Pharmacy Practice News - February 2010 - Digital Edition

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Volume 37 • Number 2 • February 2010

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in this issue In Afghanistan, Reserve Up Front Pharmacist Answers Call Capsules To Join the Trauma Team 3

Pharmacists Lend a Hand In Earthquake-Ravaged Haiti

Safety alert on migraine drug.

A

rmy Reserve Major Charles G. (“Chuck”) Boenig, PharmD, had read the literature: when pharmacists help care for the critically ill, patients prosper. But during his second tour in Afghanistan, that academic knowledge was quickly put to the test.

“I hadn’t even been Capt. Boenig prepares an IV in trauma ward. there for 24 hours when I was told I would be working on the trauma team,” Maj. Boenig told Pharmacy Practice News. “This was not something I had ever done before, but boy, did I learn fast.”

Overseeing drugs administered by trauma surgeons, managing medications in cardiac arrest “crash carts” and even working the defibrillator to administer shocks to coding patients were just a few of the clinical duties that Maj. Boenig had to master.

•

see AFGHANISTAN, page 8

New Multiple Myeloma Regimen Benefits Elderly New Orleans—A large two-part study has outlined a potential new standard for the treatment of multiple myeloma (MM) in elderly patients.

The results of the first part reaffirmed the previously demonstrated efficacy of the induction combination of bortezomib (Velcade, Millennium), melphalan (Alkeran, Celgene) and prednisone (VMP), while showing that a modification to the bortezomib dosing schedule improved tolerability. The second part demonstrated that a bortezomib and thalidomide (VT) maintenance regimen following induction almost doubled the proportion of patients who achieved a complete response (CR) and substantially extended progression-free survival (PFS). The results indicate that VMP induction followed by VT maintenance provides the best treatment sequence for MM in older patients.

“These novel bortezomib-based schemes appear to

•

Opinion

New Section!

Bill Jones, MS, BSPharm on why patients need to be the focus of pharmacy practice.

10

Clinical

Educational Review The Bone Continuum of Cancer: Early to Advanced Stage Disease.

12 William Drake, PharmD (upper left, blue shirt) and Shannon Manzi, PharmD (lower right) helped spearhead pharmacist relief efforts in post-quake Haiti.

Pain Medicine Genetic variations may determine response to opioid therapy.

27

Critical Care Simulator can help cut ICU infections.

30

Pain Medicine New treatment option for refractory fibromyalgia.

34

xperienced medical relief pharmacists were among the first clinicians to reach Haiti after the devastating earthquake that struck the island nation on Jan. 12. Arriving as members of federal Disaster Medical Assistance Teams (DMATs) or as professionals sent by private humanitarian groups from around the world, the pharmacists faced stark conditions on the ground and an around-the-clock urgency to treat or evacuate the severely injured.

Their stories, obtained from exclusive interviews with Pharmacy Practice News and e-mail dispatches from the field, underscore the myriad challenges the pharmacists faced—and how they overcame them to deliver much-needed medication-related services.

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see HAITI, page 4

Repeated Scanning Exposes ICU Patients to High Radiation Level

Technology

Drug Distribution Wireless tracking system reduces inventory costs, streamlines drug delivery.

E

38

Web Exclusive!

Antifungal Prophylaxis In High-Risk Oncology Patients

See www.pharmacypracticenews.com

Miami—Patients on mechanical ventilation in the intensive care unit often undergo multiple radiologic scans during their treatment, in some cases receiving cumulative exposures akin to survivors of atomic warfare, a new study has found.

The study, presented at the 2010 annual meeting of the Society of Critical Care Medicine, did not try to determine if ICU patients were at

see NEW STANDARD, page 25

increased risk for cancer because of their exposures to medical radiation.

However, such a link has been established in the scientific literature. A recent study in Archives of Internal Medicine by researchers at the National Cancer Institute found that computed tomography (CT) scans performed in 2007 may account for an estimated 29,000 future cancers in the United States alone

•

see ICU PATIENTS, page 32

New Products Bioniche Pharma launches Ibutilide Fumarate Injection.

Mycophenolate Mofetil among new unit-dose products from American Health Packaging.

See page

26

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Data derived from the use of information under license from the following IMS Health Information Service: IMS NSP Audit, MAT 9/08. Data is proprietary to IMS Health. ©2009, Teva Pharmaceuticals USA

8349 A

19 Hughes • Irvine, California 92618 800.729.9991 • www.tevausa.com

Up Front 3

Pharmacy Practice News • February 2010

Capsules Web Site Provides Patient Information on GI Risks of NSAIDs

surf

FEBRUARY 2010

watch

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.

heard here first

Web site is now available to help consumers understand and successfully manage the serious gastrointestinal (GI) risks that can result from chronic and/or innappropriate use of nonsteroidal anti-inflammatory drugs (NSAIDs). The site, www.connecttoprotect.com, also includes resources for clinicians.

Connect to Protect is a program of the American Gastroenterological Association Institute that is funded by Horizon Therapeutics. In addition to helping to improve patient and clinician understanding of the risks associated with NSAID treatment, the programs aims to “promote dialogue between [clinicians] and patients about the connection between NSAIDs and gastrointestinal (GI) ulcers, and ways to reduce the risks, including but not limited to, adding GI protective co-therapy,” according to the program’s Web site.

It is estimated that more than 107,000 individuals are hospitalized each year due to NSAID-related GI toxic effects; 16,500 deaths annually are linked to NSAID toxicity. The direct costs attributed to NSAIDrelated toxicity exceed $2 billion annually (Am J Therapeutics 2008;15:444-449). The occurrence of GI problems leads more than 10% of arthritis patients to discontinue use of NSAID treatment (Scand J Rheumatol 2009;38:2:133-143).

Visitors to the site will find printable fact sheets about the risks associated with NSAID use; tips and strategies to manage the risks of short- and long-term NSAID treatment; and discussion guides for patients and clinicians to help both prepare for a conversation on NSAID use.

In 2009, the FDA began requiring manufacturers of NSAIDs to post a warning on package labels about the potential for GI events, including stomach bleeding.

FDA Reiterates Birth Defect Dangers of Common Migraine Drug

T

he FDA has issued an updated MedWatch safety summary urging physicians to consider other options in pregnant patients taking valproate sodium and related antiepileptic medications because of the significantly increased risk for neural tube defects and other major birth defects.

Valproate sodium, valproic acid and divalproex sodium have long been linked to much higher than normal—in some instances threefold—rates of birth defects such as craniofacial and cardiovascular malformations when taken during pregnancy (Reprod Toxicol 2009;28:1-10. Epub 2009 Mar 13).

According to the MedWatch safety summary, health care providers should inform women of childbearing potential about these risks and consider alternative therapies, especially if they are using valproate to treat migraines or other conditions not usually considered life-threatening. Divalproex sodium (Depakote, Abbott) is approved for migraine prevention.

Women of childbearing potential should only use these agents if it is essential to manage ge their medical condition, according to the MedWatch alert. Women taking these drugs who are not actively planning a pregnancy should use effective contraception, as birth defect risks are particularly high in the first trimester, before many women know they are pregnant. A valproate medication guide, provided with each outpatient prescription, will explain the benefits and risks of valproate and encourage patients to discuss options with their health care professional.

Pregnant women using valproate or other antiepileptic drugs should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (1-888-233-2334; www.aedpregnancyregistry.org).

‘Your mission as a pharmacist ... in the Reserves is to deploy and potentially serve in a combat zone.’

—Charles G. (“Chuck”) Boenig, RPh

See article, page 1

A

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4 Up Front

Pharmacy Practice News • February 2010

Late-Breaker

HAITI

continued from page 1

Aftershocks were a continual threat, and relief teams often abandoned risky indoor quarters to sleep in tents or “under the stars,” said Shannon Manzi, PharmD, a member of the Massachusetts-1 DMAT, who spent two weeks on deployment to Haiti.

The severity of a 6.1-magnitude tremor startled both Dr. Manzi and William Drake, PharmD, chief pharmacist for a U.S. government Incident Response Coordination Team (IRCT). “I had never seen trees move toward a building before,” said Dr. Manzi, who in civilian life is an emergency department clinical pharmacist and team leader of emergency services and combined programs at Children’s Hospital Boston.

Dr. Drake’s reaction to the moving floors and threat of ceiling collapse in his office at the American Embassy: “You know you’re not in Kansas anymore.”

Dr. Manzi’s Mass-1 team of physicians, nurses and other medical support personnel arrived in Port-au-Prince on Jan. 15. They had been flown in on a U.S. Coast Guard C-130 transport plane from Turks and Caicos in the British West Indies, after a chartered flight from Atlanta the previous day got diverted because of chaotic conditions at the Port-au-Prince airport.

“There are always some delays,” said Dr. Manzi, who has been deployed on six disaster relief missions since 2001, including two during Hurricane Katrina relief efforts. After arriving at the airport, she said, “we started to get all of our cache [of equipment and supplies] together, but we needed force protection and we had to wait for the 82nd Airborne to be tasked to us. So we ended up staying the night in the embassy and then meeting the 82nd Airborne the next day. Then we went out to our site in the middle of the night.”

The site was the Union School, built by the U.S. government in the 1960s. It had been turned over to a university and used as a medical school at one

Correction

I

n Pharmacy Practice News Special Edition 2009, there was an error on page 54 in the educational review “Assessment Tools and Guidelines: Parenteral Nutrition Therapy” in the section on glucose control. Regular insulin should be increased by 0.05 units per gram of dextrose each day rather than 0.5 units per gram. The sentence correctly reads, “If glucose values consistently exceed 150 mg/dL over 24 hours, regular insulin should be increased by 0.05 units per gram of dextrose each day in the PN formulation.”

Clinics and housing for pharmacy relief personnel suffered major earthquake damage.

point, according to Dr. Manzi, but was now “pretty much abandoned because they were building a new school up the road that unfortunately was destroyed” in the earthquake.

The abandoned school and its courtyard had a layout that fit the DMAT needs because “we had an operating room, a pre-op and a post-op with an intensive care unit,” Dr. Manzi said.

“We ended up putting the pharmacy,

the lab and the sick bay into a classroom that we cleared out” after the building was declared structurally sound by engineers. “We set up tents with the OR in the courtyard,” she added.

Morphine for Fractures In the pharmacy, Dr. Manzi oversaw the dispensing of “a lot of morphine for fractures and ketamine for fracture reductions and laceration repairs. We also used a lot of ibuprofen and a little bit of Tylenol here and there. We used ceftriaxone for septic patients and for those who couldn’t take oral antibiotics.”

Same Name. New Size.

Introducing 3 mL of Humalog®® and Humulin®® R U-100 in a Smaller Vial* The New Smaller Vial, Another Insulin Delivery Option Intended To: Give hospitals more flexibility when evaluating insulin storage and distribution (floor stock vs individual patient supply), in addition to the 10 mL vial and Humalog®® KwikPen™™.

Indication Humalog 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.

• Same Bar-Coding Technique, New Size • Same Color-Differentiating System, New Size • National Drug Code (NDC) Humalog - NDC Number - 0002-7510-17 Humulin R U-100 - NDC Number - 0002-8215-17

Select Safety Information Hypoglycemia is the most common adverse effect associated with insulins, including Humalog.

When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal.

*3 mL of Humalog and Humulin R U-100 are in a 5 mL vial.

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.

Up Front 5

Pharmacy Practice News • February 2010

Late-Breaker They also used oral cephalexin for skin and soft tissue infections. “The MRSA [methicillin-resistant Staphylococcus aureus] rate is very low there, so we were able to use [cephalexin] pretty easily,” Dr. Manzi said.

When the team needed to intubate patients, she added, they used advanced cardiopulmonary life support and pediatric advanced life support medications.

“We used these more than in past disasters,” she said. Additionally, anywhere from 45% to 50% of the patients were children, a far higher percentage than in previous deployments. Two of the intu-

Dr. Manzi’s first order for medications and supplies in Haiti.

bated patients were babies. “I’m very comfortable with this population,” Dr. Manzi said. “This is what I do.”

Dr. Manzi’s first order for medications

and supplies was written on cardboard because “the only paper I had I was using for patient reports. I just grabbed the edge off one of the boxes and wrote down the first set of orders of what I was going to need, handed it to my logistics chief, and somehow that made it to Bill (Drake, the chief pharmacist for IRCT).

I thought that was very funny.”

The cardboard order wound up in a photograph that Dr. Drake brought back as a reminder of the do-whateveris-necessary spirit that prevailed among DMAT responders in Haiti. In civilian life, Dr. Drake is the president of

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.

HI59950-4 HI59950-4

1109 1109 PRINTED PRINTED IN IN USA USA

©2009, ©2009, LILLY LILLY USA, USA, LLC. LLC. ALL ALL RIGHTS RIGHTS RESERVED. RESERVED.

Advanced Care Pharmacy, a Michiganbased network of health care companies that supplies traditional retail and other types of pharmacies.

Dr. Drake’s two-week experience as a logistical leader in the U.S. government’s Haitian relief effort was different from Dr. Manzi’s, but no less crucial.

As part of the command and control group, his role was to “interact with other sectional leads and divisional chiefs, identifying the pharmaceuticals needed for the mission and facilitating getting those assets into the theater

•

see HAITI, page 6

6 Up Front

Pharmacy Practice News • February 2010

Late-Breaker

HAITI

continued from page 5

of operation—and once there, getting them out to the actual teams.”

Dr. Drake also acted as the DMAT pharmacists’ primary go-to person for any “questions, problems, challenges, surprises” that arose during the relief mission. He also made sure that DMAT pharmacies were “in a safe, controlled environment and that drugs were being stored and managed in an appropriate way that met FDA requirements and standards of practice.”

Called into service the day after the earthquake, Dr. Drake left Detroit Metro Airport on a flight to Atlanta at 5:30 a.m. the following morning. From Atlanta, he was on the same chartered plane as Dr. Manzi that got diverted to Turks and Caicos. He also arrived in Haiti on the same Coast Guard transport plane the next day.

“We were the first group representing the U.S. government’s medical response,” he said. “The military was already there, thankfully, because they were the ones who took control of airport traffic, which made it far safer for us to land.”

An International Effort “This was not a U.S. operation,” Dr. Drake said. “It was a U.N. operation.”

Israeli, French, Spanish and Venezuelan teams were among those setting up field hospitals. “The U.S. used DMAT teams to set up surgical centers. The teams also supported the [U.S. Naval Ship] Comfort mission,” Dr. Drake said. “Our DMAT team acted as the collection point where people were brought, evaluated and, if stable enough, were taken by medevac to the Comfort.”

“There was a lot of freelancing going on” by well-intentioned people, he said.

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 cartridges3 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.

“I came across a group that landed at the airport the second day we were there.

There were two physicians, a nurse and a pharmacist.” They told Dr. Drake they were there to help. “What can we do?”

They had brought along a case of water and some food. “I told them the best thing they could do was get back in their plane and go home” before they became victims or refugees themselves.

“There are no 7-Elevens on the other side of the wall out there,” he told them. “The Hotel Montana used to have five or six stories. Now there are only two stories and not much room between the floors.”

Dr. Drake said that people sometimes refer to him as a hero in their e-mails to him. “I have to say I am not a hero, but I had the privilege and proud opportunity to serve with many heroes.”

In addition to government efforts, many private humanitarian groups sent medical teams that included pharmacists to Haiti. Lisa Kerr Johnson, PharmD, RN, an IV therapy specialist with St. Joseph’s Mercy Hospital in Ann Arbor, Mich., joined a Haiti-bound group of volunteer physicians, nurses and others from Michigan, Georgia and New Jersey called “Team Ange”—Haitian for Angel Team.

“People are realizing that they need to get pharmacists in there to help support the medical teams,” Dr. Johnson told Pharmacy Practice News on the eve of her departure. She had been to Haiti on 16 previous medical missions.

Ceftriaxone ‘Like Gold’ Dr. Johnson and a group of Haiti relief supporters at the First Presbyterian Church in Ann Arbor collected thousands of dollars’ worth of donated pharmaceuticals and supplies to take to Haiti. The cache included 1,500 doses of ceftriaxone, which Dr. Johnson said was “like gold” in Haiti because it could be given once a day “and we have to try to do everything as efficiently as we can.”

The medicines and supplies filled 12 large black duffel bags that Dr. Johnson, her husband, and Bridget Holtz, RN, a nurse who accompanied her, stuffed into two cars before heading for Detroit Metro Airport in the early morning hours of Jan. 22. They loaded the bags, weighing a total of 600 pounds., onto two rental carts and wheeled them to the counter of Delta Airlines, which had waived the substantial fees that the extra baggage would have cost.

Web Exclusive Q&A with William Drake, PharmD, chief pharmacist for the U.S. government’s Incident Response Coordination Team pharmacypracticenews.com

Up Front 7

Pharmacy Practice News • February 2010

Late-Breaker Dr. Johnson and Ms. Holtz flew to Atlanta where they connected with other Team Ange members. They then flew to the Dominican Republic and from there were transported by a Dominican navy ship to Jacmel, Haiti. The team set up operations in Cayes-Jacmel, about eight miles east of the port city.

Communications from Haiti were sparse. Debra Hutton, PhD, a psychologist who acted as the Ann Arbor support person, told Pharmacy Practice News that when the team arrived in Cayes-Jacmel, “there were 60 surgeries waiting for them. They operated through the night. They are operating in a medical clinic that was established by a Baptist minister. They are now performing five to 10 surgeries a day and they’ve delivered a baby.” Dr. Johnson plans to remain in Haiti for a month.

The room where Lisa Kerr Johnson, Pharm, often stayed during relief missions to Haiti suffered major damage.

pharmacy profession: nearly 2,600 pharmacists responded to calls for volunteers and funds to help people seriously injured in the disaster, accord-

ing to Mitch Rothholz, BPharm, MBA, chief of staff of the American Pharmacists Association (APhA).

Mr. Rothholz, who led the effort to compile a database of pharmacists offering aid, said that approximately 1,000 of those who replied expressed interest in taking part in Haitian medical relief efforts. “We’ve been making the names available to organizations that are interested, be it the government through USAID and the Department of Health and Human Services or private relief organizations,” he said.

“We’ve heard the federal government is

looking for physicians and nurses primarily right now,” he added, “but at some point I think they are going to realize that somebody is needed to ensure that these folks have access to medications and how to take them.”

—Bruce and Joan Buckley

Next Issue: a pharmacist on the USNS Comfort details his experiences in postearthquake Haiti.

Husband and Wife Team Help David Fluitt, RPh, and his wife Kelly, a nurse practitioner, were another pharmacist-nurse team that traveled to Haiti as part of the international medical relief effort. Mr. Fluitt, based in Carson City, Nev., is a district pharmacy manager for the Raley’s supermarket chain.

Mr. Fluitt previously had been to Haiti on medical missions. Before departing on Jan. 22, Mr. Fluitt told Pharmacy Practice News, “when these medical teams find out that a pharmacist is coming, their eyes light up. They just don’t have knowledge of medications when they’re out there in the field.” He and his wife also packed bags full of donated medicines and supplies to take on the mission. They were headed for two weeks of service at King’s Hospital in Port-au-Prince, where, Mr. Fluitt had been told, doctors and nurses were seeing about 200 patients a day.

A week after they arrived, Pharmacy Practice News received an e-mail message from Mr. Fluitt: “Set up hospital at King’s last 6 days and pharmacy looks great!

Most of the need now shifts to post-op and wound care. Have met remarkable medical teams from all over the world.

We see tremendous devastation. Kelly and I worked in an outpatient clinic/ food dispensary (our own design) and met a woman with two children, one a newborn, who we treated for allergies.

She said her husband had been killed and they were living on the street. We gave her $20 along with all the food and meds she could carry. Today we found another need. Haitian Community Hospital is in urgent need of a pharmacist and trauma providers. No phone service yet.”

Pharmacy Community Responds These accounts of relief efforts by individual pharmacists are compelling.

But within 72 hours of the earthquake in Haiti, an impressive response was also heard from a wide swath of the

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8 People in Pharmacy

Pharmacy Practice News • February 2010

Medical Missions

AFGHANISTAN continued from page 1

“I guess some pharmacists would be satisfied sitting back and just giving out medications,” he said. “But in Afghanistan, that wouldn’t have worked. This was a far-forward position with limited resources, and anyone with clinical skills had to quickly become an integral part of the critical care team.”

The location, at Forward Operating Base Salerno, Afghanistan, underscores how different this deployment was for Maj. Boenig. During his first tour, he explained, he worked in a Level 3 Combat Support Hospital that was part of Bagram Air Base. Most of the hospital was located in tents, with 24 beds that were expandable to 42 as needed.

Salerno, in contrast, started out “as a real lean, mean surgical outfit, where patients got the care they needed and then moved on,” he said. “There really was no holding capacity.”

Longer-term care was needed for the injured or seriously ill U.S. and Coalition soldiers as well as Afghanis, he said, in part because “the operations tempo of the war had increased pretty dramatically.” So just prior to his tour, Maj. Boenig noted, the Army decided to “2-plus” the forward-positioned hospital and significantly expand available services. “They added in functions such as laboratory testing, expanded radiologic services such as a CT [computed tomography] scanner, and they also ‘plussed up’ the personnel to include me, a pharmacist, along with one pharmacy technician.” The Salerno facility also now had holding capacity—about nine beds for long-term care.

Trauma Care Detailed The call to join the trauma team was by far the biggest change in duty, Maj. Boenig stressed. As for the type of patient care he helped provide, it was typical for a combat zone—or at least, typical for Afghanistan in the era of the improvised explosive device (IED).

“The first time I was deployed, the Afghan insurgents had not yet discovered IEDs,” Maj. Boenig said. “During this last tour, these devices were unfortunately very common—usually in the form of roadside bombs—and the trauma they can cause is horrible.”

The pharmacist’s role in treating patients wounded by IEDs most often focused on supportive drug therapy, he noted. For example, patients with crushing limb wounds and/or body trauma were given antibiotic therapy to prevent postsurgical infections. Those with severe head wounds could be given mannitol, a sugar/alcohol solution that can be effective in reducing brain swelling.

But when Maj. Boenig first arrived at Salerno, he found some problems

Capt. Boenig (above, second from right) readies a drug from the “crash cart” for a patient in cardiac arrest. In the other photos, he’s seen building a new pharmacy, administering a tetanus vaccine and traveling with two Afghani patients.

‘When you hear a trauma physician telling you to defibrillate the patient and then everybody kind of just stops what they’re doing and looks at you, there’s really no place to hide; it’s time to do your part for the trauma team.’ with the way medications were being managed. “There were a lot of drugs in the trauma area, but only a few of them were really needed,” he said. “Pharmacy is not a free-for-all; I didn’t like the lack of oversight of medication use at such stressful times, so I changed that practice. Not only did this help streamline care, it also reduced opportunities for error.”

Why was that such an important initiative for pharmacy? “I was there as a medication expert, but I can’t offer that expertise if nobody is consulting with me on the use of drugs,” he explained.

“I needed to take control of the medication process, review the medications administered prior to arrival, and then when appropriate, make recommendations and changes to the regimens to ensure safety and efficacy.”

Maj. Boenig added that it was not just his own “take” on what medications were needed in a given situation.

The Army has protocols for the most common trauma-related medications, not only for antibiotic prophylaxis, but also for factor VIIa in cases of severe bleeding, he noted. “There are detailed instructions for how these drugs get administered, how they are dosed, how we determine when to use them, etc.”

It didn’t take long for the other caregivers in the Salerno facility to begin relying on Maj. Boenig’s medication management skills, with the crash cart being a prime example. “After one of the first codes I ever did, more than one nurse, including the chief nurse, came up to me and said how good it was to have someone who took care of the code cart because it let her and the rest of the trauma team focus more on the patient,” he said. “If they needed a pressor drip, I could make it right there at the bedside;

they didn’t have to wonder about how much to put in, how to compound it, etc. I could hand over medications such as atropine, epinephrine and calcium chloride, all prepared and ready to go for administration. And when we had pediatric patients coding, I had a copy of the Broselow chart so I could make sure that I knew how to make the right dosage adjustments.”

But when a more hands-on approach was needed, Maj. Boenig was ready for service. “I’m not certified in advanced cardiac life support, but I quickly learned how to work a LIFEPACK 12 defibrillator.”

What was it like to “shock” a patient for the first time? “Well, you kind of hesitate, but when you hear a trauma physician telling you to defibrillate the patient and then everybody kind of just stops what they’re doing and looks at you, there’s really no place to hide; you do your part for the trauma team.”

Having the life of a trauma patient literally in your hands brought home, in real terms, “how incredibly needed” pharmacists are in critical-care situations, Maj. Boenig said. “I’ve read articles describing how more and more pharmacists are being used in emergency departments,” he explained. “But I didn’t appreciate just how valuable a team member we can be until I experienced this myself.”

A Few Good Pharmacists How did Maj. Boenig join the Army Reserves as a pharmacist? “I was at a point in my career where I’d done hospital and retail pharmacy, and also was the director of the dispensary in a free health clinic for a couple of years. I was looking for a new challenge, so I got commissioned 10 years ago, at age 38.”

Maj. Boenig said he chose the Army because of the high demands it places on clinical personnel.

“Don’t come into the Reserves and expect to get called up to work at Walter Reed [Army Medical Center] or in the Office of the Surgeon General,” he said.

“That does happen, but make no mistake: your mission as a pharmacist or a pharmacy technician in the Reserves is to deploy and potentially serve in a combat zone. So when we train on weekends, we train to deploy.”

That training does touch on some clinical skills. “But it also involves soldiering skills,” Maj. Boenig said. “We have to know how to react to hostile fire and how to lay down a field of fire, when appropriate. We even train how to evacuate a HumVee after a rollover.”

Army reservists also are trained to develop something called “situational awareness”—the ability to be tuned into your surroundings to detect threats.

Those skills were not top-of-mind when Maj. Boenig was caring for patients in the main Salerno facility. But the time came when those soldiering skills were in fact needed.

Directly outside the gate of the American hospital, he explained, there was an Afghan gate, and in the intermediary zone, a clinic had been built for treating injured or ill local Afghanis. “When you drove into that middle zone, you had to have your full body armor on, you had to have your weapon and you definitely had to have your situational awareness on high alert, because the threat risk increased dramatically.”

Hearts and Minds Making that excursion, although risky, proved to be one of the most

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People in Pharmacy 9

Pharmacy Practice News • February 2010

Medical Missions rewarding aspects of Maj. Boenig’s latest tour of duty. When he first arrived at the Afghani clinic, he said, the local physicians had almost no resources and only a minimal understanding of how to provide medications and care to patients.

“Basically, I had to build a pharmacy from scratch, with desks, shelves, etc.

Then I had to stock it with medications from the local economy and teach the staff how to create and then maintain a basic drug formulary.”

Those efforts triggered an interest in American pharmacy practice that

Two vaccine cards developed by Maj. Boenig are used by Afghani patients to keep track of their tetanus boosters and ensure full immunity.

was so strong among the Afghani physicians—many of whom were working as translators—that Maj. Boenig set up a one-day training program that covered even more aspects of medication management. “I taught them how to compound sterile IV admixtures, how to calculate pediatric and adult drug dosages, how to determine diluents and infusion times, and how to counsel

patients about the administered drugs,” he said. “They were absolutely fascinated by all of this, and really were great students.”

Another initiative that Maj. Boenig said he was particularly proud of was the creation of a tetanus vaccination program. All Afghan patients who came into the hospital with traumatic injuries would get a tetanus vaccination, which was usually the first one they had ever received. “I had one of our medics teach me how to administer the tetanus shots, so basically I just drew

•

see AFGHANISTAN, page 36

10 Opinion

Pharmacy Practice News • February 2010

The Missing Piece in the Pharmacy Practice Model M any would agree that pharmacy practice should be focused on the patient to ensure optimal outcomes. But I experienced a convergence of information while Bill Jones, MS, attending the ASHP BSPharm Midyear Clinical Meeting in December 2009 that made it clear we’re still falling far short of that goal.

During a session at the Midyear meeting, top-line results from ASHP’s 2009 National Survey on pharmacy practice were released. Approximately 2,000 hospitals answered questions on patient monitoring and education. The survey also measured compliance with the ASHP 2015 Initiative, which seeks to help health systems achieve the group’s vision for pharmacy practice.

The survey included this sobering statistic: only 17.4% of hospitals said they

provided discharge counseling when patients had been given complex or highrisk medications. The largest hospitals (>600 beds) fared a bit better: 38.7% said they complied with this ASHP 2015 Initiative. The overall results are only slightly better than those from the 2007 practice survey (16.8%), and both years are lower than the 2004 survey (22.4%).1 That same week, I came across a newspaper article by The Associated Press about the high rate of hospital readmis-

sions among Medicare patients—one of every five patients overall, and one of every four with heart failure.2 The three major risk factors for readmissions were problems with medications, lack of post-discharge follow-up and patients not being able to recognize and handle the signs and symptoms of worsening disease.

So, what do the results from the ASHP survey and Medicare study have in common? They both raise a troubling question: if problems with medications are among the most common reasons why patients don’t do well post-discharge, and pharmacists are considered the medication experts, then where are we in this patient care process? Is it not our profession’s societal responsibility to ensure that patients receive optimal drug therapy throughout the continuum of care?

If it were you or a family member who was hospitalized, what would you want— a pharmacist who only dispensed the medications, or one who also reviewed the prescription and offered expertise on potential drug interactions, dosing, efficacy, etc., with some continued guidance post-discharge? We’ve all had experiences where we’ve asked our pharmacist colleagues to make sure that the right things are done for our loved ones. Why, then, are we allowing the majority of patients to not get the same level of care that we all would demand?

We’re All Clinical Pharmacists Perhaps the problem is the notion that some pharmacists must be delegated to drug distribution, whereas others are better suited to clinical tasks. Luis S. Gonzalez III, PharmD, wrote a brief yet powerful commentary in the American Journal of Health-System Pharmacy challenging that idea.3 If the profession is going to not only survive but prosper, he noted, “we must come out from behind the counters and computer terminals and stand at the bedside of patients, who are dying without our needed expertise.”

I could not agree more. And yet we are now discussing another development that I find frustrating—requiring pharmacists to undergo residency training and board certification as a prerequisite for taking care of patients. Such a policy ignores the fact that all pharmacists are clinicians.

Not convinced? Then consider this: pharmacy technicians and automation can take care of most drug dispensing and distributive functions. If that’s how you allow yourself to be defined professionally, it’s not too long before the supposed shortage for your mode of practice disappears. In fact, the Pharmacy Manpower Project’s Aggregate Demand Index shows that the demand for pharmacists already may be waning: it is lower this

Opinion 11

Pharmacy Practice News • February 2010

year than last and not one state reported high demand.4 Could that be yet another warning sign for our profession to refocus on the patient?

It’s also important to remember the economic reasons for putting the patient first. The Medicare study, according to The Associated Press report, estimated that the high rate of readmissions is costing taxpayers $17 billion annually.

If even half of that cost was avoidable because pharmacists were doing what patients need instead of merely taking care of drug-related services, there would be enough money to pay for more than 100,000 pharmacists.

of changing levels of care, systems are needed to avoid the pitfalls of handoffs between the various health care practitioners. This involves not just talking to a patient at the time of discharge, but ensuring that the patient understands how to take medications and has appropriate monitoring and follow-up.

Developing the practice model from the patient’s perspective will lead to a safer, more effective and overall less costly system of health care. Rather than embarking on ways to work in parallel or collaboratively with physicians and other prescribers, pharmacists should develop

a model of practice where patients, prescribers, and pharmacists are partners.

Mr. Jones is retired from the Veterans Affairs (VA) after 35 years of federal government service. During that time, he spent 28 years as the clinical coordinator and residency director at the Southern Arizona VA Health Care System and three years as the VA PBM pharmacy program manager for educational development. Mr. Jones can be reached via e-mail at wnjones49@cox.net

References 1. 2015 ASHP Health-System Pharmacy Initiative (Revised March 2008). http://www.ashp. org/DocLibrary/Policy/2015/2015Goals.aspx.

Accessed January 18, 2010.

2. Neergaard L. Groups try simple steps to avoid hospital rebound. www.business report.com.

Accessed January 18, 2010.

3. Gonzalez LS. What are pharmacists, and what do they do? Am J Health-Syst Pharm.

2005;2039-2040.

4. Aggregate Demand Index. http://www.pharmacymanpower.com/summary.html. Accessed January 18, 2010.

5. Walker PC, Bernstein SJ, Jones JNT, et al.

Impact of a pharmacist-facilitation hospital discharge program. A quasi-experimental study. Arch Intern Med. 2009;169:2003-2010.

6. ACCP Board of Directors. The definition of clinical pharmacy. Pharmacotherapy. 2008; 28:816-817.

What Data Are We Checking?

We also need to do a better job of documenting downstream savings from pharmacist interventions. A study in Archives of Internal Medicine found that although a pharmacist-facilitated hospital discharge program reduced medication discrepancies—a laudable goal—there was no effect on post-discharge health care resource utilization.5 What this article does not tell us is what happened after discharge.

Did the patients have a pharmacist in the outpatient setting who could contribute to their care, or was it the far more common approach—providing prescriptions and (maybe) one-time counseling? That gap in the study is not surprising. How many times are pharmacists focused on the metrics of doing something, such as discharge counseling, yet not assessing the long-term impact?

Discharge counseling can’t be a sole focus; we have to cast a wider net when it comes to being part of the clinical care team. That means decentralizing pharmacists to patient care areas and ensuring they are responsible for all medication-related issues for patients. And we can’t be content with leaving discharged patients to the vagaries of communitybased care. The Medicare study shows that just doesn’t work.

The American College of Clinical Pharmacy has defined a clinical pharmacist as someone who does not provide services, but takes care of patients in any setting.6 It seems to me that any new practice model needs to start with the patient, and then work backward from there.

Unfortunately, the results of the ASHP 2009 National Practice survey suggest we are still focusing primarily on distributive services.

If we are serious about improving our practice model, one goal must be to ensure that patients actually need the drugs that are prescribed. Additionally, at each point

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12 Clinical

Pharmacy Practice News • February 2010

Educational Review

The Bone Continuum of Cancer: Early to Advanced Stage Disease LARISSA A. KORDE, MD, MPH Assistant Professor

JULIE R. GRALOW, MD Director of Breast Medical Oncology Associate Professor

Department of Medicine Division of Oncology University of Washington Seattle Cancer Care Alliance Fred Hutchinson Cancer Research Center Seattle, Washington

I

t is estimated that nearly 1.5 million people will be diagnosed with cancer in the United States in 2009.1 Survival rates of many cancers are improving, leading to an emerging population of individuals living with cancer.

Bone health is an increasingly important issue in patients with cancer, for both those who have developed metastatic disease in the bone and those receiving treatment to prevent recurrence that can affect bone health.

This article reviews the risk factors and management options for treatment-related bone loss, factors associated with, and treatment of, bone metastases, and emerging strategies for prevention of bone recurrence.

The American Cancer Society estimates that there will be 192,370 new cases of invasive breast cancer and 192,280 new cases of prostate cancer in the United States in 2009. In addition, it is estimated that 219,440 individuals will develop lung cancer.1 Although a large number of these individuals will not develop metastatic disease, the incidence of bone metastases among those who develop distant disease is 73% for patients with breast cancer, 68% for patients with prostate cancer, and 30% to 40% for those with lung cancer.2 The median survival time for patients with bone metastases from breast and prostate cancer is on the order of several years3,4; in contrast, survival for metastatic lung cancer is measured in months. Other cancers also can give rise to bony involvement; nearly 100% of cases of multiple myeloma involve the bone, and carcinomas of the thyroid and kidney also commonly give rise to bone metastases.2 Complications of bone metastases include bone pain, bone marrow suppression, hypercalcemia, nerve compression, and pathologic fracture, all of which can place significant and complex demands on the health care system. Furthermore, a number of cancer treatments, including hormone therapy, systemic glucocorticoids, and chemotherapy in premenopausal women (leading to premature menopause) can cause accelerated bone loss, resulting in osteoporotic fracture, pain, and adverse effects on quality of life. Oncologic and non-oncologic risk factors for osteoporosis are listed in Table 1.

The management of bone health in patients with cancer requires an understanding of normal bone metabolism and how it is affected by metastatic disease and cancer treatments, including chemotherapy and hormone therapy. Bone is a dynamic tissue, undergoing continuous remodeling throughout life. Bone homeostasis is maintained by a balance of bone matrix and mineral resorption, mediated by osteoclasts, and bone formation, controlled by osteoblasts. Bone remodeling is regulated by both locally acting cytokines, such as receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG), and systemic hormones, including calcitonin, parathyroid hormone, insulin-like growth factor-1, and platelet-derived growth factor (Table 2).5 Systemically, parathyroid hormone, calcitonin, calcitriol, and vitamin D work together to maintain serum calcium levels by regulating bone resorption. Steroid hormones such as glucocorticoids, estrogens, and androgens also contribute to bone growth and maintenance. Local regulation of bone turnover is mediated via the OPG/RANKL/RANK system. RANKL binds to RANK on the surface of osteoclastic precursor cells, causing maturation and differentiation, and thus is critical for survival of mature osteoclasts. OPG inhibits this process by binding RANKL, decreasing osteoclast formation and survival, resulting in decreased bone resorption. Cytokines such as tumor necrosis factor-α and interleukin-10 also modulate bone turnover, primarily by stimulating production of macrophage colony-stimulating factor and increasing RANKL expression.

Evaluation and Treatment Of Osteoporosis Bone health is generally evaluated by bone mineral density (BMD) levels, and usually is assessed using dual-energy x-ray absorptiometry (DEXA) scanning of the hip and spine. Significant variation in DEXA measurements can exist due to differences

in calibration and detectors used, and thus serial monitoring of BMD should be performed using the same piece of equipment and the same reference standards. BMD can be expressed in absolute terms (grams per square centimeter) or, more commonly, it is described on a relative scale as the difference in standard deviations from the expected BMD for the patient’s age and sex (Z-score) or from that of “young normal” adults of the same sex (T-score). The World Health Organization (WHO) defines a normal BMD as that within one standard deviation of a young normal adult value (T-score of >1.0); a T-score of –1.0 to –2.5 is considered osteopenia; and a T-score of less than –2.5 constitutes osteoporosis.6 It is estimated that fracture risk doubles for each standard deviation reduction in BMD.7 Age is an important additional risk factor for fracture. Recently, the WHO developed a risk assessment tool (FRAX) that combines BMD measures with other clinical risk factors for fracture, including age, to provide estimates of 10-year risk for fracture.8 Current Medicare guidelines recommend therapeutic intervention if a patient has a 10-year FRAX risk of 3% for hip fractures and more than 20% for all major fractures. Cancer patients with elevated risk for bone loss and fracture should be evaluated periodically to assess the impact of their cancer treatment on bone mass.

Initial strategies for prevention and treatment of bone loss include lifestyle modifications such as performing regular weight-bearing exercises, strength training and balance exercises, avoiding tobacco, and limiting alcohol intake. In addition,

Clinical 13

Pharmacy Practice News • February 2010

Educational Review Table 1. Risk Factors for Osteoporotic Fractures

Table 2. Effects of Systemic Hormones On RANK/RANKL/ OPG System

Non-Oncologic

Oncologic

Age

Treatment-induced menopause

Frequent falls

Hormonally active medication use: • Androgen deprivation therapy • Ovarian function suppression • Aromatase inhibitors

Family history of osteoporosis Personal history of fragility fracture Rheumatoid arthritis Low body mass index

Other medications: • Glucocorticoids

Smoking

Hormone

Effect on RANKL

Transforming growth factor-β

Effect on OPG ↑

Parathyroid hormone

↑

1,25 dihydroxyvitamin 2D

↑

Glucorticoids

↑

↓

↓

Alcohol consumption Estrogen

all patients should be counseled to ensure adequate intake of calcium (at least 1,200 mg/d for all individuals older than 50 years of age and those with risk factors for osteoporosis) and vitamin D (800-1,000 IU/d).9 Preventing falls is key to reducing fractures. Therapeutic intervention (described below) should be strongly considered for patients with a T-score below –2.0, particularly in those with additional risk factors for fracture. An algorithm for the management of cancer patients at risk for bone loss is shown in Figure 1. The optimal duration of therapy for osteoporosis is unknown.

Bone Health in Breast Cancer Aromatase Inhibitor–Induced Bone Loss A number of cancer therapies can significantly affect bone health. Aromatase inhibitors (AIs) have become increasingly common as adjuvant therapy for hormone receptor–positive breast cancer in postmenopausal women. AIs inhibit peripheral conversion of androgen to estrogen, resulting in a rapid decrease in circulating estrogen levels

and thus accelerated bone loss and increased risk for fracture. In the large adjuvant trials comparing AIs, such as anastrozole (Arimidex, AstraZeneca), with tamoxifen, absolute rates of fracture among patients treated with AIs were 1% to 3% higher than those among tamoxifen-treated patients.10-12 In the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial, in which patients were randomized to 5 years of either anastrozole or tamoxifen, fracture rates after discontinuation of therapy were similar, suggesting that the increased risk for fracture with AI therapy is not permanent.11 The MA17 trial, which compared 5 years of letrozole to placebo after completion of 5 years of tamoxifen, showed a nonsignificant difference in the incidence of a new diagnosis of osteoporosis in the 2 arms (5.8% for letrozole vs 4.5% for placebo; P=0.07), whereas fracture rates were similar in the 2 groups.13 This suggests that the difference in fracture rates between AIs and tamoxifen may be predominantly due to a bone-protective effect of tamoxifen rather than a detrimental effect of AIs. In a prospective

Cancer patients at increased risk for bone loss and fracture due to therapy or age

History and physical examination, BMD screening, FRAX analysis

Lifestyle modification, calcium, and vitamin D supplementation

T-score >–1.0

T-score between –1.0 and –1.5

T-score between –1.5 and –2.0

T-score between >–2.0 FRAX 10-y risk >20% for major fracture or >3% for hip fracture

Consider checking 25(OH) vitamin D level

Consider pharmacologic therapy

Repeat DEXA scan every 2 y

Figure 1. Algorithm for management of bone health in cancer patients at risk for bone loss.

BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry; FRAX, World Health Organization Fracture Risk Assessment Tool; OH, hydroxyvitamin

Strongly consider pharmacologic therapy

↑

Basic fibroblast growth factor

↑

↓

Prostaglandin E2

↓

↑

substudy of the ATAC trial that assessed BMD changes among 197 women, the median change in lumbar spine BMD was –6.08% in anastrozole-treated women and 2.77% in tamoxifen-treated women. Importantly, in that study, no patients with normal bone density at baseline developed osteoporosis during the 5 years of therapy, and 5% of patients with osteopenia at baseline became osteoporotic.14 Among AI-treated patients, older age and baseline osteopenia have been identified as risk factors for fracture.

Several studies have evaluated the impact of oral and IV bisphosphonate therapy on BMD in women undergoing adjuvant AI therapy for breast cancer. In SABRE (Study of Anastrozole with the Bisphosphonate RisedronatE), women receiving anastrozole were assigned to therapy based on baseline T-scores: Patients with a lowrisk T-score (>–1.0) received no additional therapy; those with a T-score between –1.0 and –2.0 were randomized to risedronate or placebo; and those with a T-score less than –2.0 were treated with risedronate. Over 24 months, risedronate at a dose of 35 mg weekly resulted in favorable effects on BMD.15 The ARIBON trial (effect of oral ibandronate on anastrozole-induced bone loss) used a similar design (patients with a T-score of –1.0 to –2.5 were randomized to either ibandronate or placebo). In that study, the addition of ibandronate (Boniva, Roche) to anastrozole led to a significant increase in BMD at the spine and hip after 1 year of therapy.16 The ZometaFemara Adjuvant Synergy Trials (Z-FAST and ZoFAST) evaluated the efficacy of immediate versus delayed initiation of zoledronic acid (Zometa, Novartis) in preventing AI-associated bone loss.

Patients in the immediate arm received zoledronic acid every 6 months beginning at initiation of AI therapy; those in the delayed arm received zoledronic acid only if they developed clinically significant bone loss (T-score <–2.0) or fracture. In a pooled analysis of approximately 1,600 patients treated in these 2 trials, immediate use of zoledronic acid was significantly associated with preservation of BMD,17 although fracture

•

see BONE CONTINUUM, page 14

14 Clinical

Pharmacy Practice News • February 2010

Educational Review

BONE CONTINUUM

60

continued from page 13

52

50

Prevalence of Event

rates were not significantly different between the 2 arms. No trials to date have compared oral with IV bisphosphonates for this indication, but taken together, these data suggest that both formulations of bisphosphonates can mitigate the bone loss associated with AI therapy.

Another agent being assessed for its effects on AI-induced bone loss is denosumab, in development by Amgen. Denosumab, a humanized monoclonal antibody to RANKL (which enhances osteoclast production and survival, resulting in increased bone resorption), has been assessed in a Phase II placebo-controlled study of adjuvant therapy for nonmetastatic breast cancer.18 Patients in the treatment arm received 60 mg of denosumab subcutaneously every 6 months for 2 years. At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group compared with the placebo group (P<0.0001), and increases were also seen in BMD at the hip and radius.

Pathologic fracture

Radiation therapy

Surgical intervention

Spinal cord compression

43

40

37 34

34

33

30 25 22

20 11

10

8 5

4

3

5

3

4

0 Breast Cancer (24 mo)

Prostate Cancer (24 mo)

Multiple Myeloma (21 mo)

Other Solid Tumors Including NSCLC (21 mo)

Figure 2. Prevalence of skeletal-related events in patients with metastatic bone disease not treated with bisphosphonates.

NSCLC, non-small cell lung cancer Based on references 53-56.

Chemotherapy-Induced Ovarian Failure Premenopausal women with early-stage breast cancer who receive adjuvant chemotherapy generally experience at least temporary amenorrhea, and more than 50% will experience premature ovarian failure19-21; the risk for ovarian failure increases with increasing age at diagnosis and with type of treatment.22 Several studies have reported accelerated bone loss as a consequence of chemotherapy-induced premature ovarian failure. In a prospective study by Shapiro et al, 71% of young women undergoing adjuvant chemotherapy experienced ovarian suppression, and in these patients a highly significant loss of bone density was seen in the lumbar spine at 6 months.23 Additional data suggest that bone loss associated with chemotherapy-induced menopause is several times higher than that seen with natural menopause or with AI treatment in postmenopausal women.9 Oral clodronate (Bonefos, Berlex) and risedronate have been studied in the setting of chemotherapy-induced ovarian failure. Compared with placebo, both agents imparted about a 2% to 3% absolute improvement in BMD.24,25 Zoledronic acid was evaluated in the Cancer and Leukemia Group B (CALGB) 79809 study, in which premenopausal women beginning adjuvant chemotherapy were randomized to immediate versus delayed administration of zoledronic acid.26 At 12 months, patients in the immediate treatment arm had a 2.6% improvement in BMD, whereas those in the delayed arm, who had not yet received zoledronic acid, experienced a 6.4% loss of BMD. Intravenous zoledronic acid also is effective for minimizing bone loss in women receiving ovarian suppression with a gonadotropin-releasing hormone (GnRH) agonist.27 Although these results are positive, no studies to date have shown an impact of bisphosphonate therapy on reducing fracture rates in this population.

Effect of Bisphosphonate Therapy On Risk for Recurrence In addition to beneficial effects on bone health, emerging evidence suggests that bisphosphonates

Table 3. Results of Phase III Trials Comparing Denosumab to Zoledronic Acid in Metastatic Cancer

Trial

N

Population

Time to 1st SRE (D vs ZA)

Stoppeck et al65

2,046

Breast cancer patients with bone metastases

Not reached vs 26.5 mo

0.82 (0.70-0.95)

20 vs 14

Henry et al66

1,776

Bone metastases due to solid tumor (non-breast, non-prostate) or multiple myeloma

20.6 vs. 16.3 mo

0.84 (0.71-0.98)

10 vs 11

Hazard Ratio

Number of ONJ cases (D vs. ZA)

D, denosumab; ONJ, osteonecrosis of the jaw; SRE, skeletal-related event; ZA, zoledronic acid

also may have antitumor and antimetastatic properties. Possible mechanisms include inhibition of angiogenesis and tumor cell invasion, induction of apoptosis, and immunomodulatory effects.28,29 Early studies assessing the effect of clodronate on risk for recurrence produced promising yet conflicting results.30 A recent meta-analysis of trials using oral clodronate in the adjuvant setting did not show improvements in overall or recurrencefree survival.31 However, there was marked heterogeneity among the trials and wide confidence intervals (CIs) around their hazard ratio (HR). The ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group trial 12) studied the effect of adding zoledronic acid to endocrine therapy in 1,800 premenopausal women with stage I or II breast cancer.32 All patients received ovarian suppression for 3 years with goserelin (Zoladex, AstraZeneca), and patients were randomized in a 2 × 2 design to receive tamoxifen versus anastrozole, with or without zoledronic acid (4 mg every 6 months). After a median follow-up of 47.8 months, the addition of zoledronic acid resulted in an absolute reduction of 3.2% in the risk for disease recurrence versus endocrine therapy without zoledronic acid (HR, 0.64; 95% CI, 0.46-0.91; P=0.01). Furthermore, subset analyses of the site

of recurrence revealed reductions in the incidences of distant recurrences, locoregional recurrences, and contralateral breast cancer, although the overall number of recurrences in both arms is small to date.

Results from several other studies examining the question of whether bisphosphonates affect disease recurrence are expected in the near future. The National Surgical Adjuvant Breast and Bowel Project Study 34 (NSABP B34) randomized 3,300 women with stage I or II breast cancer to 3 years of clodronate or placebo. The trial closed to accrual in March 2004, but the results have not yet been reported because the requisite number of events has not been reached.

The AZURE trial is testing a “more intensive” dosing regimen of zoledronic acid (monthly for 6 months, followed by every-3-month dosing and finally every-6-month dosing to complete 5 years) versus control in women receiving chemotherapy and/or endocrine therapy for the treatment of stage II or III breast cancer. This study closed to accrual in January 2006 and will likely report results sometime in 2010. The ongoing SWOG 0307 (Southwest Oncology Group Study 0307) trial is comparing the efficacy of “more

•

see BONE CONTINUUM, page 16

Expanded broad-spectrum coverage1* is on your side

*TYGACIL does not cover Pseudomonas aeruginosa.

TYGACIL is indicated for the treatment of adults with: • Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis • Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros • Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila

Important Safety Information • TYGACIL is contraindicated in patients with known hypersensitivity to tigecycline • Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening. TYGACIL should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics • Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function. Adverse events may occur after the drug has been discontinued • The safety and efficacy of TYGACIL in patients with hospital-acquired pneumonia have not been established • TYGACIL may cause fetal harm when administered to a pregnant woman • The use of TYGACIL during tooth development may cause permanent discoloration of the teeth. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated • Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis • Monotherapy should be used with caution in patients with clinically apparent intestinal perforation • TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL • To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat infections proven or strongly suspected to be caused by susceptible bacteria. As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi • The most common adverse reactions (incidence >5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased SGPT • Prothrombin time or other suitable anticoagulant test should be monitored if TYGACIL is administered with warfarin • Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective • The safety and effectiveness of TYGACIL in patients below age 18 and lactating women have not been established Please see brief summary of Prescribing Information on adjacent page.

Reference: 1. TYGACIL® (tigecycline) Prescribing Information, Wyeth Pharmaceuticals Inc. Wyeth is a wholly owned subsidiary of Pfizer Inc. To learn more, please visit www.pfizer.com. © 2009, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101

November 2009

262202-01

Expanded broad-spectrum coverage

16 Clinical

Educational Review

BONE CONTINUUM continued from page 14 TYGACIL® (tigecycline) Brief Summary See package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.

INDICATIONS AND USAGE TYGACIL is indicated for the treatment of adults with complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillinsusceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.

TYGACIL is indicated for the treatment of adults with complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

TYGACIL is indicated for the treatment of adults with community-acquired pneumonia infections caused

by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila.

CONTRAINDICATIONS TYGACIL is contraindicated for use in patients who have known hypersensitivity to tigecycline.

WARNINGS AND PRECAUTIONS Anaphylaxis/Anaphylactoid Reactions Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including TYGACIL, and may be life-threatening. TYGACIL is structurally similar to tetracycline-class antibiotics and should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics.

Hepatic Effects Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse events may occur after the drug has been discontinued.

Mortality Imbalance and Lower Cure Rates in Ventilator-Associated Pneumonia A study of patients with hospital acquired pneumonia failed to demonstrate the efficacy of TYGACIL. In this study, patients were randomized to receive TYGACIL (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received TYGACIL had lower cure rates (47.9% versus 70.1% for the clinically evaluable population) and greater mortality (25/131 [19.1%] versus 14/122 [11.5%]) than the comparator.

Use During Pregnancy TYGACIL may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline [see USE IN SPECIFIC POPULATIONS].

Tooth Development The use of TYGACIL during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with TYGACIL have shown bone discoloration. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.

Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Patients With Intestinal Perforation Caution should be exercised when considering TYGACIL monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with TYGACIL and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/ septic shock. The 6 patients treated with TYGACIL had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.

Tetracycline-Class Effects TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL. Superinfection As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi.

Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.

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

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

In clinical trials, 2514 patients were treated with TYGACIL. TYGACIL was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of treatment-emergent adverse reactions through test of cure reported in 2% of patients in these trials.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in 2% of Patients Treated in Clinical Studies Body System Adverse Reactions Body as a Whole Abdominal pain Abscess Asthenia Headache Infection Cardiovascular System Phlebitis Digestive System Diarrhea Dyspepsia Nausea Vomiting Hemic and Lymphatic System Anemia Metabolic and Nutritional Alkaline Phosphatase Increased Amylase Increased Bilirubinemia BUN Increased Healing Abnormal Hypoproteinemia SGOT Increasedb SGPT Increasedb Nervous System Dizziness Skin and Appendages Rash

TYGACIL (N=2514)

Comparatorsa (N=2307)

6 3 3 6 8

4 3 2 7 5

3

4

12 2 26 18

11 2 13 9

4

5

4 3 2 3 4 5 4 5

3 2 1 1 3 3 5 5

3

3

3

4

a

Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.

LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy.

In all Phase 3 and 4 studies that included a comparator, death occurred in 3.9% (147/3788) of patients receiving TYGACIL and 2.9% (105/3646) of patients receiving comparator drugs. In a pooled analysis of these studies, the risk difference of all-cause mortality was 1.0% (95% CI 0.2, 1.8) between TYGACIL and comparator treated patients. No significant differences were observed between treatments by infection type (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening or complications of infection or underlying co-morbidities.

Table 2. Patients with Adverse Events with Outcome of Death by Infection Type b

TYGACIL Infection Type cSSSI cIAI CAP HAP Non-VAPa VAPa RP DFI

n/N

%

n/N

Comparator %

Risk Difference* % (95% CI)

12/834 40/1382 12/424 65/467 40/336 25/131 11/128 7/553

1.4 2.9 2.8 13.9 11.9 19.1 8.6 1.3

6/813 27/1393 11/422 56/467 42/345 14/122 2/43 3/508

0.7 1.9 2.6 12.0 12.2 11.5 4.7 0.6

0.7 (-0.5, 1.9) 1.0 (-0.3, 2.2) 0.2 (-2.3, 2.7) 1.9 (-2.6, 6.4) -0.3 (-5.4, 4.9) 7.6 (-2.0, 16.9) 3.9 (-9.1, 11.6) 0.7 (-0.8, 2.2)

CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections. * The difference between the percentage of patients who died in TYGACIL and comparator treatment groups. a These are subgroups of the HAP population.

Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).

In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see WARNINGS AND PRECAUTIONS].

The most common treatment-emergent adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with TYGACIL and comparators were either mild or moderate in severity. In patients treated with TYGACIL, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL and 6% for levofloxacin.

Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%).

For comparators, discontinuation was most frequently associated with nausea (<1%).

The following adverse reactions were reported infrequently (<2%) in patients receiving TYGACIL in clinical studies: Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis Cardiovascular System: thrombophlebitis Digestive System: anorexia, jaundice, abnormal stools Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia, hyponatremia Special Senses: taste perversion Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia Skin and Appendages: pruritus Urogenital System: vaginal moniliasis, vaginitis, leukorrhea Post-Marketing Experience The following adverse reactions have been identified during postapproval use of TYGACIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Anaphylaxis/anaphylactoid reactions, acute pancreatitis, hepatic cholestasis, and jaundice.

DRUG INTERACTIONS Warfarin Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin [see CLINICAL PHARMACOLOGY (12.3) in full Prescribing Information].

Oral Contraceptives Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects—Pregnancy Category D [see WARNINGS AND PRECAUTIONS] Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg·hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.

There are no adequate and well-controlled studies of tigecycline in pregnant women. TYGACIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.

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 TYGACIL is administered to a nursing woman [see WARNINGS AND PRECAUTIONS].

Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of effects on tooth development, use in patients under 8 years of age is not recommended [see WARNINGS AND PRECAUTIONS].

Geriatric Use Of the total number of subjects who received TYGACIL in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.

No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline [see CLINICAL PHARMACOLOGY (12.3) in full Prescribing Information].

Hepatic Impairment No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response [see CLINICAL PHARMACOLOGY (12.3) and DOSAGE AND ADMINISTRATION (2.2) in full Prescribing Information].

OVERDOSAGE No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of TYGACIL at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose intravenous toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD50 was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis.

This Brief Summary is based on TYGACIL direction circular W10521C013 ET01, revised 09/09.

© 2009, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101

262202-02

intensive” IV zoledronic acid with oral clodronate and ibandronate in premenopausal and postmenopausal women with stage I to III breast cancer receiving standard adjuvant systemic therapy.

In summary, breast cancer patients on AI therapy, and those who undergo premature menopause due to chemotherapy, experience accelerated bone loss and are at increased risk for osteoporosis and bone fracture. BMD in these patients should be monitored with serial DEXA scans, and treatment should be considered for women with a T-score less than –2.0 or additional risk factors for fracture. Both oral and IV bisphosphonates have been shown to mitigate bone loss associated with cancer therapy, and data also suggest that these agents may protect against recurrence. Recently closed and currently accruing clinical trials will help to further elucidate the effect of bisphosphonates on recurrence of breast cancer.

Bone Health in Prostate Cancer Prostate cancer is the most common malignancy among men in the United States.1 Prostate cancer growth is driven by endogenous androgens, and thus androgen deprivation therapy (ADT), by either surgical orchiectomy or administration of GnRH agonists is commonly used for this disease. ADT lowers testosterone levels, leading to the desired therapeutic effect, but because estradiol is produced from testosterone via aromatase activity, ADT also reduces estradiol levels. A number of studies have shown that men treated with ADT for prostate cancer exhibit accelerated bone loss.33-37 A Medicare claims-based study evaluated the relationship between GnRH agonist use and fracture risk, and found that GnRH agonist use was associated with a faster time to fracture and a significantly increased risk for hip, femur, and vertebral fractures.37 Similarly, a SEER (Surveillance, Epidemiology and End Results) study, which included 50,000 men with prostate cancer, showed that men treated with ADT had an approximately 7% higher absolute rate of fractures compared with men who did not receive ADT; there also was a statistically significant association between the number of doses of GnRH agonist and fracture risk.36 A number of therapeutic agents have been evaluated for the prevention of ADT-associated bone loss. In a

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Educational Review randomized study of pamidronate in men receiving ADT for prostate cancer, pamidronate-treated patients had no significant change in BMD, whereas untreated patients had a decrease in BMD.38 In one study evaluating zoledronic acid given every 3 months, mean lumbar spine density improved by 5.6% in patients treated with zoledronic acid, and decreased by 2.2% in placebo patients.39 In a study evaluating a single yearly dose of zoledronic acid, lumbar spine and hip BMD increased by 4.0% and 0.7%, respectively, in men receiving zoledronic acid, and decreased by 3.1% and 1.9% in the placebo arm.40 One study has evaluated oral alendronate in patients with nonmetastatic prostate cancer who were receiving ADT; this study showed a 3.7% increase in BMD in men receiving weekly oral therapy for 1 year.41 Although there are no studies examining the effect of bisphosphonate therapy on fracture risk, these data provide evidence that treatment can effectively reduce bone loss in men receiving ADT for prostate cancer. However, the optimal agent and dosing schedule have yet to be defined. Numerous other agents have been evaluated in the setting of ADT-induced bone loss, including raloxifene (Evista, Lilly), a selective estrogen receptor modulator (SERM) that is approved for treatment and prevention of osteoporosis in postmenopausal women,42 and toremifene (Fareston, Shire), a SERM approved for treatment of advanced breast cancer.43,44 Additionally, several trials evaluating the role of denosumab for both prevention of bone loss and treatment of bone metastases are expected to report results in the next several years.

In conclusion, ADT for prostate cancer can result in significant morbidity associated with bone loss and increased risk for fracture. Strategies to reduce morbidity include patient education, lifestyle modifications such as weight-bearing exercises, supplementation with calcium and vitamin D, screening for osteoporosis, and when appropriate, medical intervention to mitigate ADT-induced bone loss. Future trials will help to establish evidencebased guidelines for prevention of osteoporotic fracture in prostate cancer survivors.

swallowing the medication with 180 to 240 mL of water on arising in the morning, remaining upright for at least 30 minutes after swallowing the tablet and until the first food of the day has been ingested, and discontinuing the drug promptly if esophageal symptoms develop.45 IV bisphosphonates can cause renal toxicity and thus are generally not recommended for use in patients with creatinine clearance less than 30 mL per minute.46 The risk for renal toxicity is likely related to dose, infusion rate, and hydration.

Osteonecrosis of the jaw (ONJ) has recently emerged as a complication of bisphosphonate treatment.

The incidence of ONJ appears highest in patients receiving monthly IV bisphosphonates for the treatment of bone metastases.47 However, ONJ also has been reported in trials of bisphosphonates in the adjuvant setting48 and rarely, in patients taking oral bisphosphonates.49 Dental extraction appears to be the strongest risk factor for ONJ in bisphosphonate-treated patients; thus, dental examination and prophylactic

measures should be performed prior to initiating therapy, and invasive oral surgery should be approached with caution during bisphosphonate treatment.50

Bone Metastases Normal bone homeostasis is maintained by a balance of osteoblastic and osteoclastic activity.

Metastatic bone disease associated with breast cancer is often predominantly osteolytic, whereas bony lesions due to prostate cancer

•

see BONE CONTINUUM, page 20

Coming soon from Cadence Pharmaceuticals—

IV acetaminophen

Bisphosphonate Toxicities Oral bisphosphonates can cause mucosal irritation of the upper gastrointestinal tract, leading to esophagitis or esophageal ulceration. Recommendations to reduce the risk for esophagitis include © 2009 Cadence Pharmaceuticals, Inc

9/09

CAD1001

Printed in USA

www.cadencepharm.com

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&#x201E;˘) 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

For more information on the E.A.S.E. Program, contact Adolor Corporation at 1.866.4ADOLOR (1.866.423.6567) or visit www.entereg.com.

The first and only FDA-approved agent indicated to accelerate the time to upper and lower gastrointestinal (GI) recovery following partial large or small bowel resection surgery with primary anastomosis

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

20 Clinical

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BONE CONTINUUM continued from page 17

are generally osteoblastic. However, bone metastases are frequently heterogeneous, with histologic evidence of both osteolytic and osteoblastic features.51 Patients with bone metastases are at risk for skeletal-related events (SREs), which include fracture, need for radiation to bone, spinal cord compromise, hypercalcemia, or surgery. In a study conducted in the United Kingdom, SREs

accounted for 63% of hospital costs for patients with metastatic breast cancer.52 In addition, bone metastases often cause significant pain, with attendant negative effects on quality of life. Figure 2 illustrates the prevalence of SREs in patients with metastatic bone disease not treated with bisphosphonates.53-56 The mainstay of oncologic care for bone metastases is control of tumor burden, which typically involves chemotherapy and/or hormone therapy. Surgery and radiation also can be used for local control of specific

bony lesions. Bisphosphonates commonly are used as systemic therapy for patients with bony involvement of metastatic cancer.

In clinical trials in breast cancer patients, pamidronate and zoledronic acid have been shown to reduce the frequency of skeletal morbidity.

In a placebo-controlled trial in breast cancer, pamidronate increased the time to skeletal complications (12.7 vs 7 months; P<0.0001) and reduced the incidence of SREs (51% vs 64%; P<0.001). 55 In a trial of patients with metastatic breast cancer and

in vitro

In vitro

[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. Š 2009 Adolor Corporation. All rights reserved. Printed in USA. ETG249R0 December 2009

multiple myeloma, zoledronic acid appeared to be at least as effective as pamidronate.57 The overall incidence of hypercalcemia and the median time to first SRE were similar with the 2 agents. In contrast, the percentage of patients requiring radiotherapy to the bone was lower in patients treated with zoledronic acid (19% vs 24%; P=0.037), and the overall incidence of skeletal complications was 16% lower with zoledronic acid (P=0.030).

The American Society for Clinical Oncology clinical practice guidelines for breast cancer suggest that patients with radiographic evidence of bone metastases should receive therapy with either zoledronic acid or pamidronate at 3- to 4-week intervals.58 In some countries, oral therapy with either clodronate or ibandronate is also an approved therapeutic option.

An estimated 65% to 75% of patients with advanced prostate cancer experience an SRE and their median 5-year survival is 25%. 52 Although bone metastases in prostate cancer are primarily osteoblastic, studies show that bone resorption also is elevated in prostate cancer, suggesting substantial osteoclastic activity.

Clodronate and pamidronate have been studied in the setting of metastatic prostate cancer, with disappointing results. Clodronate treatment did not improve pain relief or quality of life in 2 placebo-controlled trials,59,60 and pamidronate was not more effective than placebo for pain control or reduction of SREs.61 Zoledronic acid is the only bisphosphonate with proven clinical benefit in reducing skeletal complications in men with hormone-refractory prostate cancer. In a Phase III placebo-controlled trial, zoledronic acid reduced the incidence of skeletal complications (44.2% vs 33.2%; P=0.021) and delayed the onset of first SRE.62 In addition, decreases were seen in fracture, spinal cord compression, antineoplastic therapy, and need for radiation therapy and surgery in patients receiving zoledronic acid compared with placebo. In a randomized, placebocontrolled trial of zoledronic acid in patients with bone metastases from lung cancer or other solid tumors, zoledronic acid reduced the rate of SREs (HR, 0.732; P=0.017) and significantly increased the time to first SRE.63 The optimal duration and dosing interval for bisphosphonate therapy in the metastatic setting is not well defined. ASCO guidelines recommend continuing bisphosphonate

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Pharmacy Practice News • February 2010

Educational Review therapy indefinitely or until there is a substantial decline in the patient’s performance status.58 The consensus of the National Comprehensive Cancer Network task force is that the decision to continue bisphosphonate therapy should be reconsidered at 2 years, and that discontinuation should be considered in patients who have no active disease or who have experienced a significant deterioration in renal function. 9 Two ongoing clinical trials, OPTIMIZE 2 and CALGB 70604, are evaluating optimal dosing intervals in women with metastatic breast cancer, either up front or after a year of monthly dosing. A third trial, BISMARK (Costeffective use of BISphosphonates in metastatic bone disease: a comparison of bone MARKer directed zoledronic acid), is evaluating the use of bone resorption markers to determine dosing intervals versus standard monthly dosing.

Emerging Therapies Within the bone microenvironment, RANKL secretion by stromal cells and osteoblasts is stimulated by tumor cells, resulting in increased osteoclast differentiation, function, and survival.64 Results of a Phase III trial comparing denosumab to zoledronic acid in 2,046 women with metastatic breast cancer to bone were reported in September 2009 at the European Society of Medical Oncology meeting.65 Patients were randomly assigned to subcutaneous denosumab or IV zoledronic acid on a monthly schedule. Denosumab significantly delayed the time to first and subsequent on-study SRE (P=0.001). Adverse events due to toxicity were similar in the 2 groups.

Although overall toxicities were similar, the incidence of ONJ was numerically, but not statistically, higher in denosumab-treated patients than in zoledronic acid–treated patients (2% vs 1.4%). In a second Phase III trial of denosumab versus zoledronic acid in patients with solid tumors (not including breast or prostate) or multiple myeloma, the median time to first SRE was 20.6 months for patients receiving denosumab and 16.3 months for patients receiving zoledronic acid (HR, 0.84; 95% CI, 0.71-0.98).66 This result was statistically significant for noninferiority (P=0.0007). Table 3 summarizes data from these 2 trials. Another trial, of zoledronic acid versus denosumab in metastatic prostate cancer, has yet to be reported.

Although the widespread use of bisphosphonates has resulted in a decrease in the incidence of SREs, complications of bone

metastases, including pain, fracture, and decreased mobility, can have a significant impact on quality of life.

Localized therapies, including radiation and surgery, can be used for palliation and for prevention of an impending event. Radiation therapy results in response rates from 60% to 70%, and can provide complete pain relief in up to 30% of patients.67,68 Surgical management can relieve pain, provide stabilization, and prevent impending fracture or cord compression. General criteria for lesions with high risk for

fracture include lytic lesions greater than 2.5 cm, lesions encompassing more than 50% of the bone diameter, or the presence of lesser trochanter avulsion. Surgery also can be considered for impending fractures that include a lesion in a weight-bearing area and for readily identifiable painful lesions that are refractory to external beam radiation therapy.9

Conclusion Bone health is an increasingly important issue for cancer patients and their health care providers. An

understanding of factors associated with cancer therapy-induced bone loss and its treatment are essential to providing quality care to cancer survivors. Strategies to reduce morbidity include education, lifestyle modifications, calcium and vitamin D supplementation, screening for osteoporosis, and when appropriate, initiation of drug therapy. For patients on bisphosphonate therapy, careful monitoring for side effects is essential. Emerging data suggest that in addition to effectively treating

•

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BONE CONTINUUM continued from page 21

cancer therapy-induced bone loss, bisphosphonates may impact risk for recurrence in patients with early-stage breast cancer.

Bone metastases are common in a number of solid tumors and in patients with multiple myeloma. In patients with documented bone metastases, SREs lead to significant morbidity and adversely affect quality of life. Treatment should consist of a multidisciplinary approach,

including systemic anticancer therapy, osteoclast-targeted therapy such as bisphosphonates, pain control, and possibly surgery and radiation for local control. Emerging strategies, including novel bone-targeted agents such as denosumab, are being evaluated and may contribute to the management of patients with metastatic bone disease.

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Clin Cancer Res. 2006;12(20 Pt 2): 6243s-6249s, PMID: 17062708.

6. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. 1994;9(8):1137-1141, PMID: 7976495.

3. Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Br J Cancer. 1987;55(1):61-66, PMID: 3814476.

7. Marshall D, Johnell O, Wedel H. Metaanalysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312(7041):1254-1259, PMID: 8634613.

4. Fan K, Peng CF. Predicting the probability of bone metastasis through histological grading of prostate carcinoma: a retrospective correlative analysis of 81 autopsy cases with antemortem transurethral resection specimen. J Urol.

1983;130(4):708-711, PMID: 6350620.

5. Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci. 2006;1092:385-396, PMID: 17308163.

8. World Health Organization. FRAX WHO Fracture Risk Assessment Tool. http://www. shef.ac.uk/FRAX/. Accessed November 9, 2009.

9. Gralow JR, Biermann JS, Farooki A, et al.

NCCN Task Force Report: Bone Health in Cancer Care. J Natl Compr Canc Netw.

2009;7(suppl 3):S1-S32; quiz S33-S35 PMID: 19555589.

10. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081-1092, PMID: 15014181.

11. Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol.

2008;9(1):45-53, PMID: 18083636.

12. Thurlimann B, Keshaviah A, Coates AS, et al.

A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353(26):27472757, PMID: 16382061.

13. Goss PE, Ingle JN, Martino S, et al.

A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349(19):17931802, PMID: 14551341.

14. Eastell R, Adams JE, Coleman RE, et al.

Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol. 2008;26(7):10511057, PMID: 183009940.

15. Van Poznak C, Hannon R, Clack G, et al.

Managing cancer treatment-induced bone loss: 24-month results from the Study of Anastrozole with the Bisphosphonate Risedronate (SABRE). Cancer Res. 2009;69: Abstract 1137.

16. Lester J, Dodwell D, Purohit OP, et al. Use of monthly oral ibandronate to prevent anastrozole-induced bone loss during adjuvant treatment for breast cancer: twoyear results from the ARIBON study. J Clin Oncol. 2008;26(15 suppl): Abstract 554.

17. Brufsky A, Bundred N, Coleman R, et al.

Integrated analysis of zoledronic acid for prevention of aromatase inhibitorassociated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist.

2008;13(5):503-514, PMID: 18515735.

18. Ellis GK, Bone HG, Chlebowski R, et al.

Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol.

2008;26(30):4875-4882, PMID: 18725648.

19. Burstein HJ, Winer EP. Primary care for survivors of breast cancer. N Engl J Med. 2000;343(15):1086-1094, PMID: 11027744.

20. Fornier MN, Modi S, Panageas KS, Norton L, Hudis C. Incidence of chemotherapyinduced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer. 2005;104(8):1575-1579.

PMID: 16134178.

21. Pfeilschifter J, Diel IJ. Osteoporosis due to cancer treatment: pathogenesis and management. J Clin Oncol.

2000;18(7):1570-1593, PMID: 10735906.

Clinical 23

Pharmacy Practice News • February 2010

Educational Review 22. Goodwin PJ, Ennis M, Pritchard KI, Trudeau M, Hood N. Risk of menopause during the first year after breast cancer diagnosis.

J Clin Oncol. 1999;17(8):2365-2370, PMID: 10561298.

23. Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol.

2001;19(14):3306-3311, PMID: 11454877.

24. Delmas PD, Balena R, Confravreux E, Hardouin C, Hardy P, Bremond A. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study.

J Clin Oncol. 1997;15(3):955-962, PMID: 9060533.

25. Saarto T, Blomqvist C, Valimaki M, Makela P, Sarna S, Elomaa I. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol. 1997;15(4):1341-1347, PMID: 9193325.

26. Shapiro CL HS, Gibson G, Weckstein DJ, et al. Effect of zoledronic acid (ZA) on bone mineral density (BMD) in premenopausal women who develop ovarian failure (OF) due to adjuvant chemotherapy (AdC): first results from CALGB trial 79809. J Clin Oncol. 2008;26: Abstract 512.

27. Gnant MF, Mlineritsch B, LuschinEbengreuth G, et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormoneresponsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2007;25(7):820828, PMID: 17159195.

28. Daubine F, Le Gall C, Gasser J, Green J, Clezardin P. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst.

2007;99(4):322-330, PMID: 17312309.

29. Santini D, Vincenzi B, Galluzzo S, et al.

Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res. 2007;13(15 Pt 1):4482-4486, PMID: 17671133.

30. Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol. 2001;19(1):1017, PMID: 11134190.

31. Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer.

2007;96(12):1796-1801, PMID: 17325699.

32. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360(7):679-691, PMID: 19213681.

33. Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation

therapy for prostate cancer. J Urol.

2000;163(1):181-186, PMID: 10604342.

34. Diamond T, Campbell J, Bryant C, Lynch W. The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer. 1998;83(8):1561-1566, PMID: 9781950.

35. Maillefert JF, Sibilia J, Michel F, Saussine C, Javier RM, Tavernier C. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol.

1999;161(4):1219-1222, PMID: 100818873.

36. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer.

N Engl J Med. 2005;352(2):154-164, PMID: 15647578.

37. Smith MR, Lee WC, Brandman J, Wang Q, Botteman M, Pashos CL. Gonadotropinreleasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol. 2005;23(31):7897-7903, PMID: 16258089.

38. Smith MR, McGovern FJ, Zietman AL, et al.

Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med. 2001;345(13):948955, PMID: 11575286.

39. Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol.

2003;169(6):2008-2012, PMID: 12771706.

40. Michaelson MD, Kaufman DS, Lee H, et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropinreleasing hormone agonist-induced bone loss in men with prostate cancer.

J Clin Oncol. 2007;25(9):1038-1042, PMID: 17369566.

41. Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. 2007;146(6):416-424, PMID: 17371886.

42. Smith MR, Fallon MA, Lee H, Finkelstein JS. Raloxifene to prevent gonadotropinreleasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89(8):3841-3846, PMID: 15292315.

43. Smith MR, Malkowicz SB, Chu F, et al.

Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. J Urol. 2008;179(1):152-155, PMID: 18001802.

44. Smith MR, Malkowicz SB, Chu F, et al.

Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study. J Clin Oncol.

2008;26(11):1824-1829, PMID: 18398147.

45. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med. 1996;335(14):1016-1021, PMID: 8793925.

46. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med. 2003;349(17):1676-1679; PMID: 14573746.

47. Van Poznak C, Estilo C. Osteonecrosis of the jaw in cancer patients receiving IV bisphosphonates. Oncology (Williston Park). 2006;20(9):1053-1062; discussion 1065-1056, PMID: 16986349.

48. Coleman R TH, Cameron D, Bell R, et al.

Zoledronic acid is well tolerated and can be safely administered with adjuvant chemotherapy—first safety data from the AZURE trial (BIG01/04). Br Ca Res Treat.

2006;100(suppl 1): Abstract 2080.

49. King AE, Umland EM. Osteonecrosis of the jaw in patients receiving intravenous or oral bisphosphonates. Pharmacotherapy.

2008;28(5):667-677, PMID: 18447663.

50. Weitzman R, Sauter N, Eriksen EF, et al.

Critical review: updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients—May 2006. Crit Rev Oncol Hematol. 2007;62(2):148-152, PMID: 17336086.

51. Guise TA, Mohammad KS, Clines G, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006;12 (20 Pt 2):6213s-6216s, PMID: 17062703.

52. Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(8 suppl):1588-1594, PMID: 9362426.

53. Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol. 1998;16(2):593602, PMID: 9469347.

54. Body JJ, Diel IJ, Bell R, et al. Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer.

Pain. 2004;111(3):306-312, PMID: 15363874.

55. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebocontrolled trials. Cancer. 2000;88(5):10821090, PMID: 10699899.

56. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, doubleblind, placebo-controlled trial. Cancer.

2004;100(12):2613-2621, PMID: 15197804.

57. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer.

2003;98(8):1735-1744, PMID: 14534891.

58. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol.

2003;21(21):4042-4057, PMID: 12963702.

59. Dearnaley DP, Sydes MR, Mason MD, et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst. 2003;95(17):13001311, PMID: 12953084.

60. Ernst DS, Tannock IF, Winquist EW, et al.

Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/ prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol. 2003;21(17):3335-3342, PMID: 12947070.

61. Small EJ, Smith MR, Seaman JJ, Petrone S, Kowalski MO. Combined analysis of two multicenter, randomized, placebocontrolled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol.

2003;21(23):4277-4284, PMID: 14581438.

62. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormonerefractory metastatic prostate carcinoma.

J Natl Cancer Inst. 2002;94(19):1458-1468, PMID: 123559855.

63. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial— the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol.

2003;21(16):3150-3157, PMID: 12915606.

64. Lipton A, Steger GG, Figueroa J, et al.

Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancerrelated bone metastases. J Clin Oncol.

2007;25(28):4431-4437, PMID: 17785705.

65. Stopeck A, Body JJ, Fujiwara Y, et al.

Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Can Suppl. 2009;7(3): Abstract 2LBA. 66. Henry D, von Moos R, Vadhan-Raj S, et al. A double-blind, randomized study of denosumab versus zoledronic acid for the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Eur J Can Suppl. 2009;7(3);11. Abstract 20LBA. 67. Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007;25(11):1423-1436, PMID: 17416863.

68. Wu JS, Wong R, Johnston M, Bezjak A, Whelan T. Meta-analysis of dosefractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys. 2003;55(3):594605, PMID: 12573746.

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Hem/Onc Pharmacy 25

Pharmacy Practice News • February 2010

In Focus

FCR Solidified as Standard of Care for CLL

FCR FC

Harvard Medical School, both in Boston.

“But now with the OS benefit, it is that much more convincing. OS benefits are hard to come by in indolent diseases.”

The study, conducted by the German CLL Study Group, involved 817 patients with previously untreated but advanced CLL who were randomized to six courses of FC or FCR. Overall survival three years post-randomization was 87.2% in patients receiving FCR and 82.5% in patients receiving FC (P=0.012; Figure).

As of June 2009, the median observation time was 37.7 months and at this time point, OS was 84.1% in the FCR arm compared with 79% in the FC arm (P=0.01). Only patients in Binet stages A and B showed a superior OS after FCR treatment (Binet A: hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.023-1.613; P=0.09; Binet B: HR, 0.45; 95% CI, 0.296-0.689; P<0.001; Binet C: HR, 1.4; 95% CI, 0.843-2.620; P=0.168). The median OS has not been reached in either arm.

The median PFS was 51.8 months in the FCR arm and 32.8 months in the FC arm, according to the researchers.

The investigators say that the partial failure to demonstrate a benefit for FCR in Binet stage C patients may be related to insufficient treatment intensity in

these patients with higher tumor load.

Patients in Binet stages A and B received more treatment cycles (5.31) than Binet C patients (4.52; P<0.001). Only 57.1% (FC) and 60.3% (FCR) of patients with Binet C stage CLL received six cycles.

The investigators concluded that the presence of a deletion of 17p, FC versus FCR therapy, and an elevated serum β2-microglobulin level were the strongest predictors for treatment failure.

Results from the trial reveal that clinicians may have a new way of personalizing therapy for patients with CLL. “We are starting to see a way of personalizing therapy,” Dr. Hallek said.

“FCR is particularly effective in some genetically defined subgroups such as deletions of 11q, deletions of 13q and trisomy 12. FCR is not effective to prevent early relapse and death of patients with deletions of 17p.”

In the study, the doses of fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2), administered on days 1 and 3 of each 28-day cycle, were the same in both study arms. In the FCR arm, rituximab was administered in a dose of 375 mg/m2 on day 0 of the first cycle and then in a dose of 500 mg/m2 on day 1 of the five subsequent cycles.

Both treatment arms were well bal-

NEW STANDARD

same regimen with thalidomide substituted for melphalan (VTP). Both therapies were administered in six cycles, with each cycle lasting six weeks.

Both induction regimens were highly active, producing objective response rates of 80% for VMP and 81% for VTP, which did not differ significantly. However, the side-effect profiles were different, with more neutropenia (39% vs.

22%; P=0.008) and more thrombocytopenia (27% vs. 12%; P=0.001) for VMP, but more cardiac events (8% vs. 0; P=0.001) for VTP. Discontinuations due to serious side effects were significantly more common for VTP (17% vs. 11%; P=0.03).

After completing the six cycles of treatment, patients were randomized a second time. They received maintenance therapy with either VT or bortezomib and prednisone (VP). Thalidomide (50 mg) and prednisone (50 mg) were administered daily. The 1.3 mg/m2 dose of bortezomib, which was the same dose used in the induction regimen, was administered on days 1, 4, 8 and 11 of an every-three-month cycle. The maintenance regimen was continued for up to three years.

In the 178 patients who could be evaluated in the maintenance portion of the study, a CR or near CR was achieved in 59% of those on VT maintenance and 55% of those on VP maintenance,

which was nearly a doubling of the CR rates achieved at the end of induction in either treatment arm. Both maintenance regimens were well tolerated with very modest differences in the types of side effects; 5% of those on VP and 7% of those on VT discontinued therapy because of side effects.

continued from page 1

overcome the poor prognosis of highrisk cytogenetics,” said Maria-Victoria Mateos, MD, PhD, Hospital Universitario Salamanca, in Salamanca, Spain.

Presenting the results at the annual meeting of the American Society of Hematology, Dr. Mateos said that survival data so far have been almost identical between high- and low-risk patients. Importantly for a patient population in which the goal is to prolong survival rather than eradicate cancer, both the induction and maintenance regimens were well tolerated.

The primary objective of the induction portion of the trial, which compared the rates of objective response, was to identify whether the immunomodulator melphalan or the alkylating agent thalidomide was a better partner for bortezomib and prednisone (VP).

The primary objective of the maintenance portion of the study, which compared CR rates, was to evaluate whether the depth of response from induction could be improved with maintenance.

PFS, tolerability and overall safety were important secondary objectives.

In the study, 260 patients aged over 65 years with newly diagnosed MM were randomized to VMP or to the

Cytogenic Abnormalities Tied To Stronger Response One of the most remarkable findings of both the induction and maintenance portions of the study was a 29% CR rate in patients with the cytogenetic abnormalities of t(4;14), t(4;16) and del 17p. This was actually greater, although not significantly so, than the 23% CR rate in patients with normal cytogenetics.

Similarly, the rate of immunofixationnegative complete response (CRIF–) after initiating maintenance therapy was relatively high and not significantly different in patients with abnormal versus normal cytogenetics (38% vs. 42%, respectively).

Despite similar efficacy of the different regimens in the two phases of the study, VMP/VT, which produced a 60% improvement in PFS (P=0.008) compared with VTP/VP was identified as the preferred sequence. This relative advantage is likely to have been driven by the lower discontinuation rate on

Overall Survival, %

100

New Orleans—The addition of rituximab to cyclophosphamide and fludarabine (FCR) improves overall survival (OS) in patients with advanced chronic lymphocytic leukemia (CLL), according to a new analysis from a German study.

“This is the first time a randomized trial has shown that a choice of a specific first-line treatment for CLL could improve overall survival,” said Michael Hallek, MD, University of Cologne in Germany, presenting the study at the recent annual meeting of the American Society of Hematology.

Added to earlier data showing response and progression-free survival (PFS) benefits, the new data solidifies FCR as a first-line treatment for CLL. Based on that initial data, presented at the December 2008 ASH meeting, the German team deemed FCR as a new standard of care after finding that adding rituximab to FC nearly doubled complete response rates and lengthened PFS by 10 months.

Results from the earlier trial were “probably practice changing last year, with the benefit in PFS reported then,” said Jennifer Brown, MD, attending physician with the CLL & Lymphoma Program, Dana-Farber Cancer Institute, and an assistant professor of medicine at

87.2

82.5

80 60 40 20 0

Figure. Overall survival at three years.

FC, cyclophosphamide and fludarabine; FCR, rituximab, cyclophosphamide and fludarabine

‘OS benefits are hard to come by in indolent diseases.’

—Jennifer Brown, MD

anced with regard to sex, age, stage, genomic aberrations and immunoglobulin variable heavy chain (IgVH) gene status. The median age was 61 years.

More hematologic adverse events, particularly neutropenia, were observed with FCR treatment, but this did not result in an increased infection rate.

—Kate O’Rourke

VMP than on VTP during induction and by the greater PFS on VT than on VP during maintenance (not yet reached on VT and 23 months on VP [P=0.05]).

Study ‘Heralds a New Era’ For Nonresponsive Patients According to Donna M. Weber, MD, associate professor in the Department of Lymphoma and Myeloma at the University of Texas M.D. Anderson Cancer Center, Houston, this trial is the first large randomized study to investigate the value of maintenance therapy in previously untreated, elderly MM patients who did not proceed to stem cell transplantation (SCT). She suggested that the study “heralds a new era” in the effort to identify how to improve regimens in patients who are not candidates for SCT. In particular, she was impressed with the apparent ability of bortezomib to eliminate the disadvantage of certain abnormal cytogenetics. Similar to studies that tested other regimens in this patient population, the new study is limited in that it did not demonstrate an overall survival advantage. The PFS data, however, are encouraging, Dr. Weber said, and an overall survival benefit may become more apparent as the data mature.

—Ted Bosworth

26

Hem/Onc Pharmacy

Pharmacy Practice News • February 2010

In Focus Istodax for Patients With Cutaneous T-cell Lymphoma

T

he FDA has approved romidepsin (Istodax, Gloucester Pharmaceuticals) for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Approval was based on overall response rate (ORR), defined as the proportion of patients with confirmed complete response (CR) or partial response (PR).

The FDA granted approval of the histone deacetylase inhibitor based on results from two prospective, multicenter, single-arm clinical studies in

patients with CTCL. The ORRs in these two trials were similar (34% in the first study and 35% in the second study,

respectively) and CR rates were the same (6%). Median response duration was 15 months (range, one to more than 20 months) in the first study and 11 months (range, one to more than 66 months) in the second study.

Median time to first response was two months (range, one to six months) in both studies. Median time to CR was six months in the first study and four months in the second study (range, two to nine months). The most common adverse reactions were nausea, fatigue, anemia, infections, electrocardiographic T-wave changes, neutropenia, lymphopenia, thrombocytopenia, vomiting and anorexia.

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This product has a boxed warning relating to proarrhythmic effects including potentially fatal arrhythmias (e.g., polymorphic ventricular tachycardia) and consideration for use in patients with chronic atrial fibrillation.

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Amgen Assist™ and Amgen Inc. do not guarantee success in obtaining reimbursement. Third party payment for medical products and services is affected by numerous factors, not all of which can be anticipated or resolved by our Amgen Assist™ staff. ©Amgen. All rights reserved. MC48319 11/09

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“These unit-dose launches are part of an ongoing commitment to support health systems’ vital patient safety and bar coding initiatives,” AHP stated in a press release. “All of the unit-dose items are bar coded to the dose level and are [stability-tested] to support extended shelf life. In addition, our packages feature color-coded labels and ‘tall man’ lettering to more easily distinguish products when selecting them for dispensing.”

For more information, visit www.healthpack.com

Clinical 27

Pharmacy Practice News • February 2010

Pain Medicine

Genetics of Opioid Prescribing: Many Questions, Few Answers R

ecently, the son of Gavril Pasternak, MD, underwent surgery to repair a torn anterior cruciate ligament in his knee. Following the repair, he was prescribed Percocet (Endo), which contains oxycodone and acetaminophen (APAP), and which worked well to control the pain. But when he went to refill the prescription, he was given Vicodin (Abbott) a combination of hydrocodone and APAP. Vicodin is almost identical in chemical structure to Percocet. Both drugs are combinations of an opioid and APAP, with a difference of just two atoms.

When Vicodin didn’t work to control the postoperative pain, Dr. Pasternak’s son returned to the physician and got the original drug, Percocet, which worked “like a charm,” said Dr. Pasternak, who heads the Laboratory of Molecular Neuropharmacology and also serves on the neurology and palliative care services at Memorial Sloan-Kettering Cancer Center in New York City.

“That was a difference of only a simple hydroxyl group in the whole molecule,” he said. “These compounds were extraordinarily similar, and yet one worked and one didn’t.”

The problem is familiar to any clinician who prescribes opioids for pain.

One drug works well for a patient, but another from the same class doesn’t; or a “standard dose” of morphine controls pain well in one patient, but not in another patient.

In animal studies, the difference in responsiveness to morphine between individuals can be as high as 10-fold.

Although it is difficult to get an exact figure, Dr. Pasternak said that a relatively similar number would not be unlikely in humans.

A study that looked at 3,200 patients recovering from back surgery found that some patients required as much as 40 times more morphine than patients at the lowest end of the range.

However, “the issue is not efficacy,” said Charles Inturrisi, PhD, a professor of pharmacology at Weill Cornell Medical College in New York City. “We know opioids as a function of dose can relieve pain regardless of the source; rather, it is opioid responsiveness that exhibits wide variability.”

One of the unique features of opioid therapy is that, unlike most drugs, clinical experience far outweighs the understanding of how these drugs actually work. As an analgesic, opioid use dates back thousands of years.

“We don’t really appreciate the subtleties of these drug actions,” said Dr. Pasternak. “The pharmacology of the opiates is upside down. We are still using the same drugs we were using 100 years ago in some cases … we know more in

the clinical setting than we know in the preclinical.”

A Boom Phase or a “Lot of Hype”?

Essentially working backward, investigators are beginning to understand some of the factors that contribute to how patients respond to opioids, and it is becoming increasingly clear that genetic variations may play a significant role.

Jeffrey Mogil, PhD, heads the Pain Genetics Lab at McGill University in Montreal, Canada, and has spent 20 years looking at genetics and pain.

“At the start of my career, people used to deny that there was any variability at all,” he said.

“Now of course, everyone not only admits there’s variability, but actually thinks that variability is a problem.”

Of course, not all variability is genetic. Responsiveness to analgesics can be shaped by the source of pain and a patient’s psychological propensity to suffer, as much as by genetically based differences in drug metabolism. Nevertheless, genetic differences probably play a relatively significant role, according to Dr. Mogil.

Some of these differences have been well established. For example, differences in how the CYP2D6 enzyme is expressed can significantly affect how a patient metabolizes certain opioids.

Thus, drugs that require bioactivation to increase their potency—like codeine, for example—can be rendered relatively useless if a person is a poor metabolizer.

At least four other genetic variations have been found to significantly alter the effectiveness of opioids.

One example is mutations that affect P-glycoprotein, a protein that carries molecules, including opioids, across cell membranes. When the enzyme is overexpressed, drugs may be under- absorbed and never reach therapeutic concentrations; conversely, if the enzyme is underexpressed, drug plasma levels could reach toxic levels.

Another is the COMT gene, which makes enzymes that degrade neurotransmitters like dopamine, epinephrine and norepinephrine and has been shown to affect µ-opioid receptor binding.

These mutations were discovered using gene association studies, which puts the field of pain and opioid genetics about where genetic research in psychiatry was 15 years ago—in a boom phase.

“There is a lot of hype, a lot of people doing these studies and a lot of expecta-

tion that these genes are going to pan out,” said Dr. Mogil.

But like gene association studies in other fields, early, promising results in pain genetics haven’t necessarily borne fruit over the longer term.

“One person finds an association, publishes in a big [journal] and then over the next few years, papers start trickling out that say ‘well, we tried it too and didn’t find that association,’” Dr. Mogil said.

G e n o m e -w i d e association studies, which are still prohibitively expensive, would solve the replicability problem, but they do not explain much of the variance seen between individual patients.

One other major advantage with a genome-wide study is the possibility of discovering new receptors involved in pain and opioid metabolism, because it has become increasingly clear that the biology of opioid analgesia is far more complicated than researchers previously have thought.

The Tip of the Genetic Iceberg The µ-opioid receptor gene is a case in point. It was not only “biologically reasonable,” as one study put it, that polymorphisms of the gene would significantly affect opioid response, but it was also well established in both experimental and clinical studies.

In a recent study, Jörn Lötsch, Dr.med, a professor at the Institut für Klinische Pharmakologie in Frankfurt, Germany, genotyped more than 350 patients in several outpatient pain centers; he then followed their opioid dosing regimens and pain scores. Although not significant, patients with variants of the mu receptor gene showed different pain scores and opioid dosages.

As a follow-up, Dr. Lötsch conducted a meta-analysis of the available studies.

“We found no consistent association between OPRM1 118A>G genotypes and most of the phenotypes in a heterogeneous set of eight clinical studies,” he wrote at the time.

When asked which area of genetic research holds the most promise to change how clinicians treat pain, Dr. Lötsch said that a year ago, he would have said the µ-opioid receptor gene.

“Today,” he said, “unfortunately there is no prospective study that has shown that a genetic-guided pain therapy provided a real benefit for the patients.”

Genetic variation does likely play a critical role in the large differences in

patients’ pain and their opioid needs; it’s just that the µ-opioid receptor gene—or any of the others that have already been identified—aren’t responsible for all of it.

“I’m afraid we’re not as close to figuring this out as we thought we were, probably because there are a lot more genes involved than we expected. We were being incredibly naïve to think that the genetic variability of morphine analgesia would all boil down to the mu receptor gene,” Dr. Mogil said.

“That would be a nice, tidy little biological universe, but that’s not the way biology works.

“We are at the tip of the iceberg of finding relevant genes. We’ve found a tiny handful of them. But we have reason to believe that there are 20 or 50 or 180 more to find,” Dr. Mogil said. “And only when we have found a much larger number and have convinced ourselves that we have a reasonable proportion of the variance explained, can we start looking at [clinical applications].”

The ideal application “would be to base a therapy plan—dose and choice of analgesic—on genotyping information,” Dr. Lötsch said. “This works in cancer therapy and for warfarin therapy, but not yet for pain.”

For example, a patient might be genotyped before an operation and the postoperative pain interventions might be based in part on the sum total of the painrelated genetic variations.

Further down the road, a better understanding of the genetics of pain and opioid metabolism could move into other areas, like predicting a patient’s risk for developing painful disease, the clinical course it might run or even a patient’s risk for developing drug addiction.

“I’m simultaneously optimistic and pessimistic,” said Dr. Mogil. “I’m still a believer that in theory, given enough time, we’ll be able to get this information.”

But even if genetic research doesn’t immediately translate into genotyping in the clinic, the explanation of why some patients respond differently to analgesics may still be clinically important.

“The undertreatment of pain, to some degree, is due to the fact that people aren’t educated,” said Dr. Pasternak.

“What happens is that somebody will say, ‘Well, a dose of morphine is 15 mg and this person is asking for more, obviously they’re abusing. They’re not using it right, they’re not responding the way they are supposed to.’”

The genetics themselves aren’t going to give us all the answers, he added, “but what they do is enable us to tell people that are skeptical [of variability], this is why.”

—Gabriel Miller

28 Clinical

Pharmacy Practice News • February 2010

Pain Medicine

NIH Launches Study of Experimental Pain Drug First patients receiving compound for ‘molecular neurosurgery’ fter months of waiting, government researchers have begun a study in patients with terminal cancer of a drug that could revolutionize the treatment of severe chronic pain.

The trial, at the National Institutes of Health, in Bethesda, Md., so far includes only two subjects—so few that officials will not discuss them, except to say that they are suffering from end-stage malignancies that cause them extreme pain that does not respond to conventional analgesics. Indeed, enrolling participants was a significant challenge—one woman who would have been the first agreed to enter the trial several months ago, only to die of her disease before she could receive the therapy.

Under the NIH protocol, patients receive a single intrathecal injection of a molecule called resiniferatoxin (RTX). Extracted and purified from the latex of a Moroccan succulent, this substance selectively targets TRPV1 (transient receptor potential vanilloid type 1) receptors in specialized neurons that are sensitive to heat and inflammation. But unlike conventional pain therapies, RTX does not simply lock up receptors—it kills them.

Although the launch of the study is an important milestone in the evolution of so-called “molecular neurosurgery,” experts said the drug faces daunting obstacles on the road to commercialization. Drugmakers have pumped nearly $1 billion into developing drugs that target TRPV1. Yet most of those trials have been halted, and few compounds remain in the pipeline.

Victims of Their Own Success Ironically, the waning interest is not because the drugs don’t work, but because they appear to work too well, said Michael Iadarola, PhD, chief of the neurobiology and pain therapeutics section of the National Institute of Dental and Craniofacial Research.

Early tests in animals showed that the agents can shut down the pain response to heat. “If it does this effectively in patients, they can become thermally unresponsive—in other words, tolerant to dangerously hot stimuli that can be encountered frequently in daily life,” said Dr. Iadarola, who helped discover the analgesic properties of RTX. “With chronic usage—day in, day out—it could be problematic.”

In addition, companies trying to develop molecules like RTX couldn’t divorce the analgesia from the hyperthermiaproducing actions, and the unpredictable degree of hyperthermia also proved troublesome. “It seems contradictory,

but a treated person could become too hot and, at the same time, insensitive to heat,” Dr. Iadarola said.

Neurotoxins in particular are well known for their ability to muzzle pain signaling. The drug ziconotide (Prialt, Elan), which is derived from the toxin of a lethal sea snail, has been approved since 2004 for the treatment of chronic pain. However, ziconotide, which is delivered intrathecally, differs significantly from RTX in several respects.

Most notably, its effects on pain are temporary while those of RTX appear to be permanent.

The reason involves the two drugs’ mechanisms of action. Ziconotide disrupts signaling in the calcium channels of neurons, blocking the transmission of pain signals across the synapse. As long as the drug is present in adequate amounts, those signals will stall. But RTX acts differently on neurons: Rather than block signaling, it simply kills neurons or their projection to the spinal cord—a highly efficient yet irreversible effect.

Ronald Wiley, MD, PhD, chief of neurology at VA Tennessee Valley Healthcare System, and professor of neurology and pharmacology at Vanderbilt University Medical Center, in Nashville, has been working with substance P-saporin, an irreversible neurotoxin much like RTX but with different targets in the spinal cord.

Studies of substance P-saporin in animal models of neuropathic pain have proved extremely promising, Dr. Wiley said. The compound can block the heightened sensitivity in rodents caused by chronic inflammation or nerve injury.

It appears to reduce the animals’ pain response to injections of formalin into the paw, and it also seems to reduce hypersensitivity to chronic irritation of the sciatic nerve while preserving protective reflex responses to acute pain.

“Every step along the way, the substance P-toxin has performed well, but the amount of money it takes to move it forward each step is so large,” Dr. Wiley said. “We haven’t been able to get Big Pharma interested so far, at least partly because it’s a toxin and it’s irreversible.”

Another potential drawback from a commercial vantage is that treatment with the substance P-toxin likely would require only a few injections, and possibly just a single injection. “You can’t charge an infinite amount of money for a single treatment,” said Dr. Wiley, who co-founded a company, Advanced Targeting Systems, in San Diego, to commercialize the drug.

Penicillins of the Pain World?

The decision to study RTX in humans came after a decade of investigating the drug in a variety of animal models, from rodents to primates. Some of the most impressive data come from trials conducted in dogs with terminal cancer.

Collaborating with a team at the University of Pennsylvania School of Vet- of pharmacology at the University of erinary Medicine, the NIH researchers Arizona in Tucson, has conducted sevfound that a single injection of RTX eral preclinical trials of experimental could provide long-lasting analgesia neurotoxins for treating pain. “I think to the sick animals with no effect on that they could be very useful and have bladder or bowel function or other significant therapeutic promise,” Dr. activities of daily living. Many of the Mantyh said.

Although RTX and substance animals eventually returned home with their owners, although the treat- P-saporin kill cells, he said, related ment did not prevent the dogs from molecules might be able to serve as temporary “stun” agents akin to botudying of cancer.

Penn veterinary medicine researcher linum toxin for situations that call Dorothy Cimino Brown, DVM, MSCE, for less aggressive therapy. “From a led the studies of RTX, as well as sub- physician’s standpoint, if you have a stance P-saporin, in dogs. From what therapy with relatively few side effects she has seen so far, she said, the results and can titrate it over a relatively wide in animals are promising. “Whether range, you have significantly more these two compounds in particular are room to maneuver,” he said. Both of going to take over as the penicillins those issues have beset ziconotide, Dr. of the pain world, I don’t know,” Dr. Mantyh added. The drug has a narBrown said. “But something in here is row dosing range beyond which it can going to float to the top and prove to cause severe psychiatric symptoms and neurologic impairment. As a result, be useful.”

Dr. Brown has conducted trials in dogs ziconotide carries a “black box” warnof RTX infusions for a variety of pain- ing on its label.

For now, said Dr. Wiley, physicians and ful conditions, including bone cancer, arthritis—“elbow problems are a huge patients with chronic pain syndromes problem for dogs; they walk on their simply need progress—quickly. “We do a elbows and people don’t,” she said—and terrible job taking care of them,” he said. oral mucositis resulting from radiation “We don’t have enough safe and effective long-term treatments.” therapy for head and neck cancer.

“I agree,” Dr. Iadarola said. “But we are One intriguing finding, Dr. Brown said, is that the drug appears to trigger solving this problem.”

—Adam Marcus a drop in body temperature in the animals. Paradoxically, however, they wake up panting. “The dogs look like they feel hot but their body temperature is low,” she said. “The dogs pant when we give the RTX in the cerebrospinal fluid close to the brain.

In the current [NIH study] they are targeting distal disease, so they are only injecting in the lumbar area—far enough away from the brain to avoid some of the things that we see in the dogs,” she noted. Figures. X-ray (left) and photograph of dog forelimbs Patrick Mantyh, showing tumors in the radius. Treatment with RTX dramatically reduced the animals’ pain.

PhD, JD, professor

Images courtesy of Dorothy Cimino Brown, DVM, MSCE

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30 Clinical

Pharmacy Practice News • February 2010

Critical Care

New Simulator Program Cuts ICU Infections, Saves Money A

program that teaches health care workers the proper technique to place and maintain catheters sharply reduced the incidence of central line infections in the ICU and yielded a dramatic financial windfall: In cutting the cost to treat the infections by more than half, the program also paid for itself many times over.

The intervention, in which health care workers practice on medical simulators—mannequins—before graduating to live patients, shows that educational offerings can carry their own weight as well as save lives, according to the leader of a new study presented at the 2009 annual meeting of the American Society of Anesthesiologists, in New Orleans.

‘[CMS is] not reimbursing for certain infections that occur once the patient has been in the hospital.’

—Liz Garman “I wish I could say nobody cared about costs, but caring about costs has its benefits, too,” said study leader Amanda Burden, MD, medical director of the Medical Simulation Laboratory at Cooper University Hospital in Camden, N.J. Although the primary outcome was to reduce the number of infections tied to central venous catheters, the researchers were surprised by the financial benefit. In the two years after the program was introduced, the hospital’s estimated cost to treat catheter-related infections was $239,616, 53% lower than it had been in the two years before it began.

The number of infections fell from 49 in the two preintervention years to 26 in the two years after. The mean length of stays at Cooper fell in the ICU (from 5.1 to 4.1 days) and in the hospital in general (from 21.9 to 15.2 days).

Infections related to central line catheters are the third most prevalent type of nosocomial infection in the United States (about 248,000 per year),

according to the Department of Health and Human Services (HHS). These infections kill about 30,000 patients a year, more than any other infection encountered in the hospital. According to the HHS, they also are the costliest to treat, at $36,000 per episode. (At Cooper, the estimated cost was much lower—roughly $18,000 per infection.)

“Central line infections are very, very expensive,” said Liz Garman, director of communications for the Association

for Professionals in Infection Control and Epidemiology.

Last year, new rules took effect in which Medicare no longer pays hospitals for the cost of treating such infections.

“They are not reimbursing for certain infections that occur once the patient has been in the hospital,” Ms. Garman said. “It’s an effort to reduce the overall cost of health. The goal is to incentivize hospitals to do a better job.”

“It’s frustrating when one of our

interventions leads to another problem,” Dr. Burden said. “It’s not the reason the patient was in the hospital to begin with.” Although anesthesiologists, often working in conjunction with pharmacists, “are really the patient safety people,” she said, “it’s a field where, unfortunately, bad things can happen quickly.”

The laboratory moves all health care workers away from the “see one, do one, teach one” method of teaching to one

Myth:Six Sixof ofone oneequals equals Myth: halfdozen dozenof ofthe theother other half

Clinical 31

Pharmacy Practice News • February 2010

Critical Care that stresses “see one, simulate many.”

The program, which is mandatory for nurses and doctors working with catheters, began in 2006 before the new Medicare rules took effect. It involves a four-hour training program on the simulators. “Mannequins create a realistic feeling and a realistic experience for the learner of whatever procedure is happening,” Dr. Burden said. They’re lifelike, they “complain” through simulated infections. “Almost any problem that can happen to a mannequin can happen to a human,” she said.

The procedure calls for the use of

‘If you are going to save [nearly] $250,000, that definitely seems worth a 10% investment.’’

—Amanda Burden, MD

a checklist and an observer who has the power to halt the procedure if any of the required steps are not properly performed. “And we videotape them on everything they do and have them watch what they did. They see what they didn’t hit, and they’re upset; but they don’t cause any harm.”

Whereas the primary goal was to prevent infections, the investigators also looked at the intervention’s impact on associated costs to the hospital. It is not insignificant, Dr. Burden said, because the laboratory is “one of those spaces that isn’t always a great moneymaker because it’s education, and

...dispelledby byscience science ...dispelled For patients receiving Venofer® and an ESA, studies have shown that the Brown or white, nutritionally and functionally, an egg is an egg.

For patients receiving Venofer® and an ESA, studies have shown that the Brown or white, nutritionally and functionally, an egg is an egg.

Just like iron replacement therapy is iron replacement therapy. combination has an additive effect on Hct response, and Just like iron replacement therapy is iron replacement therapy. combination has an additive effect on Hct response, and Or not? While iron in any form is efficacious in replenishing Reality: almost all anemic pre-dialysis patients can reach and Or not? While iron in any form is efficacious in replenishing Reality: ® almost all anemic pre-dialysis patients can reach and hemoglobin (Hb), not all irons perform equally in the maintain the target Hct of 35% over a 1-year hemoglobin (Hb), not all irons perform equally in the (iron maintain OnlyVenofer Venofer® (iron the target Hct of 35% over a 1-year treatment of iron deficiency anemia caused by chronic Only period. 5,6 Another advantage of maintaining treatment of iron deficiency anemia caused by chronic period. 5,6 Another advantage of ® maintaining kidney disease (CKD). adequate iron stores with Venofer® is that a lower sucroseinjection, injection,USP) USP) adequate kidney disease (CKD). iron stores with Venofer is that a lower sucrose dose of ESA may be sufficient to achieve the Avoid the Shell Game dose of ESA may be sufficient to achieve the has a distinctive iron sucrose 5 Avoid the Shell Game , potentially target Hct than if ESA is used alone has a distinctive iron sucrose target Iron deficiency commonly complicates anemia in Hct than if ESA is used alone 5, potentially Iron deficiency commonly complicates anemia in avoiding the incremental costs of ESA therapy. formulawith withefficacy efficacyproven proven avoiding pre-dialysis patients. As many as 25% to 40% of formula the incremental costs of ESA therapy. pre-dialysis patients. As many as 25% to 40% of males and 35% to 85% of females with superior to oral iron in pre-dialysis males and 35% to 85% of females with Notethe theDifferences Differences pre-dialysis anemia show evidence superior to oral iron in pre-dialysis Note pre-dialysis anemia show evidence 2 of iron deficiency.

Oral iron therapy in these and dialysis patients, as well as Venofer® ® contains no dextrans which have 2 of iron deficiency. Oral iron therapy in these and dialysis patients, as well as Venofer contains no dextrans which have patients may not be as effective as IV been associated with antibody-induced patients may not be as effective as IV associated with antibody-induced iron, potentially leading to iron deficient demonstrated safety and tolerability been anaphylaxis. Unlike iron dextran products, iron, potentially leading to iron deficient demonstrated safety and tolerability anaphylaxis.

Unlike iron dextran products, erythropoiesis. Oral iron is unlikely to maintain Venofer® ® does not require a test dose prior erythropoiesis. Oral iron is unlikely to maintain hemodialysispatients patientswith with Venofer does not require a test dose prior target iron indices in erythropoiesis stimulating ininhemodialysis to therapy. And, unlike injectable iron target iron indices in erythropoiesis stimulating to therapy. And, unlike injectable iron agent (ESA)-treated patients due t o t h e a prior intolerance to iron agent (ESA)-treated patients due t o t h e products that contain dextran or a modified resultant increase in red blood cell production, Hb, a prior intolerance to iron products that contain dextran or a modified resultant increase in red blood cell production, Hb, dextran derivative, there is neither a post-dose and hematocrit (Hct). dextran,sodium sodiumferric ferric dextran derivative, there is neither a post-dose and hematocrit (Hct). dextran, observational period nor any resuscitation observational period nor any resuscitation ® 1 In pre-dialysis studies, Venofer was well tolerated and gluconate, or both.1 equipment required for administration of Venofer ®.

In pre-dialysis studies, Venofer ® was well tolerated and equipment required for administration of Venofer ®. more effective than oral iron. A course of therapy gluconate, or both. more effective than oral iron. A course of therapy Most importantly, hemodialysis patients who have increased Hb levels and improved adequacy of iron for Most importantly, hemodialysis patients who have increased Hb levels and improved adequacy of iron for erythropoiesis with fewer gastrointestinal side effects than oral iron. experienced previous intolerance to iron dextran, sodium erythropoiesis with fewer gastrointestinal side effects than oral iron. experienced previous intolerance to iron dextran, sodium ® Only Venofer® ® produced a statistically significant increase in both Hb and ferric gluconate, or both, have been treated successfully with Venofer® Only Venofer 3,4produced a statistically significant increase in both Hb and ferric gluconate, or both, have been treated successfully with Venofer ferritin levels.

7 without serious adverse events.

For pre-dialysis patients with ferritin levels.3,4 without serious adverse events. 7 For pre-dialysis patients with multiple drug allergies, or patients who are starting IV iron therapy for the first OptimizeTherapy Therapy multiple drug allergies, or patients who are starting IV iron therapy for the first Optimize time, Venofer® ® is a proven choice.

Venofer® ® can provide effective anemia management, with or without ESA time, Venofer is a proven choice.

Venofer can provide effective anemia management, with®or without ESA therapy. For patients not on ESA, treatment with Venofer avoids the high In reality, there really are differences between iron preparations, beyond what therapy. For patients not on ESA, treatment with Venofer ® avoids the high In reality, there really are differences between iron preparations, beyond what incidence of gastrointestinal adverse effects frequently associated with oral might be visible at first glance. So look for the right package of efficacy, safety, of efficacy, safety, incidence of gastrointestinal adverse effects frequently associated with oral might be visible at first glance. So look for the right package iron therapy. This may improve patient compliance and thereby improve and tolerability; and when warranted, prescribe Venofer ®. iron therapy. This may improve patient compliance and thereby improve and tolerability; and when warranted, prescribe Venofer ®. treatment success. treatment success. ® IMPORTANT SAFETY INFORMATION: Venofer (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known 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 ® 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 hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving IV iron, reported with IV iron products. Hypotension has been reported frequently in hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving IV iron, and has also been reported in non-dialysis dependent (NDD) and peritoneal dialysis dependent (PDD)-CKD patients receiving IV iron. Hypotension following and has also been reported® in non-dialysis dependent (NDD) and peritoneal dialysis dependent (PDD)-CKD patients receiving IV iron. Hypotension following administration of Venofer may be related to rate of administration and total dose delivered. administration of Venofer® may be related to rate of administration and total dose delivered. ® administration, were In multi-dose efficacy studies in HDD-CKD patients (N=231), the most frequent adverse events (>5%), whether or not related to Venofer werein Inhypotension, multi-dose efficacy studiesnausea, in HDD-CKD patients the most frequent adversehypertension, events (>5%), whether related In to post-marketing Venofer® administration, muscle cramps, headache, graft(N=231), complications, vomiting, dizziness, chest pain, or andnotdiarrhea. safety studies hypotension, muscle cramps, nausea, graft adverse complications, hypertension, pain,toand diarrhea.

In post-marketing safety studiesheart in ® administration, were congestive HDD-CKD patients (N=1051), the headache, most frequent eventsvomiting, reporteddizziness, (>1%), whether or notchest related Venofer ® HDD-CKD patients (N=1051), the most frequent adverse events reported (>1%), whether or not related to Venofer administration, were congestive heart failure, sepsis, and taste disturbance. In multi-dose efficacy studies in NDD-CKD patients (N=91), the most frequent adverse events ( 5%), whether or not related to failure, sepsis, and taste disturbance. multi-dose efficacy studies in NDD-CKD (N=91),nausea, the most frequentand adverse events ( In5%), or not related to ® Venofer administration, were tasteIndisturbance, peripheral edema, diarrhea,patients constipation, dizziness, hypertension. the whether study of PDD-CKD patients ® Venofer were taste events, disturbance, peripheral edema,todiarrhea, constipation, nausea, dizziness, and hypertension.

In theperitoneal study of PDD-CKD patients ® (N=75), administration, the most frequent adverse whether or not related Venofer , reported by 5% of these patients were diarrhea, infection, vomiting, (N=75), the mostpharyngitis, frequent adverse events, whether or not related to Venofer®, reported by 5% of these patients were diarrhea, peritoneal infection, vomiting, hypertension, peripheral edema, and nausea. hypertension, pharyngitis, peripheral edema, and nausea.

Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2009 American Regent, Inc. 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 Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com

Leading anemia management.™ Leading anemia management.™

Please see brief prescribing information and references on following page.

Please see brief prescribing information and references on following page.

Millions prescribed. Millions treated.

Millions prescribed. Millions treated.

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VMvR2 VMvR2 Iss. 11/2009 Iss. 11/2009

education costs money.”

The program cost about $25,000 to implement (the equipment is donated), and the savings were nearly 10 times that amount. “If you’re going to save [nearly] $250,000, that definitely seems worth a 10% investment,” Dr. Burden said. “It’s nice to show that an educational offering more than pays for itself.”

The team now plans to study what steps in the procedure the trainees were most likely to get wrong and how to prevent those errors, she said.

—John Dillon

32 Clinical

Pharmacy Practice News • February 2010

Critical Care

ICU PATIENTS continued from page 1

(2009;169:2078-2086).

“There is far more radiation from medical CT scans than has been recognized previously, in amounts projected to cause tens of thousands of excess cancers annually,” wrote Rita F. Redberg, MD, MSc, of the University of California, San Francisco, and editor of Archives of Internal Medicine, in an editorial accompanying the CT article (2009;169:2049-2050). “Although a guiding principle in medicine is to

ensure that the benefit of a procedure or therapy outweighs the risk, the explosion of CT scans in the past decade has outpaced evidence of their benefit.”

‘You’re talking about a potential risk for cancer 20 to 30 years down the line, but I don’t know if a critically ill patient is going to live until tomorrow.’

—Mannudeep Kalra, MD

The CT Ascendancy For decades, the daily chest x-ray has been standard breakfast fare for patients on ventilators in the ICU. Although many hospitals are moving away from such a practice, it is still not uncommon. CT scans expose patients to significantly more radiation than conventional x-rays, but they provide

more detailed images and have become increasingly popular in the ICU and other settings.

Eduardo Oliveira, MD, chairman of medicine and medical director of the ICU at Cleveland Clinic Florida, in

References: 1. Aronoff GR, Bennett WM, Blumenthal S, et al for the United States Iron Sucrose (Venofer ®) Clinical Trials Group. Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens. Kidney Int. 2004; 66:1193-1198. 2. Hsu CY, McCulloch CE, Curhan GC. Iron status and hemoglobin level in chronic renal insufficiency. J Am Soc Nephrol. 2002;13(11):2728-2786. 3. Charytan C, Qunibi W, Bailie GR, and the Venofer Clinical Studies Group. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis. Nephron Clin Pract. 2005;100(3):c55-c62. 4.

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. 5. Silverberg DS, Blum M, Agbaria Z, Schwartz D, Zubkov A, Yachnin T, et al. Intravenous iron for the treatment of predialysis anemia. Kidney Int. 1999:55(suppl 69);S79-S85. 6. Silverberg DS, Blum M, Agbaria Z, Deutsch V, Irony M, Schwartz D, et al. The effect of i.v. iron alone or in combination with low-dose erythropoietin in the rapid correction of anemia of chronic renal failure in the predialysis period. Clin Nephrol. 2001;55:212-219. 7. Venofer® [package insert]. Shirley, NY: American Regent, Inc. Rev. 10/08.

(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 in 2% of patients by dose Treatment-emergent adverse events reported by 2% of treated patients group are shown in Table 3. with NDD-CKD in the randomized clinical trials, whether or not related to Venofer® administration, are listed by indication in Table 2.

Table 3. Most Common Treatment-Emergent Adverse Events Table 2. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Dose Group Reported in 2% of Patients with NDD-CKD by Clinical Indication (Multidose Safety Population) (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 extravasation Injection site pain Peripheral edema Pyrexia Infections and Infestations Catheter site infection Nasopharyngitis Peritoneal infection Sinusitis NOS Upper respiratory tract infection NOS Urinary 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 Arthritis NOS

NDD-CKD Oral Iron Venofer® (N=139) (N=139) % % 76.3 73.4 2.2

0.7

0

0

1.4 4.3 7.2 7.9 8.6 5.0

2.9 12.9 10.1 0 12.2 8.6

0.7 1.4 6.5 3.6 0 3.6 2.2 2.2 7.2 0.7

2.2 0 6.5 5.8 0 0 0 0 5.0 0.7

0 0.7 0 0.7 0.7 0.7

0 2.2 0 0.7 1.4 5.0

1.4

0

2.2 1.4

2.2 3.6

1.4 2.9 2.9 0.7

0.7 1.4 0 0.7

1.4 0

2.2 0

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

6.7

0

0

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

0

2.8 1.8

0 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

2.2 1.4

4.3 2.2

6.5 2.2

4.3 0.7

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

4.6

3.3

5.5 3.7

10.0 0

0.9 1.8 0

6.7 10.0 0

0.9

6.7

6.4 0.9

6.7 6.7

*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

2.8 2.8

6.7 0

0

6.7

Weston, who led the study, said CT scans in particular have become invaluable in the practice of intensive care medicine. However, Dr. Oliveira said both clinicians and patients need to understand the potential hazards associated with overusing the technology— particularly for younger patients who have more time for cancer to develop.

“In many cases, there are alternatives to CT scans in nonacute circumstances.

You can postpone it, or use more clinical reasoning in your physical exam.

That might guide you not to overuse CT scans,” Dr. Oliveira said.

Dr. Oliveira and colleagues reviewed the medical records of 100 patients at their institution who were on mechanical ventilation for at least 48 hours.

Patients underwent a total of 2,006 x-ray tests and 341 CT scans.

The mean cumulative dose of radiation was 19.4 mSv for women and 13.6 mSv for men, a difference that was statistically insignificant. Patients who stayed in the hospital longer were exposed to greater overall levels of radiation (P<0.01), the researchers said. At the extreme, six patients had total exposures comparable to those experienced by some survivors of the atomic bomb blasts in Japan during World War II—50 to 60 mSv—the researchers said. That level of radiation is approximately 20 times what people typically experience environmentally.

Dr. Oliveira said his institution has

*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 Dosages of Venofer® (iron sucrose injection, USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis. Periodic monitoring 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 [1]. 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: [1] 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.

VMvR2 Iss. 11/2009 © 2008 American Regent, Inc

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Clinical 33

Pharmacy Practice News â&#x20AC;˘ February 2010

Critical Care discussed providing every ICU patient a Geiger counter to monitor their exposure to radiation while in the hospital.

He said he and his colleagues plan to use the counters to conduct a follow-up study to precisely measure exposures on the ward. â&#x20AC;&#x153;I would not doubt that there are physicians who will obtain scans just to make sure that there is nothing wrong, but where the likelihood of having something useful coming from the scan is on the low side,â&#x20AC;? he said.

Mannudeep Kalra, MD, an instructor at Harvard Medical School and assistant radiologist at Massachusetts General Hospital, in Boston, said that while x-rays are six to seven times more common in the hospital, two-thirds of medical radiation exposure in the United States is from CT scans. A typical CT generates about 300 to 500 times more radiation than an x-ray, said Dr. Kalra, who has published nearly 100 papers on radiation dosing and related subjects.

ignored is, whatâ&#x20AC;&#x2122;s the benefit? Youâ&#x20AC;&#x2122;re talking about a potential risk for cancer 20 to 30 years down the line, but I

donâ&#x20AC;&#x2122;t know if a critically ill patient is going to live until tomorrow. If there are fair chances that CT will provide

useful information that can potentially help management or even prognosis of such patients, why should I care about the dose?â&#x20AC;?

However, he said radiologists should expose patients to just enough radiation to produce an image. That starts with making sure the scan is justified. If it is, and CT is warranted, radiologists can adjust the technology to deliver the lowest possible dose, which varies widely depending on the machine. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s not about getting pretty pictures.â&#x20AC;? â&#x20AC;&#x201D;Adam Marcus

V[ F\b_ 6[O\e 2 [Rd`YRaaR_ NYR_a` [\d NcNVYNOYR

Six patients had total exposures comparable to those experienced by some survivors of the atomic bomb blasts in Japan during World War IIâ&#x20AC;&#x201D;50 to 60 mSv. Although no data are available yet to back the impression, experts generally believe that CT scans are becoming more common in the ICU, Dr. Kalra said. Plain radiography in the ICU may not provide the required information due to limited image quality and inherent limitation of a projectional twodimensional image, whereas crosssectional imaging examination such as CT often can provide more valuable information, he said. â&#x20AC;&#x153;Thereâ&#x20AC;&#x2122;s a lot of hoopla about dose,â&#x20AC;? said Dr. Kalra, â&#x20AC;&#x153;and some of it is justified, especially when CT is unlikely to add information or make a difference to patient management or when CT is performed with inappropriately higher radiation dose. But what keeps getting

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GO TO PharmacyPractice News.com/Awards09 and enter a drawing for a FREE iTouch.

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34 Clinical

Pharmacy Practice News • February 2010

Pain Medicine

Study Suggests Pregabalin May Be Useful in Refractory Pain Philadelphia—Pregabalin may be a good alternative for patients with treatment-refractory fibromyalgia pain, according to a small subanalysis from a larger trial reported at the annual meeting of the American College of Rheumatology (ACR).

The patients in this subanalysis had notable reductions in fibromyalgia-related pain severity and experienced pain relief after reintroduction of pregabalin following drug holidays,

explained Brett R. Stacey, MD, an anesthesiologist and pain medicine physician at the Oregon Health & Science University in Portland.

“A proportion of people with fibromyalgia have intractable pain that does not respond to commonly used medications,” Dr. Stacey said. “These findings suggest that pregabalin may be beneficial in patients with fibromyalgia who have had an unsatisfactory response to treatment with other medications.”

The study was a five-month, openlabel trial of pregabalin (Lyrica, Pfizer) 150 to 600 mg per day in a subset of 25 patients who had previously participated in an eight-week, double-blind, placebo-controlled trial of pregabalin.

This subset was refractory to treatment with gabapentin (Neurontin, Pfizer) 1,800 mg per day or higher, tricyclic antidepressants 75 mg per day or higher and a third-line agent (an antiepileptic drug, opioid, non–tricyclic

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Dale N. Gerding, MD

This activity is intended for physicians and pharmacists.

Professor of Medicine Loyola University Chicago Stritch School of Medicine Associate Chief of Staff for Research Edward Hines Jr. Veterans Affairs Hospital Hines, Virginia

Learning Objectives

Frank K. Friedenberg, MD, MS Professor of Medicine Department of Gastroenterology Temple University School of Medicine Philadelphia, Pennsylvania

David P. Nicolau, PharmD Director Center for Anti-Infective Research and Development Hartford Hospital Hartford, Connecticut

Accreditation Statement Physician: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of AKH Inc. and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians. AKH Inc. designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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antidepressant or nonsteroidal antiinflammatory drug). For purposes of the study, “refractory” was defined as inadequate pain relief and/or intolerable adverse effects after a minimum of two weeks of treatment.

Patients received pregabalin 150 to 600 mg per day three times a day for up to five treatment periods of three months each, separated by four drug holidays lasting from three to 28 days until a relapse occurred. Only those patients who relapsed continued on another treatment cycle of pregabalin.

Nineteen patients completed the study: 76% were women; the mean age of study participants was 54.2 years; the mean duration of fibromyalgia symptoms was 11 years; and 88% were taking other pain medications at baseline, including treatments to which they were refractory.

For each treatment cycle, pregabalin was associated with clinically meaningful and sustained pain reduction for the first 15 months of treatment analysis. Mean Short-Form McGill Pain Questionnaire (SF-MPQ) visual analog scale (VAS) level decreased from 73.6 at baseline to 51.7 at end point. Median time to relapse and mean pain scores across the four drug holidays indicated that pain quickly reverted to baseline levels but was again reduced when pregabalin was resumed.

At baseline, 71% of patients reported severe pain (>70 on SF-MPQ VAS) compared with 38% after 15 months of treatment. More than half of patients in the study (54.2%) reported a reduction of 30% or more in mean pain scores from baseline to the third month, and 45.8% did so from baseline to end point. Half of patients had a reduction of 50% or more in mean pain scores from baseline to the third month, and 37.5% reported this result from baseline to end point.

Pregabalin was safe and generally well tolerated, with few treatment-related discontinuations. Every patient reported at least one treatment-emergent adverse event during the study. The most commonly reported adverse events were headache (24%), asthenia (20%), somnolence (20%), sinusitis (20%) and rash (20%). Weight gain was minimal, with a mean change in weight from baseline to the end of the study of 2.4 kg (range, 10-g loss to 15-kg gain).

Study Adds Support “Among medications for fibromyalgia, the antidepressants duloxetine [Cymbalta, Eli Lilly] and milnacipran [Savella, Forest] and the antiepileptics pregabalin and gabapentin are considered to be highly effective therapies.

•

see PREGABALIN, page 36

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36 People in Pharmacy

Pharmacy Practice News • February 2010

Medical Missions

AFGHANISTAN continued from page 9

it up in a syringe and it I’d stick the patients and say, ‘tetanus given’ and then step back from the table.”

But the vaccination program didn’t stop there. In many cases, Maj. Boenig said, patients who had been vaccinated came back to an outpatient clinic in the hospital weeks or months later for follow-up. That’s when he realized that he needed to create a system for administering and tracking booster vaccinations.

“One shot does not confer immunity; they needed the entire series,” he explained. So, working with an Army doctor, he established a vaccination series for both adults and children, and then had a local printer make up cards that said in the local language, “Tetanus Record.”

“We gave the cards to the patients when they left the hospital and said, ‘If you ever see any doctor, if you ever come to a U.S. hospital or facility, bring this card,’ with the hope that they could continue this series and build immunity for tetanus.”

A Few Caveats For pharmacists thinking of joining the Reserves, Maj. Boenig offered a few caveats. “The Reserves didn’t repay my student loans, they don’t pay you very much money, and if you join, you owe them significant time—for me, it was eight years,” he said. “But what they do give you is the opportunity to serve your country and work to save lives with some of the most talented, dedicated people that you will ever meet.”

Maj Boenig also pointed to the stress that comes from prolonged deploy-

ments. “You will have to be mentally and physically ready to leave, sometimes on short notice, and your family has to be prepared for you to be away from home for quite a while,” he said.

During his first tour, Maj. Boenig was gone for six months. During his latest tour, he was gone for one year.

Although he was able to come home for one visit, other, more creative strategies were sometimes needed to keep the family connection strong.

“I actually participated in a parentteacher teleconference call during my last tour,” he said. “I’m not sure how much good it did—it can be frustrating to not be able to step in and be there physically for your loved ones—but you do what you can.”

Maj. Boenig said he always tries to take away life lessons from his tours of duty, summed up in mottos. “During my first tour, my motto was, ‘Work the Problem,” because there sure were a lot of them and they could overwhelm you if you let them,” he said. “This time around, my motto was, ‘You Can Always Do More.’ When I felt tired or frustrated, I repeated that motto and it really helped me get through some tough times.”

The bottom line for being an Army Reserves pharmacist? “This is an incredibly valuable service that we provide— one that we should all be proud of.”

—David Bronstein

Pain Medicine

PREGABALIN continued from page 34

The current study adds to the growing literature supporting a good response to pregabalin, which offers increasing hope to patients suffering from this common disabling condition,” said Dawn A. Marcus, MD, an associate professor in the Department of Anesthesiology at the University of Pittsburgh Medical Center.

Dr. Marcus said patients and clinicians should keep in mind that although medications can be effective in treating fibromyalgia, their benefit is generally mild to moderate. Consequently, pharmacologic therapy is best considered in a broader context of treatment that includes both drugs and nondrug options, including aerobic exercise and relaxation training.

—Alice Goodman

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Basic and Clinical Pharmacology, 11th Edition

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Basic Pharmacokinetics

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Clinical Pharmacy in the United States:

Bertram Katzung; Susan Masters; Anthony 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.

Sunil Jambhekar; Philip Breen

Basic Pharmacokinetics enables the reader to become adept at solving pharmacokinetic problems arising in drug therapy and to understand the applications and utility of equations in clinical practice.

ORDER ONLINE

For pricing, a more complete Transformation of a Profession review and easy ordering Robert M. Elenbaas, PharmD, FCCP; Dennis B. Worthen, PhD with a credit card, go to Clinical Pharmacy in the United States: Transformation of a Profession is a comprehenMcMahonMedicalBooks.com. sive account of the evolution of clinical pharmacy and is an insightful must-read for anyone who cares about the profession of pharmacy.

We can supply any medical book in print, so if you don’t Demystifying Opioid Conversion Calculations: find the book you want, A Guide to Effective Dosing e-mail your request with Mary Lynn McPherson billing information to RMcMahon@ Against a backdrop of the growing scrutiny of appropriate dosages, this textbook takes a fresh, new approach to helping health professionals strengthen care to and possibly McMahonMed.com.

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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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save the lives of patients living with pain. This easy-to-understand and often humorous book is the most comprehensive to date on opioid calculations for pain management and palliative care. It carefully walks clinicians through a five-step process for performing opioid conversion calculations in the real-world situations they often see. The book has case examples, simple charts and tables, and practice problems throughout.

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Dictionary of Weighing Terms: A Guide to the Terminology of Weighing

Roland Nater; Arthur Reichmuth; Roman Schwartz; Michael Borys; Panagiotis Zervos This Dictionary of Weighing Terms is a comprehensive practical guide to the terminology of weighing for all users of weighing instruments in industry and science. It explains more than 1,000 terms associated with weighing technology and related areas; numerous illustrations assist understanding.

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Disease Management, 2nd Edition

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Pharmacy Case Studies

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Stockley’s Drug Interactions 2009 Pocket Companion

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The Pharmacy Informatics Primer

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Pocket Guide to Injectable Drugs: Companion to the Handbook on Injectable Drugs, 15th Edition

Michael Randall; Karen E. Neil

Disease Management is a comprehensive introduction to the management of diseases which are commonly encountered in, but not exclusive to, primary care.

Pharmacology is considered in the context of clinical practice and a holistic approach is taken to patient care to include lifestyle issues, concurrent disease and treatment and the use of alternative remedies and complementary medicine.

Soraya Dhillon; Rebekah Raymond

Primarily aimed at pharmacy students and pre-registration pharmacists, Pharmacy Case Studies will also be useful for qualified pharmacists as well as medical students, nurses and others with a professional interest in therapeutics.

Karen Baxter

Stockley’s Drug Interactions 2009 Pocket Companion provides busy health care professionals with a small and conveniently sized, quick-reference Stockley text. It draws on the wealth of clinically evaluated, evidence-based information on drug-drug, drug-herb and drug-food interactions that is presented in the full reference work, Stockley's Drug Interactions.

Doina Dumitru

The proliferation of information sources, constantly evolving technology and the growth of evidence-based medicine are forcing changes on the practice of pharmacy.

These phenomena have driven the growth of the informaticist as a practice specialty, while creating a need for an understanding of key elements of that specialty by clinical pharmacists and pharmacy managers.

Lawrence A. Trissel, FASHP

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.

PPN0210

38 Technology

Pharmacy Practice News • February 2010

Drug Distribution

Going Wireless With Medication Tracking H

ow confident is Riverside Methodist Hospital in its new wireless tracking system for medications since beta testing last April and going live in July?

So confident that in late January 2010, the 1,058-bed, tertiary care hospital in Columbus, Ohio, began to change its medication distribution process for inpatients. Rather than deliver to medication storage areas on each unit, Riverside has started to deliver medications directly to patient rooms. The plan is for each patient to have his or her own locked cabinet, bar coded as a secure location, in order to help nurses save steps and improve work flow.

The MedBoard bar code–driven technology (from Pharmacy OneSource) will track delivery to each box, Charles McCluskey, PharmD, director of pharmacy and pulmonary services at Riverside Methodist, told Pharmacy Practice News.

Dr. McCluskey estimated that the strategy will deliver drugs to 850 bedside boxes in patient rooms versus 130 storage rooms pre-implementation—a sixfold increase in the scope of drug distribution.

With that significant expansion, “We hope to maintain or further reduce missing doses and lessen stress on the nurses,” Dr. McCluskey said. “Nursing leadership is pretty excited about this initiative.”

The plan arose after Riverside Methodist, part of the OhioHealth system, calculated its gains from using MedBoard to better manage the distribution and tracking of IV admixtures. The hospital processes approximately 6,000 medication orders per day; about 90 of them are stat orders, and nearly 800 are IV admixtures, including chemotherapy for an oncology clinic remote to the hospital.

In the first six months of use, MedBoard helped Riverside reduce lost medication waste by 32%. Projected savings for fiscal year 2010 exceed $90,000. “The majority of our waste is generated in the IV area because these are the expensive and perishable drugs. The clock starts once we make a solution,” Dr. McCluskey said.

MedBoard tracks in real time the preparation of medications and their delivery route from pharmacy to nurses; pharmacists and technicians scan labels through each step in the chain to instantly update the progress. Two HIPAA-compliant electronic status boards on plasma screens within the pharmacy display the priority, order status and location of each medication; authorized nurses can see the same on any hospital computer. Color codes show if medications are overdue (red), approaching overdue status (yellow) or in progress (green).

The ability to see where medications are in the distribution process reduces nurse anxiety, lessens phone calls or

electronic messages to the pharmacy for missing doses (from nearly 175 per day to 90 per day over the six-month period), and reduces the number of wasteful reorders. Specific gains that Dr. McCluskey cites: $12,000 in freedup time for a medication-safety pharmacist and $50,000 in hospital staff productivity, due to the fewer phone calls and missing medication requests.

“We’re starting to see some significant improvements in the service of our nurse customers,” he said.

“Our goal is to get the highest-priority medications to patients within 15 minutes,” added Robert Hammond, RPh, MS, pharmacy operations manager at Riverside. MedBoard improves pharmacy performance and reduces staff diversion by identifying the latest person to handle the product, Mr. Hammond noted.

The pharmacy at Riverside Methodist is the first of 17 OhioHealth hospitals to use MedBoard, and there are no current plans to roll out this technology to the rest of the health system. However, Dr. McCluskey is already eyeing other ways to extract value from MedBoard: • Track medications not only from order to administration, but back to the pharmacy if they haven’t been administered for any reason.

• Project more accurately the number of IV admixtures to prepare at different times, based on utilization rates and returns back to the pharmacy.

• Integrate with Riverside’s 100 Pyxis cabinets (each with two sidecars) to better understand where bottlenecks exist in the replenishment process.

Saint Barnabas Eyes Technology Robert T. Adamson, PharmD, corporate vice president of clinical pharmacy services at Saint Barnabas Health Care System, West Orange, N.J., said his facility also is very focused on streamlining drug inventories and is interested in MedBoard’s wireless technology. “With increased pressures on the reimbursement side from payers, we want to move toward just-in-time inventory,” he said.

To that end, “we measure our effectiveness in managing inventory by turns, with a goal of [cycling through] inventory at least 12 times a year.”

If that goal proves elusive, a secondary target “is to at least take our Top 50 medications and turn them as often as we can, because they account for between one-fourth and one-third of our annual drug budget. We purchase 8,000 different pharmaceutical products each year. We want to manage the Top 50, including oncology, very well.”

As for the MedBoard approach, Dr. Adamson said “it’s a significant first step toward a true electronic tracking system

A monitor shows the status of prescription orders in the MedBoard wireless tracking system.

‘The majority of our waste is generated in the IV area because these are the expensive and perishable drugs. The clock starts once we make a solution.’

—Charles McCluskey, PharmD that will help manage inventory within the health care environment.”

One particularly effective application for MedBoard, Dr. Adamson noted, would be in the management of manually prepared IV admixtures. The manual systems at most hospitals send IV admixtures to patient floors without tracking, in bulk shipments with other medications, he said. This prompts anxious nurses to call for status and location, which robs the nursing units and pharmacy of productivity; it also leads to wasteful reorders.

“Everyone experiences this particular problem to some degree. It’s something everyone would love to fix,” Dr. Adamson said. “When nurses say, ‘We’re missing medication X for patient Y, telling them ‘we don’t know where it is’ and ‘we’ll get back to you’ doesn’t cut it.”

Cost is certainly a factor driving the need for a better alternative. “Remember,” he said, “manually compounded medications are very expensive—up to $500 per dose—and are short-dated, sometimes with as little as two to six hours to use.” If such a dose is misplaced or expires, “we can’t just say, ‘we’ll make another one.’”

The situation also frustrates pharmacists “because they know they prepared an IV admixture for a patient,” he said.

“Once it leaves their possession, until now they’ve had no way of knowing where

it is. Since we can’t use Pyxis for IVs, especially those that are made custom, MedBoard is a bridge for more accountability, status updates and information that enables us to say ‘the filled order will be right over,’ if that is the case.”

Dr. Adamson and three of the six pharmacy directors from Saint Barnabas saw the MedBoard technology at the 2009 ASHP Midyear Clinical Meeting and were intrigued enough to arrange for an online conference/demonstration in mid-February. If they go ahead and implement the technology, he envisions status boards in the central pharmacy and possibly at nursing units so nurses could see identical information at the same time. “That would save a lot of steps and phone calls,” he said.

Dr. Adamson gave MedBoard a further kudo: “It doesn’t force you to use their steps. We would be able to customize the system to meet our health-system’s needs.

It’s like an empty shell we could populate to address our own operations.”

Because the six campuses at Saint Barnabas produce several thousand admixtures per week on average, Dr. Adamson said his team has “solely thought of this as an IV solution.” With Pyxis tracking other forms of medications, and MedBoard tracking IVs, he noted, “we’d have one continuous information loop.”

—Al Heller

Midazolam Hydrochloride Injection CIV Brief Summary See package insert for full prescribing information Adult and Pediatric Intravenous midazolam HCl has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam HCl should be used only in hospital or ambulatory care settings, including physicians’ and dental offices, that provide for continuous monitoring of respiratory and cardiac function, i.e., pulse oximetry. Immediate availability of resuscitative drugs and age- and sizeappropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. (See WARNINGS.) For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure and route dependent (see DOSAGE AND ADMINISTRATION in full prescribing information).

Neonates Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl (see DOSAGE AND ADMINISTRATION in full prescribing information).

INDICATIONS AND USAGE Midazolam HCl Injection is indicated: intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia; intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants; intravenously for induction of general anesthesia, before administration of other anesthetic agents.

With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia); continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.

Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours (see CLINICAL PHARMACOLOGY in full prescribing information).

CONTRAINDICATIONS Injectable midazolam is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with openangle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied. Midazolam HCl Injection is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form.

WARNINGS Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression. Prior to the intravenous administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Patients should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry.

Hypoventilation, airway obstruction and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because intravenous midazolam depresses respiration (see CLINICAL PHARMACOLOGY in full prescribing information) and because opioid agonists and other sedatives can add to this depression, midazolam should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway and supporting ventilation. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients.

Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. See DOSAGE AND ADMINISTRATION in full prescribing information.

Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic.

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients.

Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly (see CLINICAL PHARMACOLOGY in full prescribing information). Because elderly patients frequently have inefficient function of one or more organ systems, and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered.

Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.

There have been limited reports of intra-arterial injection of midazolam hydrochloride. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established.

Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided.

The safety and efficacy of midazolam following nonintravenous and nonintramuscular routes of administration have not been established. Midazolam should only be administered intramuscularly or intravenously.

The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam (see CLINICAL PHARMACOLOGY in full prescribing information) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation.

Usage in Pregnancy An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section).

Usage in Preterm Infants and Neonates Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration.

The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam.

Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including midazolam hydrochloride) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of midazolam for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources.

PRECAUTIONS General Intravenous doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS above and DOSAGE AND ADMINISTRATION in full prescribing information). These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia.

Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia.

Use with Other CNS Depressants The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient and the use of concomitant medications capable of depressing the CNS. Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Care must be taken to individualize and carefully titrate the dose of midazolam to the patient’s underlying medical/surgical conditions, administer to the desired effect being certain to wait an adequate time for peak CNS effects of both midazolam and concomitant medications, and have the personnel and size-appropriate equipment and facilities available for monitoring and intervention (see BOX WARNING, WARNINGS above and DOSAGE AND ADMINISTRATION section in full prescribing information.) Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management. For information regarding withdrawal, see DRUG ABUSE AND DEPENDENCE section.

Drug Interactions The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION in full prescribing information).

Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole.

These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam.

For additional drug interaction information, refer to full prescribing information.

Pregnancy Teratogenic Effects – Pregnancy Category D (see WARNINGS) Labor and Delivery In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug. Following intramuscular administration of 0.05 mg/kg of midazolam, both the venous and the umbilical arterial serum concentrations were lower than maternal concentrations.

The use of injectable midazolam in obstetrics has not been evaluated in clinical studies. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, midazolam is not recommended for obstetrical use.

Nursing Mothers Midazolam is excreted in human milk. Caution should be exercised when midazolam is administered to a nursing woman.

ADVERSE REACTIONS See WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, e.g., upper endoscopy and dental procedures.

Adults: The following additional adverse reactions were reported after intramuscular administration: headache (1.3%); Local effects at IM injection site included: pain (3.7%), induration (0.5%), redness (0.5%), muscle stiffness (0.3%).

Administration of IM midazolam hydrochloride to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION in full prescribing information).

The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: hiccoughs (3.9%), nausea (2.8%), vomiting (2.6%), coughing (1.3%), “oversedation” (1.6%), headache (1.5%), drowsiness (1.2%); Local effects at the IV site included: tenderness (5.6%), pain during injection (5.0%), redness (2.6%), induration (1.7%), phlebitis (0.4%).

Pediatric Patients The following adverse events related to the use of IV midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent.

Neonates For information concerning hypotensive episodes and seizures following the administration of midazolam to neonates, see BOX WARNING, CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections.

DRUG ABUSE AND DEPENDENCE Midazolam is subject to Schedule IV control under the Controlled Substances Act of 1970.

Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs.

Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam.

Withdrawal symptoms similar in character to those noted with barbiturates and alcohol (convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuation of benzodiazepines, including midazolam. Abdominal distention, nausea, vomiting and tachycardia are prominent symptoms of withdrawal in infants. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. There is no consensus in the medical literature regarding tapering schedules; therefore, practitioners are advised to individualize therapy to meet patient’s needs. In some case reports, patients who have had severe withdrawal reactions due to abrupt discontinuation of high-dose long-term midazolam, have been successfully weaned off of midazolam over a period of several days.

Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) BAXTER is a trademark of Baxter International Inc. 462-051-06 4/2009

Midazolam HCI Injection

Now available with Distinctive Labels.

To learn more, contact your Baxter representative at 1-888-229-0001.

Please see preceding page for brief summary of full Prescribing Information including boxed warning.

Baxter, Committed to a Safer Healthcare Environment, and the distinct product label design are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111198B 09/09