcement action if manufacturing and distribution of unapproved prescription pain products was not halted within 60 and 90 days, respectively. The FDA stated at the time of the initial letters that “removal of the unapproved narcotic products will not create a shortage for consumers,” but the move was met with immediate criticism from patients, clinicians and health care organizations— particularly those in the palliative care community—over a potential shortage of 20 mg/mL morphine sulfate oral solution if the ban was put into effect. Concern centered on the potential for making pain control for patients receiving end-of-life care more difficult by removing the easyto-swallow 20 mg/mL morphine liquid from the market. Calling it an “enforcement discretion” on the part of the agency, manufacturing and distribution of highconcentrate morphine sulfate solutions was allowed under a temporary amendment to the FDA’s decision—but only until an FDA-approved version “or another acceptable alternative therapy” became available. Groups that had initially been critical of the FDA’s decision, such as the American Pain Foundation, praised its reversal. “This is the only FDA-approved morphine sulfate oral solution available at this concentration,” the FDA said on its Web site in announcing the new approval. “The firm [Roxane Laboratories] has sufficient supply to meet the entire market demand and no shortage is anticipated.” Morphine 20 mg/5 mL and 10 mg/ 5 mL remain available as approved products. —Donald M. Pizzi
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36 Operations & Management
Pharmacy Practice News • March 2010
Leadership in Action
“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Caritas Christi, Boston, Mass. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ caritaschristi.org.
Applying Emotional Intelligence Table 1: The Competencies of Emotional A Intelligence
s we look at the successful leaders in pharmacy (and in life), I would suggest to you that they have one thing in common—emotional intelligence. Emotional intelligence (EI) is different than regular intelligence, as measured by the “intelligent quotient” (IQ). IQ is fixed. We either have a lot of it, or we don’t. It’s not something that we can change. On the other hand, EI, the intuition or natural charisma that great leaders usually have, can be inborn, or (fortunately) developed. Those with high EI are the people we admire—the star performers; the ones we instinctively follow. I want to be one of those people, as I’m sure you do, too. Although some people seem to be born with a higher degree of EI, we can improve our EI, just as an athlete works with a coach and a “playbook” to improve his or her skills. This column is dedicated to doing just that. We, too, will use a “playbook.” In this case, we will explore Reldan Nadler’s “Leaders’ Playbook: How to Apply Emotional Intelligence—Keys to Great Leader-
Building bonds Conflict management Teamwork and collaboration
ship.”1 Let’s get started. First, we need to define what EI is and establish why it is, perhaps,
the most important single ingredient that successful leaders possess. Peter Salovey and John Mayer first
Ernest R. Anderson Jr., MS, RPh
identified EI in 1990.2 Daniel Goleman popularized the concept in his book “Emotional Intelligence” 3 in 1995. The Hay Group, a global management-consulting firm that works with leaders, developed an Emotional Competence “inventory,” using a 360-degree assessment tool, which I have used as a part of my own EI assessment.4 There are 20 competencies of EI (Table 1), which are grouped into four categories, differentiated between the personal and the social: self-awareness (understanding yourself ); self-management (managing yourself ); social awareness (understanding others); and relationship management (managing others). High EI means having a good balance of personal and social competencies in these four areas, and it has become
see INTELLIGENCE, page 38
Table 2: How To Apply Emotional Intelligence PERSONAL Self-Awareness 1. Emotional self-awareness: Recognizes feelings and how feelings affect one’s job performance 2. Accurate self-assessment: Recognizes strengths and weaknesses and works on improvements 3. Self-confidence: Presents in assured, forceful, impressive and unhesitating manner Self Management 4. Emotional self-control: Stays calm, unflappable and clear-headed in high-stress situations 5. Trustworthiness: Openly admits faults or mistakes and confronts unethical behavior 6. Adaptability: Is comfortable with ambiguities and adapts to new challenges 7. Conscientiousness: Takes personal responsibility to make sure that tasks are completed 8. Achievement orientation: Works through obstacles and takes risks to meet challenging goals and continually improve 9. Initiative: Seizes or creates opportunities for the future SOCIAL Social Awareness 10. Empathy: Understands others’ perspectives; is open to diversity 11. Organizational awareness: Understands the political forces and unspoken rules at work 12. Service orientation: Is proactive about customer satisfaction and addresses underlying needs Relationship Management 13. Developing others: Gives timely and constructive feedback; mentors 14. Inspirational leadership: Communicates a compelling vision; inspires others to follow 15. Influence: Finds the right appeal to build buy-in; develops a network of influential parties 16. Change catalyst: Leads change efforts and champions the new initiative 17. Communication: Effective give and take with others; continually fine tunes delivery 18. Building bonds: Builds strong networks and uses them for answers and support 19. Conflict management: Understands all sides and finds common ideals to endorse 20. Teamwork and collaboration: Is encouraging and draws others into an active commitment for the collective effort
Self Rating Direct Report 1 -10 Rating 1 -10
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38 Operations & Management
Pharmacy Practice News • March 2010
Leadership in Action
INTELLIGENCE continued from page 36
mandatory in the pharmacy profession. It is no longer possible to work in silos. Everything we do as pharmacists now requires working with others in multidisciplinary teams. For example, where I work, we are implementing computerized prescriber order entry, bar-code medication administration and electronic medication administration records in all six of the Caritas Christi hospitals. This requires the cooperation of physicians, pharmacists, nurses,
Star peformers are those who have technical skills, aptitude and—most importantly— emotional intelligence. But only a small number of star performers exist in any organization. information-systems analysts, project managers, unit secretaries and senior administrative support. Implementing
projects successfully requires collaboration, teamwork, communication, networking, initiative and empathy.
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CLOSING KEYNOTE: Barbara Olson, MS, RN, FISMP It’s Not “Sophie’s Choice”: Creating and Sustaining Work Processes That Enhance Medication Safety at the Point of Care Barbara Olson, newly appointed director of patient safety at HCA is the colorful, popular, always insightful writer on blogspot’s “FlorenceDotCom” and Medscape Blog’s “On Your Meds: Straight Talk about Medication Safety.”
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Recently, we had a brainstorming session on the correct billing processes for an expensive clinic injectable drug. It took several people from billing and reimbursement, pharmacy, nursing and information technology to clarify and solidify the process to assure the correct billing and payment. Success in these types of projects requires high levels of EI. Again, star performers are those who have technical skills, aptitude and— most importantly—EI. The reality is that only a small number of star performers exist in any organization. It is probably impossible to be a star in every one of the 20 competencies. Instead, the goal should be to have strong attributes in several of the competencies across all four areas. Go back to the Table and assess your strengths as you look at the competencies. Go with your strengths. These usually are the areas about which you feel passionate. Pay particular attention to the “self-management” column. A lack of impulse control or selfcontrol can easily derail you. Leaders who lack self-control are unpredictable, untrustworthy and can fly off the handle.
No Place for Anger I remember a former hospital executive for whom I once worked. He was a screamer. You never knew when he was going to just snap and begin a deprecating diatribe—often in front of others. As a result, people were reluctant to share critical information with him, for fear of being yelled at, belittled and embarrassed. People tiptoed around him. He eventually left the institution. These types of bosses suck the passion out of people and stifle their creativity and commitment. Sometimes impulse control is a matter of delaying gratification. Strengths are defined as characteristics that provide you with a great deal of self-satisfaction and are a part of your character. Most people who have found great meaning and satisfaction in life find it using their strengths in serving others, rather than themselves. Great leaders get to know and value their people’s talents and abilities and understand what it is that motivates them to become high performers. Great managers can look at the landscape of
Operations & Management 39
Pharmacy Practice News • March 2010
Leadership in Action their people and understand the unique aspects of each individual, figuring out a way to combine them all in a complementary fashion, coordinating their activities toward common goals. Great managers bring out the best in people. Great managers win the hearts and souls of their people. Average managers, on the other hand, treat each employee in a similar fashion and do not discover hidden strengths and abilities.
Are You Driving Staff Away? In my experience, most employees leave their jobs due to lack of apprecia-
tion by their bosses. So we need to ask ourselves, “What kind of boss am I?” The “Leaders’ Playbook: How to Apply Emotional Intelligence—Keys to Great Leadership1” is just that—a “playbook.” There are exercises that I encourage you to complete. Take a look at the EI competency table and do an honest self-evaluation (Table 2). Rate yourself on each competency on a 10-point scale. For instance, if you exhibit a competency 80% of the time, give yourself an 8. First, rate how important the competency is to your position, on a three-point scale, where
1 is “it’s a must,” 2 is “it’s important, but not a must” and 3 is “not necessary in my position.” There also is a column where you can fill in feedback from direct reports. Remember that most people don’t score highly on all areas of EI. So it’s important to identify your strengths and work with them. If there are weaknesses that can derail you, learn how to improve these areas. Finally, I would also suggest you keep in mind what Aristotle said: “Educating the mind without educating the heart is no education at all.”
References 1. Nadler R. Leaders’ Playbook: How to Apply Emotional Intelligence—Keys to Great Leadership. Santa Barbara, CA: Psyccess Press; 2006. 2. Salovey P, Mayer JD. Emotional intelligence. Imagination, Cognition, and Personality. 1990;9:185-211. http://mindfulconstruct. com/2009/03/31/salovey-mayer-on-emotional-intelligence-1990. 3. Goleman D. Emotional Intelligence. New York, NY: Bantam Books; 1995. 4. Cherniss C, Goleman D. The Emotionally Intelligent Workplace: How to Select for, Measure and Improve Emotional Intelligence in Individuals, Groups and Organizations. San Francisco, CA: Jossey-Bass; 2001.
NOVEL APPROACH continued from page 28
nontraditional means may have to be employed to meet these service requirements. The model demonstrated in this QIP might serve as a viable alternative to staffing an ED on a 24-hour per day, 7-day per week basis. Further research will need to be done. Like many other new projects, this one had its own set of challenges. The project depended on staffing patterns in the main pharmacy to free up pharmacists to complete the training. During the summer months when this QIP was operating, staffing for many weeks was minimal and training could not occur as a result of other operational obligations. Another challenge was that training was conducted only during the day shift. This limited the exposure of evening and night shift ED staff to these pharmacists and may have muted the effect of the intervention. Ideally, all ED shifts would receive some degree of exposure to pharmacy personnel.
Conclusion Use of staff pharmacists in the ED represents a possible alternative to hiring additional specialists. With intensive, proper training, these pharmacists could help to meet some of the unique needs of the ED.
Brown JN, Barnes CL, Beasley B, et al. Effect of pharmacists on medication errors in an emergency department. Am J HealthSyst Pharm. 2008;65(4):330-333.
2. Lada P, Delgado G. Documentation of pharmacists’ interventions in an emergency department and associated cost avoidance. Am J Health-Syst Pharm. 2007;64(1):63-68. 3. Fairbanks RJ, Hildebrand JM, Kolstee KE, et al. Medical and nursing staff highly value clinical pharmacists in the emergency department. Emerg Med J. 2007;24:716-718. 4. ASHP position statement on pharmacy services to the emergency department. Am J Health-Syst Pharm. 2008;65(24):2380-2383.
In the treatment of VWD, Humate-P® stands alone
Humate-P® is the only von Willebrand factor (VWF) concentrate that: In over 20 years and more than one-half billion units infused, there is no documented evidence of viral transmission with Humate-P ®.1
Visit us at www.Humate-P.com
• Is approved for the treatment of von Willebrand disease (VWD) and d the prevention of excessive bleeding during and after surgery • Can be used for prevention of bleeding during and after surgery in all VWD types • Contains high molecular weight multimers of VWF—important for correcting the coagulation defect in patients with VWD1
Close as it gets to normal VWF
Important Safety Information Humate-P® is contraindicated in individuals with a history of anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor preparations, or to any of its components. Thromboembolic events have been reported in VWD patients receiving coagulation factor replacement, especially in the setting of known risk factors for thrombosis. Caution should be exercised and antithrombotic measures considered. Humate-P® is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The most common adverse reactions reported in patients receiving Humate-P® are allergic-anaphylactic reactions, including urticaria, chest tightness, rash, pruritus, edema, shock, chills and fever, and hypervolemia. For patients undergoing surgery, the most common adverse reactions are postoperative wound or injection-site bleeding. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see brief summary of prescribing information on next page. Reference: 1. Data on ﬁle, CSL Behring LLC. ©2009 CSL Behring LLC, 1020 First Avenue, PO Box 61501, King of Prussia, PA 19406-0901, USA | www.CSLBehring-US.com
40 Operations & Management
Pharmacy Practice News • March 2010
USNS COMFORT continued from page 1
orders were simply floor stock requests, “it was pretty intense,” he said. Moreover, the staff carried out its duties in pharmacy quarters that were extremely tight compared with those of similar-capacity shore hospitals and with only minimal technological support. Pharmacists used a computer system for order entry, but had no robotic devices or automated dispensing cabinets to help with medication distribution. “We don’t have that luxury here,”
Cmdr. Volstorf told Pharmacy Practice News in a telephone interview from the USNS Comfort. (These maritime efforts were occurring at the same time that pharmacists on the ground in Haiti also were helping deliver care to the severely injured or ill. For details of those efforts, see Pharmacy Practice News, February 2010, page 1).
Making Do in a Crisis Before the hospital ship’s Jan. 21 arrival in Port-au-Prince Bay, “we didn’t really have a lot of guidance as to how many patients or what types of
BRIEF SUMMARY OF PRESCRIBING INFORMATION
Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized Humate-P Manufactured by: CSL Behring GmbH 35041 Marburg, Germany US License No. 1765
Distributed by: CSL Behring LLC Kankakee, IL 60901 USA
Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. INDICATIONS AND USAGE Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P , is indicated in adult patients for treatment and prevention of bleeding in hemophilia A (classical hemophilia). Humate-P is also indicated in adult and pediatric patients with von Willebrand disease for (1) treatment of spontaneous and trauma-induced bleeding episodes and (2) prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin is known or suspected to be inadequate. Controlled clinical trials to evaluate the safety and efﬁcacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects. Adequate data are not presently available on which to evaluate or to base dosing recommendations in this setting. CONTRAINDICATIONS Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P , is contraindicated in individuals with a history of anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor preparations. It is also contraindicated in individuals with a known hypersensitivity to any of its components. WARNINGS Thromboembolic events have been reported in VWD patients receiving Antihemophilic Factor/von Willebrand Factor Complex replacement therapy, especially in the setting of known risk factors for thrombosis.16,17,18 Early reports might indicate a higher incidence in females. In addition, endogenous high levels of FVIII have also been associated with thrombosis but no causal relationship has been established. In all VWD patients in situations of high thrombotic risk receiving coagulation factor replacement therapy, caution should be exercised and antithrombotic measures should be considered. See also DOSAGE AND ADMINISTRATION. Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P , is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Humate-P is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current viral infections and by inactivating and/or removing certain viruses during manufacture. Stringent procedures, utilized at plasma collection centers, plasma testing laboratories, and fractionation facilities are designed to reduce the risk of virus transmission. The primary virus reduction step of the Humate-P manufacturing process is the heat treatment of the puriﬁed, stabilized aqueous solution at 60 C for 10 hours (i.e., pasteurization). In addition, the puriﬁcation procedure, which includes several precipitation steps and an adsorption step, used in the manufacture of Humate-P also provides virus reduction capacity (see DESCRIPTION section for virus reduction factors). Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identiﬁed. Thus the risk of transmission of infectious agents cannot be totally eliminated. Any infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring at 1-800-504-5434 (in the U.S. and Canada). The physician should discuss the risks and beneﬁts of this product with the patient. PRECAUTIONS It is important to determine that the coagulation disorder is caused by factor VIII or VWF deﬁciency, since no beneﬁt in treating other deﬁciencies can be expected. Thromboembolic events have been reported in VWD patients receiving coagulation factor replacement therapy, especially in the setting of known risk factors for thrombosis. In these patients, caution should be exercised and antithrombotic measures should be considered. As a precaution, the administration equipment and any unused Humate-P should be discarded after use. Information for Patients Some viruses, such as parvovirus B19 or hepatitis A, are particularly difﬁcult to remove or inactivate at this time. Parvovirus B19 may most seriously affect pregnant women, or immune-compromised individuals. Although the overwhelming number of hepatitis A and parvovirus B19 cases are community acquired, there have been reports of these infections associated with the use of some plasma-derived products. Therefore, physicians should be alert to the potential symptoms of parvovirus B19 and hepatitis A infections and inform patients under their supervision receiving plasma-derived products to report potential symptoms promptly. Symptoms of parvovirus B19 may include low-grade fever, rash, arthralgias and transient symmetric, nondestructive arthritis. Diagnosis is often established by measuring B19 speciﬁc IgM and IgG antibodies. Symptoms of hepatitis A include low grade fever, anorexia, nausea, vomiting, fatigue and jaundice. A diagnosis may be established by determination of speciﬁc IgM antibodies. Laboratory Tests Antihemophilic Factor/von Willebrand Factor (Human), Dried, Pasteurized, Humate-P , contains blood group isoagglutinins (anti-A and anti-B). When very large or frequently repeated doses are needed, as when inhibitors are present or when pre- and post-surgical care is involved, patients of blood groups A, B and AB should be monitored for signs of intravascular hemolysis and decreasing hematocrit values and be treated appropriately, as required. The Factor VIII levels of VWD patients receiving Humate-P should be monitored using standard coagulation tests, especially in cases of surgery. Strong consideration should also be given to monitoring VWF:RCo levels in VWD patients receiving Humate-P for the prevention of excessive bleeding during and after surgery. It is advisable to monitor trough VWF:RCo and FVIII:C levels at least once daily in order to adjust the dosage of Humate-P as needed to avoid excessive accumulation of coagulation factors (see DOSAGE AND ADMINISTRATION). Pregnancy Category C Animal reproduction studies have not been conducted with Antihemophilic Factor/von Willebrand Factor (Human). It is also not known whether Humate-P can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Humate-P should be given to a pregnant woman only if clearly needed. Pediatric Use Hemophilia A Adequate and well-controlled studies with long-term evaluation of joint damage have not been done in pediatric subjects. Joint damage may result from suboptimal treatment of hemarthroses. For immediate control of bleeding for Hemophilia A, the general recommendations for dosing and administration for adults, found in the DOSAGE AND ADMINISTRATION section, may be referenced. Von Willebrand Disease The safety and effectiveness of Humate-P for the treatment of von Willebrand disease was demonstrated in 26 pediatric subjects, including infants, children and adolescents but has not been evaluated in neonates. The safety of Humate-P for the prevention of excessive bleeding during and after surgery was demonstrated in 8 pediatric subjects (ages 3 through 15) with VWD. Of the 34 pediatric subjects studied for both treatment of VWD and prevention of excessive bleeding during and after surgery, four were infants (1 month to under 2 years of age), 23 were children (2 through 12 years), and 7 were adolescents (13 through 15 years). As in adults, pediatric patients should be dosed based upon weight (kg) in accordance with information in the DOSAGE AND ADMINISTRATION section. Geriatric Use Clinical studies of Humate-P® did not include sufﬁcient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation. ADVERSE REACTIONS The most serious adverse reaction observed in patients receiving Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P®, is anaphylaxis. Thromboembolic events have also been observed in patients receiving Humate-P® for the treatment of VWD (see WARNINGS). Reports of thromboembolic events in VWD patients with other thrombotic risk factors receiving coagulation factor replacement therapy have been obtained from spontaneous reports, published literature, and a European clinical study. Early reports might indicate a higher incidence in females. In some cases, inhibitors to coagulation factors may occur. However, no inhibitor formation was observed in any of the clinical trials. Although few adverse reactions have been reported in clinical studies and in the postmarketing setting in patients receiving Humate-P® for treatment of hemophilia A and VWD, the most commonly reported are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock). For patients undergoing surgery, the most common adverse reactions are postoperative wound or injection-site bleeding.
casualties we’d being seeing,” Cmdr. Volstorf said. “So as far as supplies, it was basically making do with whatever we had on the ship.” It turned out that many of the hundreds of patients being ferried by helicopter to the USNS Comfort from Haitian shore facilities were suffering from traumatic head wounds and crush injuries. Tetanus and gangrene were common. “Unfortunately, a lot of these crush injuries ended up requiring amputations,” he said. Additionally, many of the patients coming aboard were children, he said, and “we’ve had
Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reﬂect the rates observed in practice. von Willebrand Disease Treatment of VWD Allergic symptoms, including allergic reaction, urticaria, chest tightness, rash, pruritus, and edema, were reported in 6 of 97 (6%) subjects in a Canadian retrospective study. Four of 97 (4%) subjects experienced seven adverse events that were considered to have a possible or probable relationship to the product. These included chills, phlebitis, vasodilation, paresthesia, pruritus, rash, and urticaria. All were mild in intensity with the exception of a moderate case of pruritus. In a prospective, open-label safety and efﬁcacy study of Humate-P® in VWD subjects with serious life- or limbthreatening bleeding or undergoing emergency surgery, seven of 71 (10%) subjects experienced nine adverse reactions. These were mild vasodilation (1/9), allergic reactions (2/9), pruritus (1/9), and paresthesia (2/9); moderate peripheral edema (1/9) and extremity pain (1/9); and severe pseudothrombocytopenia (platelet clumping with a false low reading) (1/9). Humate-P® was discontinued in the subject who experienced the peripheral edema and extremity pain. VWD Subjects Undergoing Surgery Among the 63 VWD subjects who received Humate-P for prevention of excessive bleeding during and after surgery, including 1 subject who underwent colonoscopy without the planned polypectomy, the most common adverse events were postoperative hemorrhage (35 events in 19 subjects with ﬁve subjects experiencing bleeding at up to three different sites), postoperative nausea (15 subjects), and postoperative pain (11 subjects). Postoperative hemorrhagic adverse events are shown in Table 7. Table 7: Hemorrhagic Adverse Events in 63 Surgical Subjects Adverse Event
Surgical Procedure Category
Number of Subjects/ Events
Onset* (Number of Events) Post
Minor Oral Major Minor
2/2 2/6 4/4 1/1
2 – 2 1
– 6 2 –
1 3 3 1
1 3 1 –
– – –
Cerebral hemorrhage/ subdural hematoma Gastrointestinal bleeding Menorrhagia Groin bleed Ear bleed Hemoptysis Hematuria
Major Oral Major Major Major
1/1 1/1 1/1 1/1 1/1
1+ – 1 1 1
– 1 – – –
– 1 1 1 1
1 – – – –
– – – – –
On Wound/injection site bleeding
* # § +
Severity (Number of Events)
On = on-therapy; onset while receiving Humate-P or within 1 day of completing Humate-P administration. Post = post-therapy; onset at least one day after completing Humate-P administration Reported as serious adverse events after intracranial surgery Two of these events reported as serious adverse events occurring after gastrojejunal bypass Reported as serious adverse event requiring hysterectomy after hysteroscopy and dilation and curettage
Table 8 lists the non-hemorrhagic adverse events reported in at least two subjects, regardless of causality, and the adverse events that were possibly related to Humate-P . Pulmonary embolus that was considered possibly related to Humate-P occurred in one elderly subject who underwent bilateral knee replacement. Table 8: Non-Hemorrhagic and Possibly Related Adverse Events (AE) in 63 Surgical Subjects Body System
Body as a Whole
Hemic and Lymphatic System Metabolic/Nutritional Nervous
Skin and Appendages Urogenital
Pain Fever Abdominal Pain Infection Surgery Back Pain Facial Edema Chest Pain Pulmonary Embolus# Thrombophlebitis# Nausea Constipation Vomiting Sore Throat Anemia / Decreased Hemoglobin Increased SGPT Dizziness Headache Increased Sweating Insomnia Pruritus Rash Urinary Retention Urinary Tract Infection
Number of Subjects with an AE Possibly Related to Humate-P® – – – – – – – – 1 1 1 – 1 –
Number of Subjects with an AE Regardless of Causality* 11 4 3 3 3 2 2 3 1 1 15 7 3 2
1 1 1 – – – 1 – –
1 5 4 3 2 3 1 4 2
A pharmacy technician reconstitutes acyclovir with sterile water before adding it to an IV solution for Haitian patients aboard USNS Comfort.
several births on board.” The nature and severity of the injuries prompted heavy requests for pain medications and antibiotics—a demand that sometimes proved challenging. “We’ve been constantly running short during the whole deployment period,” Cmdr. Volstorf said. “We’ve managed to get bits and pieces of different antibiotics on board, but it’s been touch and go the whole time out here.” The pharmacy often relied on sister ships and military hospitals on shore to replenish badly needed medicines and supplies. The aircraft carrier USS Carl Vinson and the amphibious warship USS Bataan were among nearby ships from which the Comfort received supplies. Medicines also came from naval hospitals in Guantanamo Bay, Cuba, and Jacksonville, Fla. (On Feb. 5, Cmdr. Volstorf reported in an e-mail message that “the Comfort just got the bulk of its medical supplies today. We are taking on over 180 pallets of medications and medical supplies.”) Compounding IV infusions took a fair amount of pharmacy time. “We’ve done everything short of TPN [total parenteral nutrition] solutions,” Cmdr. Volstorf said. For example, he added, “we’ve had to mix hypertonic solutions” to reduce intracranial swelling in patients with traumatic head injuries. Some of the IV admixtures were made by pharmacy technicians, who filled a wide-ranging role, from “medication
What’s Your Mission? =?6;A
* Occurring in two or more subjects # These events occurred in separate subjects
Eight subjects experienced 10 postoperative serious adverse events: one with subdural hematoma and intracerebral bleeding following intracranial surgery related to an underlying cerebrovascular abnormality; one with two occurrences of gastrointestinal bleeding following gastrojejunal bypass; and one each with sepsis, facial edema, infection, menorrhagia requiring hysterectomy following hysteroscopy and dilation and curettage, pyelonephritis, and pulmonary embolus. Postmarketing Experience The following adverse reactions have been identiﬁed during postapproval use of Humate-P®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Humate-P® exposure. Adverse reactions reported in patients receiving Humate-P® for treatment of VWD or hemophilia A are allergicanaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock), development of inhibitors to Factor VIII, and hemolysis. Additional adverse reactions reported for VWD are thromboembolic complications, chills and fever, and hypervolemia. Evaluation and interpretation of these postmarketing events is confounded by underlying diagnoses, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance. Healthcare professionals should report serious adverse events possibly associated with the use of Humate-P® to CSL Behring at 1-800-504-5434 or FDA’s MedWatch reporting system at 1-800-FDA-1088. Adapted from October 2007 revision.
Are you involved in medical missions abroad? If so and you would like to share your story with PPN readers, contact us at:
Operations & Management 41
Pharmacy Practice News • March 2010
Medical Missions ordering to filling patient and hospital staff outpatient medications to filling floor stock requests,” he said. Of the five pharmacists on board, three, including Cmdr. Volstorf, were Navy reservists. Many of the ship’s company were also reservists. “In my opinion, you wouldn’t really notice a difference,” Cmdr. Volstorf said. “They blended in so well.” Nine minutes away from the Comfort by Navy helicopter, the Georgia-3 Disaster Medical Assistance Team (DMAT) provided emergency treatment for severely injured adults and children who had been designated for advanced care aboard the hospital ship. Georgia-3 DMAT members treated a pregnant woman for life-threatening preeclampsia at Terminal Varreux, a private shipping facility overlooking Port-au-Prince Bay. Roland Tam, PharmD, a clinical pharmacist at the 110-bed Emory Johns Creek Hospital in Johns Creek, Ga., was one of two pharmacists serving with the Georgia-3 DMAT. The other was Mark L. Lasoff, RPh, a retired retail pharmacist from Florida on his first deployment. The team also included physicians, nurses, respiratory therapists, paramedics and emergency medical technicians, a chaplain and even a psychologist.
‘The feeling of being able to help was so rewarding. The adrenaline was kicking in the whole time.’ —Roland Tam, PharmD
For the woman with preeclampsia, Dr. Tam prepared a hydralazine injection to stabilize her blood pressure. She was also given antibiotics, IV fluid and acetaminophen for a fever. A little over an hour later,
she was on her way to the USNS Comfort where her baby was born. Drugs requested by physicians were not always available. If they weren’t, Dr. Tam said, “I had to come up quick-
ly with an alternative that would not jeopardize a patient’s care. It was a challenge for me to think quickly and logically under less-than-optimal conditions.” Despite the 12- to 16-hour workdays, Dr. Tam said the pharmacists never had time to feel tired. “The feeling of being able to help was so rewarding. The adrenaline was kicking in the whole time. To me it was a physical and mental challenge, and I’m glad I was able to meet that challenge.” —Bruce and Joan Buckley
MASH-Style Pharmacy Dr. Tam, a 10-year DMAT veteran, and Mr. Lasoff worked from daybreak to sunset—and sometimes longer—in a makeshift field pharmacy inside a MASH-style tent set up on a hot grassy landfill area that lacked running water. Mosquitoes swarmed at dusk. Toilet facilities consisted of a small tent with a bucket and plastic bag liners. Portable showers didn’t arrive for several days. “We used a lot of sunblock and bug spray—and baby wipes,” Dr. Tam said. The original concept for the Terminal Varreux mission, Dr. Tam said, had been for the team to work with Haitian Ministry of Health personnel in coordinating the transport of patients from local hospitals and clinics to the USNS Comfort for more advanced treatment. However, Dr. Tam said, word of the DMAT’s presence soon spread and the team mission expanded to include the treatment of many walk-ins. One such patient had been injured in a motor vehicle accident. Dr. Tam had to mix a steroid drip to treat the man’s spinal cord injury. Anywhere from 70 or 80 patients arrived at the station every day, according to Dr. Tam. Crush injuries, amputations and head wounds were prevalent. Some of the patients were in sepsis. “We made dopamine drips for patients who were crashing,” he said. “We did have a lot of patients becoming septic because of infections causing the body to basically shut down multiple organs.”
Coming soon from Cadence Pharmaceuticals—
IV acetaminophen © 2009 Cadence Pharmaceuticals, Inc
Printed in USA
42 Operations & Management
Pharmacy Practice News • March 2010
Speeding Drug Delivery With ‘Lean’ Management Tools W
hen Gary Kaplan, MD, CEO of Virginia Mason Medical Center (VMMC) announced that the entire 300-bed hospital would adapt a “lean” delivery system, Roger Woolf, PharmD, administrative director of pharmaceutical services, wasn’t sure what that meant, or how “lean” could benefit his department. In 2002, Seattle-based VMMC became the first American health care facility to try adapting Toyota’s “lean manufacturing” system, with its emphasis on quality and efficiency (recent brake and accelerator pedal recalls notwithstanding). VMMC’s management wanted a method that would eliminate defects and bring measurable improvements in patient safety and services. During training in Japan and the United States, Dr. Woolf realized that everything from “compounding to drug procurement and even care delivery on the floor is amenable to lean improvement processes.” Opting to start with overall drug distribution, Dr. Woolf carefully analyzed the 2.5-hour process from doctor’s order to patient receiving the medication— and discovered substantial waste in the process. After years of applying lean improvement techniques, VMMC’s average lead time from initial physician order to the drug’s availability for administration is under 11 minutes, and dropping. To pinpoint specific efficiency opportunities, Dr. Woolf’s team “flow-mapped” every step to remove waste and waiting times. “We looked at what’s a valueadded activity and what isn’t,” he said. The VMMC team found that 20% to 40% of written orders reaching the pharmacy had at least one defect. After using lean concepts and adding a computerized prescriber order entry (CPOE) system from Cerner, benefits quickly accrued. “With the CPOE system’s strong error-proofing processes, it’s become very difficult for a physician to enter an order incorrectly,” Dr. Woolf said. “Prescribing errors are below 0.2%—they’re so low we’ve stopped measuring as a routine metric.” Flow-mapping suggested an advantage to getting the drug product closer to the patient. For VMMC, that meant automated dispensing cabinets (ADCs) at each nursing station. “Lean tools helped simplify the number of drugs and doses available. Ninety-five percent of needed drugs—whatever is pre-made or injectable by vial—are already there,” explained Dr. Woolf, who continually monitors which drugs should be in each Cardinal ADC. With a central “just-intime” concept, nurses no longer go to look for a medication that isn’t there. The flurry of missing-dose morning phone calls has stopped, he said.
“This is no one-shot fix,” Dr. Woolf acknowledged. A continuous-flow electronic monitoring system, by signaling when an ADC needs restocking, maintains availability without excess inventory or care-delaying stock-outs. Each ADC’s profile blocks removal of a medication without a pharmacist-verified order in the system. For acute emergency needs, nurses have a short list of medications that they can override and remove prior to the pharmacist’s verification of the doctor’s order. The override, tightly managed for safety reasons, is used for only 0.6% of doses dispensed. “A patient safetyalert system tells us about any problems, and we look at how the system could be changed to prevent them,” he said.
Dianne Calkins, RPh (left) and Miranda Livermore, RN, both of Virginia Mason Medical Center, in Seattle, are part of a lean pharmacy process improvement program targeted to improving the efficiency of drug distribution.
Implementing Changes The system’s success wasn’t immediate. “Pharmacy is a vast profession. We batch-made everything,” Dr. Woolf said. “It took some time to prove to us that a whole new approach could not only work, but work very well. Lean is very counterintuitive. Having people do things they’ve never done before creates new challenges. I wish I’d been more skilled at helping my staff adapt to change.” The hospital’s commitment to going lean had substantial up-front costs, particularly for staff training to apply the improvement concepts. Using Cerner as its core clinical information system, VMMC partners with the company to apply lean methods.
ics, was VMMC’s medical director during the distribution system’s development. To achieve “a defect-free, safer method for our patients, we initially asked doctors to do more work—extra data entry—which helps lessen medical errors,” he said, citing a two-part learning curve. With paper orders abolished, physicians spent several difficult weeks finding electronic steps to replace each manual activity. Over several months, they gradually adjusted to an entire new process. Dr. Bender said he is especially proud of medication reconciliation improvements. A patient’s home drug list, entered as reusable data, is coded into an inpatient medication order. “At discharge, that
‘Health care has tons of waste, and we went to look for it [using lean management techniques].’
—Roger Woolf, PharmD
“Health care has tons of waste, and we went to look for it,” Dr. Woolf said. “By eliminating waste and practice variation, we were able to target the technologies that were then implemented. [Applying] different technologies, we’d see incremental changes with each improvement. We’re constantly surprised at how much better we can do.” Citing significant return on investment through procedural savings and safety improvements, he added, “we’re even using lean techniques in drug purchases and third-party billing. Applying these techniques is benefiting our bottom line.” It’s also enhancing their reputation— in December 2009, the nonprofit Leapfrog Group, which compares hospitals with respect to health care quality, named VMMC as one of America’s top hospitals . James Bender, MD, director of informat-
same order will become an outpatient order. Eliminating all those re-entries saves doctors time. Overall, lean drug delivery is time-neutral, but the system reduces errors. And making patients’ care better makes everyone’s work life better.”
Don’t Go It Alone Don’t try this alone, Dr. Woolf cautioned. “It can’t just be the pharmacy system applying ‘lean’—it has to be the whole institution. You could do some small pieces, but any significant change has to be systemwide. The key was coordinating with other leaders throughout the medical center on what we’d do.” Chief Nursing Officer Charleen Tachibana, RN, MN, a VMMC vice president and drug distribution planning team member, recalls that “medication delivery was a mess” for nurses back in 2004. “Nurses would have to wait a couple of hours for a delivery, often
dealing with the family of a patient in severe pain. Once we focused on medication administration and distribution, nurses got involved in changing the procedures for how medications are ordered and [given].” The unique methods keep nurses continually learning, Ms. Tachibana noted. “The whole process is safer—it’s greatly reduced [time-consuming] error, frustration and running around. Quality checks, including redundancy, prevent mistakes. Patient satisfaction is way up, with nurses having more time for them. Our pain management ability rose, too— we can now meet needs very quickly, and stay on top of them.” Seth Alan Kuiper, PharmD, lead pharmacy automation specialist at the Cleveland Clinic in Ohio, called VMMC’s drug delivery time “very impressive.” Cleveland Clinic also is working to expedite drug delivery, Dr. Kuiper noted. Shifting from manual order transcription, dispensing and a cart-fill model to CPOE, semi-automated dispensing, and a cartless model “has reduced turnaround time by 65%,” he said. With their cart-less model, orders are dispensed primarily from Pyxis ADCs. An order unavailable through the ADCs is dispensed from the pharmacy’s Pharmogistics carousel system. Cleveland Clinic recently started using Medboard, a FedEx-style tracking system, to follow orders from inception to delivery (Pharmacy Practice News, February 2010, page 38). Although he expects Medboard data to provide additional help in improving turnaround time, Dr. Kuiper realizes it’s important to keep goals realistic. “We can’t physically turn around orders in 10 minutes here—this hospital’s too big. With 1,500 beds, we’ll never be as fast as a 300-bed hospital.” —Carol Milano
McMahon Awards Recently, the staff of McMahon Group celebrated the company’s 38th successful year, an especially welcome event given the challenging financial situation that pervaded the medical industry in 2009. McMahon Group, however, was fortunate to find itself in a better position in 2009 than in 2008, and the next 12 months look even better.
The annual celebration recognizes the fact that some staff members truly excelled during the year and their exceptional efforts should be lauded. Here then are the winners of this year’s staff awards:
MANAGEMENT/SUPPORT PERSON OF THE YEAR:
ASSOCIATE/SENIOR EDITOR OF THE YEAR:
JEANNIE MOYER won for her ability to undertake a wide variety of both support, HR and insurance tasks, while always maintaining a smile and a pleasant demeanor.
SARAH TILYOU was recognized for her diverse skills, which include editing and writing for several of our publications. Her ability to move effortlessly from one publication to another, based on need, is much appreciated by the editorial staff.
GRAPHIC DESIGNER OF THE YEAR:
PRODUCTION PERSON OF THE YEAR:
DEANNA COSME won for her outstanding design work on General Surgery News, the best-read publication in surgery, as well as Infectious Disease Special Edition, our annual ID publication. She also was responsible for the designs of several special projects.
ACE PERSON OF THE YEAR: The company’s continuing medical education division, Applied Clinical Education (ACE), continues to negotiate the difficult terrain of CME, which would not be possible without the excellent skills of its manager of CME services, BARBARA JEAN WYNNE.
MANAGING EDITOR OF THE YEAR:
It’s fine to sell the ad space and to create the editorial, but then the newsmagazines and the special projects have to be printed and disseminated, and therein lies much detail. MARK NEUFELD won the award for his innovative production ideas and accuracy.
In the crowded field of oncology publications, the one magazine that has risen faster in readership than any other is our own Clinical Oncology News. For her success in guiding the editorial direction of our newest publication, this award went to KATE O’ROURKE.
IT PERSON OF THE YEAR:
SALES ACHIEVEMENT AWARD:
SALESPERSON OF THE YEAR:
A gifted programmer, KWANGHEE CHUNG won the award only a few days after the birth of his son. Like his programs, everything went smoothly with that, too.
KATE CARMODY was the recipient of this award for her excellent work on General Surgery News, whose ad sales continue to advance, and her ability to sell custom projects while working diligently for her clients.
This award goes to the salesperson who sold the most, pure and simple. RICHARD TUORTO, group publication director of Anesthesiology News and Pain Medicine News, both of which are the best-read newsmagazines in their specialties, was by far the big winner—for the fourth year in a row.
MOST IMPROVED SALESPERSON OF THE YEAR:
FINANCE PERSON OF THE YEAR:
MCMAHON GROUP PERSON OF THE YEAR:
Because of her extensive work in refashioning the company’s financial systems, MARY LOU CAMPANELLA, director of finance, won this year’s award. After much hard work and many late nights, the financial tracking system has been successfully upgraded.
This award is granted to the single individual whose efforts have most significantly advanced the interests and success of the company. This year’s winner, JOE MALICHIO, director of medical education, has worked tirelessly with clients to create valuable editorial products that serve to further educate clinicians about important advancements in medical care.
This award went to JULIANNA DAWSON, the former associate publication director of Clinical Oncology News, our newest newsmagazine and one that has enjoyed dramatic success over the past year— which is why she is no longer the associate publication director, but the publication director.
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2 ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com. We can supply any medical book in print, so if you don’t find the book you want, e-mail your request with billing information to RMcMahon@ McMahonMed.com. If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@ McMahonMed.com.
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Basic and Clinical Pharmacology, 11th Edition: LANGE Basic Science Bertram G. Katzung; Susan B. Masters; Anthony J. Trevor
Organized to reflect the syllabi in pharmacology courses, Basic and Clinical Pharmacology covers all the important concepts students need to know about the science of pharmacology and its application to clinical practice. It is acknowledged worldwide as the field’s most current, authoritative and comprehensive textbook. To be as clinically relevant as possible, the book features a strong focus on the choice and use of drugs in patients and the monitoring of their effects.
2010 CURRENT Medical Diagnosis and Treatment: 49th Edition Stephen J. McPhee; Maxine A. Papadakis
CMDT offers the most current insights into symptoms, signs, epidemiology and treatment for more than 1,000 diseases and disorders. For each topic you’ll find concise, evidence-based answers to questions regarding both hospital and ambulatory medicine. This streamlined reference is the fastest and easiest way to keep abreast of the latest medical advances, prevention strategies, cost-effective treatments and more.
Handbook on Injectable Drugs: 15th Edition
Pharmacology and Therapeutics: Principles to Practice: Expert Consult: Online and Print
Lawrence A. Trissel
Since the publication of its first edition, the Handbook on Injectable Drugs, edited by Lawrence A. Trissel, has sold well over 100,000 copies in print and CD-ROM format for single users and networks. It is the most popular reference of its kind, trusted by pharmacists and other health care professionals througout the world.
Scott A. Waldman; Andre Terzic
Pharmacology and Therapeutics: Principles to Practice presents everything you need to know about all of today’s drugs in a coherent, easy-to-use format—from the underlying science through innovation, translation, regulation and clinical implementation.
Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy: Second Edition
David E. Golan; Armen H. Tashjian, Jr.; Ehrin J. Armstrong; April W. Armstrong This primary textbook for a first course in pharmacology offers an integrated, systemsbased and mechanism-based approach to understanding drug therapy. Each chapter focuses on a target organ system, begins with a clinical case, and incorporates cell biology, biochemistry, physiology and pathophysiology to explain how and why different drug classes are effective for diseases in that organ system.
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This book provides busy healthcare professionals with a small and conveniently sized, quick-reference Stockley text. It draws on the wealth of clinically evaluated, evidencebased information on drug–drug, drug–herb and drug–food interactions that is presented in the full reference work, Stockley’s Drug Interactions.
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Pocket Guide to Injectable Drugs, Companion to the Handbook on Injectable Drugs, 15th Edition, is essential for all health care professionals involved in preparing and administering injectable drugs. This portable guide provides on-the-spot answers to medication questions for increased efficiency. PPN0310
Pharmacy Heritage 45
Pharmacy Practice News • March 2010
Putting Out the (Financial) Fire
In 1888, President S.E. Allen of the Ohio State Pharmaceutical Association (OPA) challenged the perception of increased hazard and loss due to fire. Allen noted the low incidence of fire claims by pharmacies in Ohio and concluded that the premiums, and the profit they contributed to corporate insurers, were excessive. He described the Cotton Factory Mutual System, which charged insurance premiums one-third of those levied by full-line companies. Allen advocated establishing a mutual insurance company for pharmacists that would be managed as part of the association. OPA established a committee to determine the feasibility of such an enterprise. In 1889, the committee reported that there was little evidence substantiating that the drugstore was more hazardous than other businesses. In fact, the drugstore may have been safer because there were only one or two rooms to monitor and “the law compelling the proprietor or his assistant to be always on hand during business hours, makes it so that some one of intelligence, who thoroughly understands the nature of fire and combustibles, is always on hand.” In 1890, the Retail Druggists’ Fire Insurance Company was established as part of the OPA, and by 1891, approximately 500 policies were in force. This was the first successful organized attempt to offer fire insurance coverage specifically for drugstores. A hallmark of the mutual companies was the return of dividends to further lower premiums. Premiums, calculated to be 30% of the premiums charged by fullline companies, still provided a substantial profit to the mutual companies. In the late 1890s, the topic of fire insurance was a
Taking the Initiative In 1906, a group of Ohio pharmacists proposed establishing a stock company to provide pharmacists with insurance across state lines. The American Druggists Fire Insurance Company’s incorporators were well-known pharmacists (including James Hartley Beal); stock ownership and insurance coverage was restricted to pharmacists. This business was successful financially in addition to meeting pharmacists’ needs. In 1923, when plans were being developed for the construction of a permanent headquarters for the American Pharmaceutical Association, the American Druggists Fire Insurance Company offered the association a permanent leasehold in its new headquarters for free. Frank Freericks, the company secretary, noted that the offer was possible “because of the help of more than 17,000 retail druggists and pharmacists,” presumably all insured by the company. Al Falkenhainer was the dominant figure in pharmacy mutual fire insurance during the formative period. When his pharmacy in Titonka, Iowa, was destroyed by fire in 1902, he experienced the usual delays and challenges in obtaining an insurance settlement. An early member of the Iowa Pharmaceutical Association (IPA), he successfully campaigned for the establishment of a mutual insurance company as part of the association. During the 1908 IPA annual meeting, Falkenhainer spelled out the process for providing mutual insurance. Pharmacists would pay the same premium that they paid the straight-line insurance companies. Expenses and claims would be paid, a percentage retained, and the rest returned to the insured in the form of dividends that could be used to reduce the following year’s premium. Policyholders had to be members of the state association during the entire life of the insurance. Druggists’ Mutual started business in 1909, and in the 1910 report, almost $300,000 of insurance had been issued, less than $1,100 had been paid in claims, and a 25% dividend was declared. The relationship between Druggists’ Mutual and IPA became especially close when Falkenhainer became the
executive secretary of the association in 1911. He served through 1924, when he resigned to devote his full time to the insurance business. Through his leadership, Druggists Mutual managed to expand beyond a single state, a barrier few other mutual companies were able to surmount. Falkenhainer was reputed to have shared his enthusiasm with Louis Liggett, founder of United Drug Company and the Rexall brand. In 1908, the United Druggists Mutual Insurance Company was launched; available only to Rexall drugstore owners, it was a natural
Dennis B. Worthen, PhD
extension of the other products offered through the Rexall franchises. Although today the topic of fire insurance seems somewhat prosaic, this was not the situation a century ago. The mutual insurance movement provided the state associations with a tool to grow membership while providing a much-needed and appreciated service to pharmacy owners.
A 1921 advertisement for The Druggists’ Mutual Insurance Company of Iowa. A 1912 advertisement for the United Druggists Mutual Fire Insurance Company for Rexall franchises.
Photo courtesy of Frank Sternad
frequent item during the annual meetings of a number of state associations, where they debated whether to form mutual companies for their members. However, the potential growth of early mutual companies was limited by state insurance regulations, which prevented expansion to other states. A number of state and local associations, mostly in the Midwest, established mutual insurance programs between 1895 and 1910, but most failed to survive through the 20th century.
Photo courtesy of Frank Sternad
harmacies have long been regarded as a safe haven for obtaining lifesaving medications and essential goods and services. But when it came to insuring drugstores against fire, the businesses were historically considered a risky endeavor. Indeed, in the 19th century, regular insurance companies rated pharmacies as “hazardous” and charged premiums accordingly. Solvents and flammable chemicals were alleged factors for charging exorbitant fees for fire insurance. Pharmacists had little choice but to pay the rates since fire could result in the loss of the store, one’s livelihood, and, since many pharmacists of the day lived above the store, even home. Hubert H. Humphrey, a U.S. senator and vice president during the 1960s, recalled that his father lost his Granite Falls, Minn., pharmacy and the living space above it to fire in 1911, forcing the family to move to Wallace, S.D. But were drugstores really at increased risk?
Photo courtesy of Pharmacists Mutual Insurance Co.
Dennis B. Worthen, PhD, the author of “Pharmacy Heritage,” is the Lloyd Scholar at the Lloyd Library and Museum in Cincinnati. He can be reached at dbworthen@ lloydlibrary.org
Armstrong Rexall Drug, in Decatur, Ill., suffered an $8,000 loss of stock from smoke and water damage on Aug. 22, 1909.
IMPORTANT SAFETY INFORMATION for SAMSCA™ (tolvaptan) 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. SAMSCA is contraindicated in the following conditions: – 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 • Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae – During initiation and after titration monitor patients to assess serum sodium concentrations and neurologic status. 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, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic ﬂuid. Fluid restriction during the ﬁrst 24 hours with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided • Gastrointestinal Bleeding in Patients with Cirrhosis – Use only when need to treat outweighs this risk • Dehydration and Hypovolemia – In patients who develop medically signiﬁcant signs or symptoms of hypovolemia, discontinuation is recommended. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are ﬂuid restricted • Co-administration with Hypertonic Saline – Not recommended • Other Drugs Affecting Exposure to SAMSCA – CYP 3A Inhibitors – Do not use with strong inhibitors of CYP 3A; avoid concomitant use with moderate CYP 3A inhibitors – CYP 3A Inducers – Avoid concomitant use with CYP 3A inducers. If co-administered, the dose of SAMSCA may need to be increased – P-gp Inhibitors – The dose of SAMSCA may have to be reduced if co-administered with P-gp inhibitors • Hyperkalemia or Drugs that Increase Serum Potassium – Monitor serum potassium levels in patients with a serum potassium >5 mEq/L and in patients receiving drugs known to increase serum potassium levels Pregnancy and Nursing Mothers – SAMSCA should be used during pregnancy only if the potential beneﬁt justiﬁes the potential risk to the fetus. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother. Commonly observed adverse reactions – (SAMSCA incidence ≥5% more than placebo, respectively): 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%). Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the adjacent page.
Available from Otsuka America Pharmaceutical, Inc.
A choice of 2 dosing strengths To place your order, call your wholesaler or distributor today. For more information about SAMSCA, visit www.samsca.com or call 1-877-726-7220.
First and only oral treatment for clinically significant hypervolemic and euvolemic hyponatremia • Promotes free water clearance • Effective correction of serum sodium • Significant increase in serum sodium concentrations in as early as 8 hours, and the change was maintained for 30 days* • Safety evaluated in >4000 patients in total clinical trials† • The most common adverse reactions in placebo-controlled studies in patients with hyponatremia (SAMSCA incidence ≥5% more than placebo, respectively) included: 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%) • Once-daily oral dosing • Starting dose is 15 mg/day—titrate at intervals of ≥24 hours, up to a maximum of 60 mg/day—without regard to meals • Patients can and should drink in response to thirst *In two identical 30-day, randomized, double-blind, placebo-controlled, multicenter studies, 424 patients with euvolemic and hypervolemic hyponatremia were treated for 30 days with tolvaptan or oral placebo, then followed for an additional 7 days after withdrawal. The primary end points for these studies were the average daily AUC for change in serum sodium from baseline to day 4 (tolvaptan, 4.0 mEq/L vs placebo, 0.4 mEq/L) and baseline to day 30 (tolvaptan, 6.2 mEq/L vs placebo, 1.8 mEq/L). Patients received either tolvaptan or placebo, at a starting dose of 15 mg. † Includes open-label and placebo-controlled trials, in which approximately 650 patients had hyponatremia.
15 mg QD 10-count blister pack 30 mg QD 10-count blister pack
INDICATION 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). Important Limitations 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. WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM 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.
Please see IMPORTANT SAFETY INFORMATION on adjacent page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. US Patent Nos: 5,258,510 and 5,753,677. Samsca is a trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.
©2009 Otsuka America Pharmaceutical, Inc.