AJP Spring 2015

ARIZONA JOURNAL OF PHARMACY THE OFFICIAL PUBLICATION OF THE ARIZONA PHARMACY ASSOCIATION BROUGHT TO YOU BY PHARMACY NETWORK OF ARIZONA

SPRING 2015

Advancing Pharmacy to Improve Healthcare

Spring 2015 • Arizona Journal of Pharmacy • 1

Arizona Journal of Pharmacy

THE OFFICIAL PUBLICATION OF THE ARIZONA PHARMACY ASSOCIATION Brought to you by Pharmacy Network of Arizona

Vol. 7, No. 1

Spring 2015

In This Issue ....

Message from Leadership

4

Special contributions A Look Back - Tobacco Enema

Time Capsule Student Perspective: Fall Conference

17 17 18

Features Rescheduling of Combination Hydrocodone Products

20

Departments Association News New Members

PAPA Legislative Update Pharmacist Spotlight

Technician Spotlight

Drug Information Question

5 5 11 13 14 16 24

Academy News: • ACCP Academy • Community Pharmacy Academy • Geriatric Care Academy

• Health-System Academy

• Managed Care Academy

• Student Pharmacist Academy • Technician Academy

27 27 28 28 28 29 29

Continuing Education: Drug-Induced Cardiotoxicity Geriatric Clinical Pearls

30 35

Advertisers Generation Rx PTCB PAAS Pharmacy Quality Commitment Pharmacists Life Insurance Rx Armory Rx Relief Suncrest Software Solutions

Editor www.azpharmacy.org/ajp

Kelly Ridgway, R.Ph. Chief Executive Officer

Editorial Board

Whitney Rice, Pharm.D. Christi Jen, Pharm.D. Scott Hardy, Pharm.D.

43 10 23 23 19 23 44 02

Managing Editor

Rachel Jimenez Marketing & Communications Manager Andrea Burns, Pharm.D. Jaime Bailey, Pharm.D. Kalani Anderson, C.Ph.T.

Spring 2015 • Arizona Journal of Pharmacy • 3

Leadership Spring is a time of new beginnings. The beautiful gardens that are full of colorful flowers or good food still require someone to put in the effort of tilling the ground, digging holes, selecting seeds, paying for the materials, and planting them. Someone must watch over the gardens and make sure they are nourished, watered, and free from weeds. AzPA is very much the same. We are really a community garden and this is a great time of year. We are looking forward to planting some new seeds, showcasing some of our finest, and nurturing some legacy plants.

Our events are cultivated, planted and doing well. We have a new certificate program coming in April called Women’s Reproductive Health. We have also started to plan for the annual convention, which will be in Tucson this year June 25-28.

We have been given some challenges in the legislative area this year. I encourage all of us to come together to work on this so that we can set ourselves up for success over the next few years. What do we need right now? We need money raised by April 1 to secure a lobbyist for the 2016 legislative session. We need talking points created and approved, and introductory materials written so we can begin to share with legislators and stakeholders. We need participation in events where we can raise awareness. We tried raising PAC funds during December and January with very poor results. Please, consider contributing to this garden area either by volunteering, donating, or both. We cannot flourish without everyone pitching in to help.

Our academies are busy with activities and I encourage you to go into your AzPA profile at azpharmacy.org/memberprofile and select one or two academies. Now is the perfect time to get your hands dirty and get involved. Please, also make sure your profile is up to date and accurate. It’s a great tool for the association and is quite user-friendly to maneuver. If you need any help, please reach out to us at our office.

We are always looking towards the future. And you can help. Please be thinking about whether you, or someone you know, would like to become a member of the AzPA Board of Directors. Elections will not be far off and you can nominate someone or self-nominate. If you have any questions beforehand, please don’t hesitate to reach out to Kelly Ridgway or myself.

It’s almost time to consider award nominations presenting during our Annual Convention. Do you know someone that deserves recognition for displaying leadership in some manner? There are many examples of pharmacists, students and technicians that go above & beyond and have enormous impact on our profession.

Don’t let them go unrecognized.

Pick up a pair gloves, grab a shovel, grab a plant, and let’s dig in our community garden together. The future of our profession in this state is in our hands.

Arizona Pharmacy Association

Kelly Ridgway, R.Ph. Chief Executive Officer Arizona Pharmacy Association

Ann Sears, R.Ph. President AzPA Board of Directors 2014-2015

ASSOCIATION NEWS WELCOME NEW MEMBERS (Oct 21 - Dec 31st 2014)

PHARMACISTS Fatty Aderoju Stefan Brettfeld Kimberly Carnegie Dorian Hollingworth Foster Bum-Jun Oh Vikas Vohra ASSOCIATES Jonathan Kim James Unsworth TECHNICIANS

Marufu Akter Patricia Barley Lacey Hoopes Roxanne Romero

STUDENTS Kimberly Alcocer Abdulhmid Althaghfi Huy Dang Ryan Frisch Adrianna Im Kimberly Jones Bambi Newman Joseph Pennington Kristin Peterson Harshal Shah RESIDENTS Osamah Alfayez Francisco Antigua Santana Desiree Ferrel

Cheers for Volunteers!

We acknowledge the contributions of the volunteers who have made a difference for our organization.

Michelle Baker Dawn Cylwik Lindsay Davis Jessica DiLeo Andrew Gaspar Lisa Goldstone Marce Honkonen Nicholas B. Hurst Brian J. Isetts Stephen Karpen Samantha Karr

Amy Kennedy Kayla Kloc Robert Lipsy Grant Metcalf Roger Morris Kate Murphy David Nix Lydia Plante Elizabeth Pogge Caryn Quieruga Nicole Scovis

VOLUNTEER WITH AzPA MISSION STATEMENT

Become more involved in our profession and our organization.

Join a committee! Visit azpharmacy.org/volunteer to learn more about the following committees:

The Arizona Pharmacy Association is committed to serving and representing all practice settings.

Mentor Connection Program Committee Marce Honkonen- Chair Instructions on how to select a committee: Communications Committee • Visit azpharmacy.org Whitney Rice - Chair • Login on the right hand side of website Membership Committee • Select Manage Profile (on Kristyn Straw-Wilson - Chair right) Dave Manchester - Co-Chair • Select Edit Bio • Scroll to the Volunteer CE Committee Interests field Terri Warholak - Co-Chair • Check the appropriate Lindsay Davis - Co-Chair committee(s) and Save profile Legislative Committee Mark Boesen - Chair Big thanks to our Committee Chairs for all their support!

AzPA will foster safe and effective medication therapy, promote innovative practice, and empower its members to serve the health care needs of the public.

VISION Empowering pharmacy professionals to provide optimal patient care.

Stay connected!

Like us on Facebook @AzPharmacyAssociation Follow us on Twitter @azpharmacy Advancing Pharmacy to Improve Healthcare Arizona Pharmacy Association

Spring 2015 • Arizona Journal of Pharmacy • 5

MEMBERS… RENEW EARLY!

Your membership to the Arizona Pharmacy Association is important to us. Don’t let this be your last issue of the Arizona Journal of Pharmacy. One lasped month could be several hours of missed free CE.

There are many ways to keep your membership current.

Upon 30 days prior to your expiration you will receive a notice asking you to renew. After your membership has expired you will have an additional 30 days to renew before your member benefits expire. To stay current you can enroll in the monthly payment plan or the annual recurring payment to keep your membership active and continue receiving all benefits.

Visit www.azpharmacy.org/memberprofile to renew or call the Office 480-838-3385

The Arizona Pharmacy Association presents PTCB EXAM REVIEW COURSE COMPLETELY REVISED CONDUCTED IN 7 ONLINE PRE-RECORDED WEBINARS*.

Only $395

Go to www.azpharmacy.org/PTCPprep to register Want to see your name in print? Submit an article for the next edition of the Arizona Journal of Pharmacy Quarter Issue Summer 2015 Fall 2015 Winter 2015

Content Deadline March 15, 2015 July 15, 2015 Oct. 15, 2015

Publication Date May 2015 September 2015 December 2015

View submission guidelines and disclosure statements at azpharmacy.org/ajp then send your article along with a signed disclosure statement to web@azpharmacy.org

Association News

SAVE THE DATE: 2015 EVENTS April

25th: Women’s Reproductive Health Certificate Program NEW!

June 25th Pharmacist & Patient-Centered Diabetes Care Certificate Program APhA’s Medication Therapy Management Certificate Program Immunization Training Program Psychiatric Certificate Program APhA’s Cardiovascular Certificate Program 26 -28th: AzPA Annual Convention

September

25th Anticoagulation Certificate Program 26th: AzPA Fall Conference azpharmacy.org/events

2015 Annual Convention REGISTRATION FORM OR REGISTER ONLINE TODAY AT azpharmacy.org/Convention2015 First Name: __________________________ Last Name: _______________________________ Organization/Pharmacy:__________________________Professional Designation ______________ Preferred First Name (for name badge): ____________________ Address: ___________________________________________________________________________________ City/State/Zip:_______________________________________________________________________________ Daytime Phone: ____________________ E-mail address: __________________________________ Date of Birth (MMDD only) __________ NABP eProfile ID # ___________ NPI _________________ (Date of Birth and NABP eProfile ID# required to receive continuing pharmacy education credit.)

AzPA Member? Yes__ No __ Dietary Need: ___ Vegetarian ___ Gluten-Free I. Early Registration Fees until 05/29/2015

Special Needs/Disabilities: ___________

AzPA Member Pharmacist

NonMember Pharmacist

AzPA Member Technician, Resident Associate

AzPA Member Student

NonMember Student

FULL: 3-DAY REGISTRATION

$345

$545

$200

$ 75

$100

SINGLE DAY __FRI __SAT __SUN

$150

$200

$100

$ 25

$ 50

SPOUSE/GUEST : 3-DAY

$200

$200

$200

$200

$200

II. Standard Registration Fees between 05/30/2015 and 6/22/2015

AzPA Member Pharmacist

NonMember Pharmacist

AzPA Member Allied Pharmacy*

AzPA Member Student

NonMember Student

FULL: 3-DAY REGISTRATION

$395

$595

$250

$ 125

$150

SINGLE DAY __FRI __SAT __SUN

$175

$225

$125

$ 50

$ 75

Section I Total

Section II Total

SPOUSE/GUEST : 3-DAY $250 $250 $250 $250 $250 *For AzPA Annual Convention Registration, Allied Pharmacy category includes associate, pharmacy technician, PGY resident, nurse, industry representative, and other non-pharmacist attendees.

Federal Commissioned Pharmacists: Please contact the AzPA office at 480.838.3385 for available discounts.

SEPARATE REGISTRATION IS REQUIRED FOR THE THURSDAY, JUNE 25, 2015 OPTIONAL CERTIFICATE TRAINING PROGRAMS. III. Multiple AzPA Certificate Programs will be offered Thursday 6/25/15

EARLY - UNTIL 05/29/15 STANDARD - Between 5/30/15 &

6/18/15

AzPA Member Pharmacist

Non-Member Pharmacist

AzPA Member Resident or Student

Non-Member Resident or Student

$350

$450

$250

$350

$400

$500

$300

$400

Section III Total

Visit the azpharmacy.org/events for a current list of the certificate programs offered June 25th. All certificate programs will run with the program fees listed above.

Spring 2015 • Arizona Journal of Pharmacy • 7

AzPA 2015 Annual Convention REGISTRATION FORM PAGE TWO Section IV. CONVENTION HANDOUTS

NUMBER

All convention handouts will be available for electronic downloading prior to and after the annual convention. If you wish to pre-order handouts, please make your selection and these will be included in your registration packet.

PRICE

Pre-loaded Flash Drive

$ 10.00

Printed Handouts (all sessions)* *Must be pre-ordered. Printed copies will not be

$35.00

Section VI Total

available for purchase at the convention.

Section V.

Section VII Total

DONATION

The Arizona Pharmacy Foundation (APF) is a 501 (c) (3) charitable organization. All donations are tax deductible.

APF Donation Section VI. Additional Optional Purchases

PRICE

Friday, June 26, 2015 Exhibit Hall Reception - Adult

$45.00

Friday, June 26, 2015 Exhibit Hall Reception - Child (ages 5-12)

$10.00

Saturday, June 27, 2015 Exhibit Hall Lunch - Adult

$45.00

Saturday, June 27, 2015 Exhibit Hall Lunch - Child (ages 5-12)

$10.00

Friday, June 26, 2015 Awards Luncheon - Single Ticket

$50.00

Friday, June 26, 2015 Awards Luncheon - Table of 10

$450.00

Adopt-A-Technician - includes AzPA Technician Dues

$200.00

Adopt-A-Student - student must be an AzPA member

$75.00

NUMBER

Section VIII Total

Name(s) of Registered Guest(s)/Spouse: Name(s) of Child(ren) Attending Events: Names(s) of Student(s)/Technician(s) [optional]:

PAYMENT SUMMARY Total Due (Sections I, II, III, IV, V)

$

Charge Card: Visa ___ MasterCard ___ Amex ____ Discover ____

Check # _____________

Card Number ______ - ______ - ______ - ______ Exp. Date _______ Security Code _______ Signature ________________________________________________________________________ Make checks payable to Arizona Pharmacy Association

Return this form to Arizona Pharmacy Association Office (Mail) 1845 E. Southern Ave., Tempe, AZ 85282 (Fax) 480 838-3557 (Email Scanned Copy) web@azpharmacy.org Or Register Online at www.azpharmacy.org/Convention2015 ALL TIMES AND PROGRAMS SUBJECT TO CHANGE.

TWEET THIS: #Pharmacist @azpharmacy (Dec 22nd 2014) #Pharmacist ranked number 1 healthcare job in 2015 by Forbes visit azpharmacy.org/forbes

Are You New to AzPA?

The Arizona Pharmacy Association (AzPA) works for you, and with you, to ensure that the profession’s perspective as it affects public health is communicated and understood. AzPA is the voice of pharmacy in Arizona!

Some of the benefits of your AzPA membership include: • Professional development opportunities, certificate programs and reduced rates on quality continuing education program - including the Annual Convention in June.

• Complimentary subscriptions to The Arizona Journal of Pharmacy, a quarterly publication which offers 8 CE home-study articles per year.

• Contribution to the volume of our collective voice with legislative, regulatory officials, and other key audiences.

• Third-Party financial and insurance services as well as discounts with AAA, Tickets@Work, and other specialties.

• Employment opportunities and ad placement through the AzPA Career Center (additional fees apply).

Learn more at www.azpharmacy.org Association News

IN MEMORY OF ...

William Fink (Passed away January 14th 2015)

William Fink was a longstanding member of the Arizona Pharmacy Association.

After serving in the Navy as a medical corpsman during World War II, William returned to Columbia University in New York City to complete his Pharmacy degree. He moved to Tucson in 1948 to join his father Myron Fink in owing and operating Stratford Pharmacy. He closed Stratford in 1990 and formed Managed Care Pharmacy Consultants, Inc., from which he retired in 2014.

He is survived by his wife of 51 years Betty Milleson Fink and his daughters and sons-in-law - Peggy and Jon Wiloughby and Debra and Roger Linn - and his three grandchildren Rachael, Tyler and Trevor Linn.

William was an enthusiastic tennis player with an astonishing double-hitch serve. He loved his early morning walks down Third Street, mostly because they involved talking to every other walker – as well as their dogs.

Not enough can be said about Tucson Medical Center Hospice staff. They were compassionate and caring, not only for William, but for his family.

Remembrances will be welcomed for the Fink Family Scholarships at the College of Pharmacy, University of Arizona, Tucson, 85721. Arrangements entrusted to ADAIR FUNERAL HOME, Dodge Chapel.

Originally published in the Arizona Daily Star on Jan. 18, 2015.

Arizona Pharmacy Association

Advancing Pharmacy to Improve Healthcare Spring 2015 • Arizona Journal of Pharmacy • 9

Have you heard about the Pharmacist Political Action Committee of Arizona (PharmPAC)?

To make sure the pharmacy profession’s voice is heard in policy debates concerning healthcare, AzPA established a political action committee called PharmPAC. PharmPAC is a non-partisan voluntary committee that allows AzPA members to pool their financial resources to advance the pharmacy industry by supporting pieces of legislation and state candidates who appreciate the value of our profession.

Learn more at www.azpharmacy.org/PharmPAC PharmPAC Needs YOU With your support we can work effectively together for the good of our profession. YOU can help us gain support for key pieces of legislation to advance pharmacy patient-centered care. Lawmakers can only represent your interests if you let them know what is important to you. You can join the PAC with the membership recurring levels of contribution, or make a one-time contribution of any size. Make sure your voice is heard in the political process.

Make your PharmPAC Contribution at www.azpharmacy.org/joinPAC or call the AzPA Office 480-838-3385

Your contribution helps support our 2015 legislative agenda (read more on page 13)

CALL FOR NOMINATIONS (COMING SOON) 2015-2016 azPA board of directors nominations A membership privilege of the Arizona Pharmacy Association is the ability to participate in the election of the Board of Directors and Officers. Your voice is important to the future of our profession and AzPA! Please consider running for a position on the 20152016 AzPA Board of Directors.

Open Positions for the 2015-2016 AzPA Board of Directors: • President-Elect • Treasurer • Community Pharmacy Academy Chair-Elect • Geriatric Care Academy Chair-Elect • Health-System Academy Chair-Elect • Managed Care Academy Chair-Elect • Technician Academy Chair-Elect • Southeast District Director • Southwest District Director • Industry Representative Association News

awards nominations Honor your peers and colleagues by nominating them to receive an award. These awards are presented during the Annual Convention.

• • • • • • • •

Bowl of Hygeia Award AzPA Pharmacist of the Year Award AzPA Technician of the Year Award AzPA Hall of Fame Awards Elias Schlossberg Award Distinguished Young Pharmacist of the Year Award Excellence in Innovation Award Exemplary Patient Care Award

LINK FOR NOMINATIONS COMING SOON! BE SURE TO CHECK YOUR EMAILS!

Pharmacists Assisting Pharmacists of Arizona (PAPA) Who is Codependent?

Do you know what codependency means? Are you aware of how prevalent a condition it is?

Most people are not aware of how many families there are these days that are dysfunctional -• do as I say, not as I do • protect family secrets at all costs • always be strong, good and perfect • don’t show how you really feel Sadly there are many Americans who have grown up under these types of constraints, and they are considered codependent. In fact, the condition is so common that every January is named National Codependency Awareness Month.

Just like interdependency, which is being mutually reliant on each other, codependency is learned behavior often passed down from one generation to another and it affects an individual’s ability to have healthy, mutually satisfying relationships. People with codependency most often form or maintain relationships that are one-sided, emotionally destructive and/or abusive verbally or physically. Does this sound like you or someone you know?

What are some behaviors that can determine whether you are codependent?

1. Excessive caretaking. Codependents feel an exaggerated responsibility for others’ actions, feelings, choices and emotional well-being. They try to anticipate every need and often are hurt because others don’t do the same for them. There is also a tendency to confuse love and pity with their desire to “love” people they pity and can rescue.

2. Low self-esteem. Codependents have an extreme need to be needed and recognized and only feel important and valuable when they are helping others. If anything goes wrong in any situation, they always blame themselves whether it was anything they had something to do with or not.

3. Denial. Codependents minimize, ignore or rationalize problems in a relationship, always believing that things “will get better when or if...”. Because of this, they also have a history of lying and other dishonest behaviors to keep the r elationship going, no matter what.

4. Codependents are afraid of their own and their loved one’s anger because they expect that it will end up destroying the relationship. Their anger is a chronic problem stemming from their lack of trust in themselves and those with whom they surround themselves.

5. Because they don’t take care of themselves, codependents often suffer from ulcers, headaches, asthma, high blood pressure, sometimes suffer from eating disorders, and oftentimes from chemical abuse and addiction.

6. Poor boundaries. Codependents have blurry or weak boundaries with friends and family members, feeling responsible for everyone’s feelings and problems. At other times, they will maintain rigid boundaries and appear closed off or withdrawn, making it hard for others to get close to them.

7. Addictive behavior. Codependents may develop addictions in an attempt to deal with their pain and frustration at being taken advantage of, instead of loved and appreciated, or because they are not being allowed to control things.

8. Dysfunctional communication. Codependents find it hard to communicate their own thoughts, feelings and needs mainly because they are usually unable to identify how they feel. Instead of admitting they don’t like something, they pretend it’s okay so they don’t upset someone. In general, they will say whatever it takes to manipulate the situation and keep the peace.

9. Problems with intimacy. Codependents have a hard time being close and open with someone in an intimate relationship, many times because of their fear of judgment or rejection. Others deny the need for closeness for fear of losing their autonomy or fear of their partner wanting too much of their time.

10. Dependency. Codependents need people to like them to feel good about themselves and need to be in a relationship, even if it is painful or abusive. They have difficulty making decisions and adjusting to change, so it is more comfortable to feel trapped in an unhealthy relationship, than to be alone.

Codependent behavior is learned by watching and imitating other family members, so when the symptoms are recognized, it is important to explore the past to see whose life was being cared for, whose behaviors were being hidden and whose anger was being avoided to cause this condition. Most often it would have been a close family member or friend suffering from alcohol or drug dependence.

But if there was no addiction to drugs, alcohol, relationships, work, food, sex or gambling in past family history, look for the presence of physical or emotional abuse or a family member suffering from a chronic mental or physical illness.

Families dealing with prolonged addiction, abuse or illness develop behaviors that help them deny, ignore or avoid difficult emotions: They detach themselves. They don’t talk. They don’t touch. They don’t confront. They don’t feel.

Spring 2015 • Arizona Journal of Pharmacy • 11

They don’t trust.

Because of all of these “don’ts”, the identity and emotional development of the dysfunctional family members can be severely inhibited. The majority of the attention and energy is focused on whoever is addicted or ill and codependent people will typically sacrifice their own needs in order to take care of the sick ones. When codependents put other people’s health, safety and welfare above their own, they lose contact with their own needs, desires and sense of self.

How can codependency be treated?

Since codependency is rooted in childhood experiences, treatment most often involves exploring early childhood issues and their relationship to the current destructive behavior patterns. Education, experiential groups plus individual and group therapy can help codependents rediscover themselves and identify their self-defeating behavior patterns. Treatment goals should include helping patients get in touch with emotions that were buried during childhood, reconstructing family dynamics and being allowed to experience their full range of feelings once again.

Pharmacists Say it Best …

“PTCB Certified Pharmacy Technicians continually demonstrate the highest excellence of professional performance across practice settings. I’ve had the pleasure to work with PTCB CPhTs and rely on their support to my pharmacist activities in providing patient care.

They are among the best qualified to participate in operational functions of dispensing and inventory management. Our pharmacy simply couldn’t function without our team of PTCB CPhTs.” —Jeanie Barkett, RPh, Long Term Care Pharmacy Lead Pharmacist, Providence Specialty Pharmacy Services, Portland, OR

Do it for your pharmacy.

Do it for your patients.

Do it for you.

Encourage your technicians to become PTCB certified today! Candidates may apply to take the Pharmacy Technician Certification Exam online at www.ptcb.org.

Certification Excellence Since 1995, the Pharmacy Technician Certification Board (PTCB) has certified over 400,000 technicians nationwide and is the only pharmacy technician certification program endorsed by the American Pharmacists Association, the American Society of Health-System Pharmacists, and the National Association of Boards of Pharmacy.

CONNECT ONLINE:

(Originally published in Enterhealth – www.enterhealth.com)

If you or someone you care about is suffering from an alcohol and/or chemical dependency problem... ...help is available.

Pharmacists Assisting Pharmacists of Arizona “A Partnership in Caring”

Contact Lisa Yates, PAPA Program Administrator at 928.532.2293 or papa@azpharmacy.org All calls confidential. Caller remains anonymous.

PAPA

is a program of the Arizona Pharmacy Foundation

Mentor Connection Program Build relationships, further professional networks, and strengthen continuous professional development! This program empowers pharmacy professionals to provide optimal patient care. Participation as a mentor or a mentee is open to all Arizona Pharmacy Association pharmacist (mentor), student pharmacist (mentee), technician and resident (mentor or mentee) members.

Program runs from October - July annually!

Want to participate in the next cycle?

Go to azpharmacy.org/mentor for more information.

LEGISLATIVE UPDATE 2015 Legislative Agenda MEDICATION SYNCHRONIZATON: SB1288 Medication synchronization is increasingly being recognized as a tool that can improve adherence when patients are on a regular chronic medication regimen.

It refers to the process of a pharmacy coordinating all of a patient’s chronic prescription medications to be filled on the same date each month. This model provides a more coordinated level of care which results in healthier, more adherent patients. The more effective delivery of care can reduce overall costs to payers and the health care system. This bill was successfully passed out of the Senate with a vote of 29-0. Stay tuned at the legislation moves through the House.

2016 Legislative Agenda IMMUNIZATION EXPANSION: Pharmacist-administered vaccinations contribute significantly to our state’s vaccination efforts, as evident with nearly 1.4 million vaccinations administered between 2005 and 2013. This service is being increasingly utilized in the Arizona community, and pharmacists’ abilities to provide vaccinations is recognized across the nation. However, Arizona pharmacists are still limited in their ability to immunize children ages 6-17, requiring a prescription order for all vaccinations except influenza. The need for children ages 6-17 to have a prescription order for any vaccination, other than influenza, is a significant barrier to improving vaccination rates. AzPA plans to run this legislation in 2016.

2015 Pharmacy Day at the Capitol was a SUCCESS

Arizona Pharmacy Association, and student from Midwestern University College of Pharmacy and University of Arizona College of Pharmacy invited Arizona Legislatures to join an important discussion regarding pharmacy-related healthcare.

Participants strolled through booths to learn more about the many patient-care services pharmacists provide.

Please consider contributing to the Pharmacy Political Action Committee of Arizona (PharmPAC) to help support the legislatvie agenda listed above. www.azpharmacy.org/PharmPAC All AzPA members are welcome to attend the monthly meetings. If you are interested in joining the discussions, contact Mark Boesen, Legislative Committee Chair at legislative@azpharmacy.org or Kelly Ridgway, AzPA CEO at kelly@azpharmacy.org

Mark Boesen AzPA Legislative Affairs Committee Chair legislative@azpharmacy.org Jeff Gray, R & R Partners AzPA Lobbyist Spring 2015 • Arizona Journal of Pharmacy • 13

PHARMACIST SPOTLIGHT Independent Pharmacy: Teresa Stickler

by Harshal Shah, Pharm. D. Candidate, Midwestern University CPG Class of 2015, and Huy Dang, Pharm. D. Candidate, Lake Erie College of Osteopathic Medicine Class of 2015 In Arizona, there is a scarce amount of independently owned pharmacies. When you’re driving around, most pharmacies you see are large corporations such as CVS, Walgreens, Target and Walmart. With a nearly impossible mountain to climb, Teresa Stickler, owner and founder of Melrose Pharmacy, located in Phoenix, AZ, has managed to start and establish a thriving independent pharmacy. In the process Teresa has recently become a Spirit Enterprise Award finalist in 2013 before winning the prestigious award this year.

If there were any barriers throughout this process, what were they and can they be overcome?

The majority of barriers were financing the pharmacy and human resources, which consisted of employee hiring, management and time management with increasing responsibilities. I was able to solve some of the issues by finding a business coach attained through PDS. He was able to help me manage time better, keep current with financial requirements and better understand the business model.

Tell us about yourself and your career path: I am from New Jersey and attended Rutgers University College of Pharmacy, where I attained my Bachelors of Science in pharmacy. While attending school I worked as a CVS technician during the summers and competed on the Division I track team. Due to scheduling conflicts, I eventually transitioned to Walgreens where I worked for 7 years; after 2 years I became the pharmacy manager. At this point I wanted to pursue more patient care opportunities and researched independent pharmacy, eventually opening Melrose pharmacy.

Where do you see independent pharmacies heading in 5-10 years?

They may be partnered with hospitals in the near future. I believe that they will have an increased focus on adherence and providing MTM services.

Over the next few years independent pharmacy owners should stay current with technology and continue to develop relationships with patients.

Can you briefly discuss the process of starting an independent pharmacy?

I started by conversing with 2 wholesalers and a buying group, United Drugs. Also, I attended the wholesaler trade show and participated in their continuing education (CE) course, Business Management. I participated in the ownership workshop offered by NCPA. I gained some perspective and advice from my mentor, David Goot, from United Drugs, who was an ex-pharmacy owner.

What do you feel are key elements to success in operating an independent pharmacy?

Attending CE business or ownership classes, staying up to date with current medications, technology, dispensing methods and services are many important ways to be successful.

At this pharmacy we have the 1st strip-packaging machine (Parata) in Phoenix. The Parata system individually packages each day’s medications with counseling information such as time, dose, and administration. Monitoring adherence to increase star ratings for types of services that pharmacies offer is also beneficial.

What particular services does your pharmacy provide?

We provide postmenopausal hormone compounding and consulting. Additionally, we synchronize medication refills. Other services we offer are door-to-door deliveries and a 13- week weight loss program. The weight loss program consists of blood pressure and weight monitoring, dietary shakes, weekly check in’s and the patient’s accountability.

Is there a pharmacist provided service you would like to add?

Currently, I would not add another service because it may dilute the specific services we provide.

What areas of specialty does your pharmacy offer?

HIV, hormonal, weight loss, and compounding. The diabetes program discontinued the program due to lack of interest by RPh’s.

Please describe your relationship with charity organizations.

Recently, we earned an award after providing vitamins at cost to March of Dimes representatives. I volunteered in “Raise bail to get out of jail” to raise money for the

muscular dystrophy awareness organization. In an effort to support patients with AIDS, I participated in Red Brunch for AIDS and annually sponsor the AIDS walk in Phoenix.

Would you please elaborate on the 2014 ASU Spirit Enterprise award you’ve won recently?

I found out about the award through the APS Business mentoring program. Nominees for the spirit enterprise award must apply for the award. The application process consists of an essay and an interview with a panel. This year there were 4 other winners from non-pharmacy businesses.

What were you able to do differently than other nominees that may have won you the award?

Surviving with the competition being large corporations, and getting reimbursements from the Pharmacy Benefit Managers and staying up to date with services and technology in addition to providing excellent patient care have allowed this pharmacy to sustain and thrive.

What does this award mean to you and how do you feel it will impact the future of your pharmacy?

It feels great and rewarding for being recognized for the hard work I have put into opening an independent pharmacy in a market where corporate pharmacies reign. Patients feel a sense of pride after seeing the awarddisplayed in the front of the pharmacy. After winning the award I felt somewhat rejuvenated and will continue to run this pharmacy for at least 10 more years.

Looking for Online CEs?

Visit the Arizona Center for Professional Education

What is your favorite leisure activity unrelated to pharmacy / career?

Swing dancing, gardening and traveling. I enjoy going on business trips as well as the cardinal trade show because they change cities each year and I am able to travel nearby after conducting my work.

If you could change one aspect of current community pharmacy, would it be?

The influence of PBMs in the pharmacy world has negatively affected independent pharmacy owners who have a harder time financially with losses on many prescriptions. I would reduce the PBMs, financial constraints and political control they have on the pharmacy industry.

Do you have advice for aspiring independent pharmacy owners?

It was a rewarding career decision and I would recommend doing a lot of independent research before jumping in with both feet. If you work first, you may be able to see what’s going on.

This way you can gain an understanding and appreciation for an independent pharmacy.

Your online source for continuing pharmacy education Visit www.azpharmacy.org/AzCPE

Spring 2015 • Arizona Journal of Pharmacy • 15

TECHNICIAN SPOTLIGHT Reg Roy - Pharmaceutical Ninja

by Kalani Anderson, C.Ph.T

Several words come readily to mind that describe Reginald Roy, Jr.: persistent, self-motivated, tactful, encouraging, and ninja. Persistent because he consistently takes on challenges and methodically sees them Reg Roy, C.Ph.T. through to the end; self-motivated because he requires little to no external pushing to do a job well; tactful in his interactions with others in what could be very sensitive situations; encouraging as a leader who sets an example for others follow while helping those around him succeed in their own endeavors; and ninja because of his uncanny ability to surprise you even after you think you have him figured out.

Reg’s family roots go back to the quiet and frigid New England state of Maine. His great-grandmother was a successful Appalachian bootlegger in the days of Prohibition, supporting her family through very difficult times. This heritage undoubtedly endowed Reg with his quiet exterior, persistent nature, and his marked sense of humor (not to mention those ninja skills). His great-grandmother did not, however, pass along the family business, so Reg decided to become the next best thing: a pharmacy technician! He worked in the Maine Medical Center in-patient pharmacy as well as a home infusion facility before he had had enough of his home state’s winters and relocated to sunny Arizona.

His professional skills transferred well to his new home and would help him turn his job into a fulfilling career.

When first starting out in Maine, it seems that pharmacy chose him first and then he with his characteristic persistence turned pharmacy into a career.

His example is one that a lot of techs can relate to, and it is one that is encouraging. From there, he continued the process of learning that would define his career. He worked in the hospital setting learning IV prep, unit dose filling, and robot operation and maintenance. He has worked in the up-and-coming field of medication therapy management providing telephone-based medication review services such as medication reconciliation. He has also learned and worked in a rehabilitation hospital pharmacy, a clinical pharmacy attached to a hospital, a home therapy pharmacy providing sterile therapies for home infusion, and a long-term care pharmacy providing treatments to hospice patients. Each experience was a challenge, but

Reg treated them as opportunities to learn something new and expand his own skills and knowledge.

He currently works two jobs - one for the University of Arizona in Medication Therapy Management since 2006 and the other for SinfoníaRx since January 2014. At SinfoníaRx his position of Compliance Manager involves communicating with clients to provide evidence of regulatory compliance issues. At the University of Arizona, his position of Coordinator of Regulatory Compliance involves applying for and renewing 40 state pharmacy licenses and assuring that all licensed staff members keep their Technician/Intern/ Pharmacist licenses active. This includes licenses needed for other states. He enjoys these nontraditional roles and states that he appreciates the support his employers have for employing technicians in such work. These positions give him ample opportunity to practice his tactfulness in relation to both internal and external customers.

Reg also serves on the AzPA Board of Directors as the Technician Academy Chair and is active in several committees. His impact has been felt in many ways at AzPA. He has been instrumental in growing technician membership over the last five years of being involved and has encouraged involvement on multiple levels. I personally have him to thank for getting me involved in the association on a deeper level than I would have of my own accord. One of his greatest leadership skills lies in his ability to recognize someone’s abilities and then encouraging them and supporting them in their efforts. His unassuming style of leadership provides an example of his ninja abilities. During sometimes energetic board meetings, he stays quietthere. But then, when you least expect it ,and need it most, his provides the precise answer to the problem at hand, or a suggestion that leads the group to a fantastic idea.

Like many technicians, he thrives in roles that are absolutely essential to the success of an organization, but he does so out of the spotlight simply wanting to help the organization succeed. He feels that a team-first focus at a pharmacy make for successful and happy work-places.

Techs should take initiative to make suggestions and take on new roles, and pharmacists should support technicians with opportunities to grow and try their ideas where feasible.

Outside of pharmacy, Reg enjoys travelling with friends and recently survived a trip to Mexico. He plays an active role in the life of his six year-old godchild, Madeline. He likes listening to music and being social in general. Reg avails himself thoroughly of AzPA’s fantastic conferences and CE offerings, so feel free to introduce yourself the next time you see him and ask about his bootlegging background. You can also contact Reg for networking purposes by email at roy@pharmacy.arizona.edu.

SPECIAL CONTRIBUTIONS A Look Back - Tobacco Enema

By Robert E. Kravetz, MD, FACP, MACG, American College of Gastroenterology The enema or clyster has played a major role in promoting health throughout the history of civilization. It has been recommended for its restorative as a well as it’s healing qualities.

The many forms that it has taken have depended upon the prevailing social attitudes and customs that were present at various times in history.

One of the most unusual devices in the “anals of enematology” has been the tobacco enema similar to the one illustrated here. This bellow-operated tobacco enema is made of wood, leather, brass and ivory. Four bottles contained cordial mixture, spirits of hartshorn, camphorated spirits, and emetic tartar. It is fitted in a mahogany case lined with green baize, circa 1790. These medications were prescribed orally in conjunction with the administration of the enema (device supplied courtesy of Fleet Pharmaceuticals).

Tobacco fumes were proposed as a laxative in 1643. This bellows-operated tobacco enema is the type recommended by the Royal Humane Society of London in 1774. “It is not only the admission of kindly warmth into the internal parts of the body, which proves advantageous, but it is a stimulus to excite irritability and to restore the languid peristaltic motion of the intestines.”

Pharmacy Time Capsules

First Quarter 2015 1990 - Twenty-five Years ago: 1940 - Seventy-five Years ago: • OBRA 1990 passed. States required to offer • Ida M. Fuller became the first person to receive prospective and retrospective DUR. Patient an old-age monthly benefit check under the new counseling mandatory for Medicaid patients Social Security law.

• Society of Infectious Diseases Pharmacists 1915 - Hundred Years ago: founded • Abraham Flexner refused to do a study of pharmacy similar to his study of medical 1965 - Fifty Years ago: education. He describes pharmacy as • Title XVIII and XIX (Medicare and Medicaid) “nonprofessional because it is unintellectual, passed highly profit motivated, without a technique of its • Quaalude (methaqualone Rorer) named own and without a primary responsibility.” to invoke the phrase “quiet interlude” was approved. The drug was discontinued in 1985 because of its addictiveness and recreational use.

By: Dennis B. Worthen, PhD, Cincinnati, OH One of a series contributed by the American Institute of the History of Pharmacy, a unique non-profit society dedicated to assuring that the contributions of your profession endure as a part of America’s history. Membership offers the satisfaction of helping continue this work on behalf of pharmacy, and brings five or more historical publications to your door each year. To learn more, check out www.aihp.org.

Spring 2015 • Arizona Journal of Pharmacy • 17

STUDENT PERSPECTIVE - Fall Conference 2014

by Huy Dang, Pharm. D. Candidate, Lake Erie College of Osteopathic Medicine Class of 2015, and co-author Harshal Shah, Pharm. D. Candidate, Midwestern University CPG Class of 2015, AzPA organizes their Fall Conference every year to provide pharmacists, student pharmacists, technicians, and any other interested parties, with an opportunity to acquire continuing education regarding topics relevant to the practice of pharmacy.

The November 15, 2014 conference program educated attendees on important issues and topics relevant in pharmacy today such as medication effectiveness, medication safety, and the use of medical devices.

Faculty from Midwestern University and the University of Arizona, pharmacists and pharmacy residents presented their perceptions, clinical pearls, and engaged the audience with participation, anecdotes and superb presentation skills. Additionally, the conference provided certificate programs for those interested in becoming educators in diabetes care and psychiatric health. The two day conference provided members and non-members with the chance to learn, refresh, or advance their knowledge of pharmacy to further improve their patient care.

Before attending the conference, I had very little information and knowledge of the organization; I had recently come to Arizona for an Advanced Pharmacy Practice Experience (APPE) at the Arizona Pharmacy Association with the CEO, Kelly Ridgway. The first day I arrived, I found out that they were planning for this conference which would be that weekend, and that I had the opportunity to participate in the certification program if I felt up to the challenge. I chose to partake in the psychiatric certification program because I believed I had a knowledge gap regarding psychiatric conditions and treatment modalities; furthermore the opportunity to partake in the certificate program augmented my confidence with the topic.

Friday approached way too quickly and I managed to complete my prerequisite reading. The live course instructors provided concise, up to date, and important information regarding the treatment approach for each psychiatric disease. The session went by rather quickly with each disease state receiving its due diligence; we were reminded that these were guidelines and recom-

mended best practices, but they emphasized patient specific treatment. By the end of the day, I was definitely well-informed and confident for the live session evaluation.

Saturday consisted of continuing education sessions divided for technicians and pharmacists plus students. I attended the sessions on SGLT2 inhibitors in diabetes management, Parkinson’s disease: therapeutic options and the pharmacist’s role, medical devices in pharmacy practice, and the practice of pharmacy through quality assurance and medication management. We reinforced inhaler use with many different types to understand counseling tips to be given to patients. All sessions contained thoughts of wisdom, but ultimately stressed the importance of a patient centered healthcare approach.

Overall, the two day conference gave me an experience that added to the foundation of my knowledge and allowed me to build from and establish my ideas of how pharmacy should be practiced. I recommend checking out the conference and learning something new or reestablishing your perspective on pharmacy.

Note: AzPA 2015 Fall Conference is tenatively scheduled for September 26th.

Check www.azpharmacy.org/events for details

TWEET THIS: #azpaFall @NohaAshy (November 4th) Heading to Phoenix to attend the Certificate Diabetes Program #WorldDiabetesDay #azpaFall @azpharmacy (November 17th) Check out all the great photos from this weekend’s Fall Conference on our Facebook page #azpaFall Join us on Twitter @azpharmacy

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FEATURES Rescheduling of Combination Hydrocodone Products: Problems for Long-term care Practitioners By: T. Joseph Mattingly II, PharmD, MBA, is assistant professor, Department of Pharmacy Practice and Science, university of Maryland School of Pharmacy, Baltimore, Maryland.

The Drug Enforcement Administration recently announced the final rule to reschedule hydrocodone combinations from schedule III of the Controlled Substances Act to the more restrictive schedule II category. This regulatory change will have broad operational implications for practitioners serving the health care needs of long-term care residents. Stakeholders will need to work collectively to identify possible efficiencies to counter some of the anticipated costs as well as its effect on patient care.

Abbreviations: ADS = Automated dispensing system, CSA = Controlled Substances Act, CSOS = Controlled Substance Ordering System, CTD = Cost to dispense, DEA = Drug Enforcement Administration, HCP = Hydrocodone combination product.

On August 22, 2014, the Drug Enforcement Administration (DEA) published the final rule to reschedule hydrocodone combination products (HCPs) from schedule III to the more restrictive schedule II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, also known as the Controlled Substances Act (CSA).1 From an outsider’s perspective, this reclassification may appear as a simple step to reduce diversion of a commonly used painkiller. With nearly 130 million prescriptions dispensed annually in the united States, HCPs rank number one in utilization among all medications for all diseases, making the implementation of this change far from simple for practitioners.2 Brief History While the news may seem astonishing to those health professionals reading about the decision for the first time, the path of HCPs moving into a more restrictive schedule began more than 15 years ago. In 1999, a physician special-izing in addiction petitioned DEA to reschedule HCPs because of the abuse potential of the products. After formally accepting the petition, DEA gathered information, and in 2004 requested a scientific and medical evaluation from the Department of Health and Human Services (HHS). HHS responded in Spring 2008 with the recommendation to keep HCPs in schedule III, but in early 2009 DEA requested that HHS re-evaluate the petition. Finally, in 2013, HHS forwarded a report and recommendation back to DEA to place HCPs in schedule II of the CSA.3 In 2014, DEA published a notice of Proposed Rulemaking in the Federal Register regarding this rescheduling and invited public comments.4 Advocates for patients and practitioners in long-term care facilities submitted several comments concerning the impact of this change on this special segment of the health care system. Two comments expressed concern about the lag time patients sometimes experience if a physician is not on site in a facility, thus delaying access to needed pain medication. Several FEATURES

comments even requested an “exemption” for longterm care facilities from the more cumbersome aspects of schedule II substances for handling HCPs. DEA’s response against such special consideration was two-fold: First, the Code of Federal Regulations (CFR) allows for schedule II prescriptions to be transmitted via facsimile, allowing rapid physician response and authorization; and second, there remained the potential for diversion by employees of long-term care facilities.1 Continuum of Care Hospital to Long-term Care Facility Challenges exist in the transition of patients between hospitals and long-term care facilities, regardless of the scheduling of controlled substances. With more than five million patient transfers between hospitals and long-term care facilities annually in the united States, practitioners spend a substantial amount of time working to safely admit and discharge a high volume of patients.5 The revised restrictions and regulatory requirements for certain medications complicate these care transitions. One of the most common challenges during a patient transfer is missing or incomplete information, more specifically, missing orders and signed prescriptions for opioids.5,6 Without a valid prescription, the pharmacy cannot dispense a controlled substance to a longterm care facility, leaving the admitting facility in a situation where there is no medication available to administer to a patient experiencing uncontrolled pain. In addition, from the facility side, it may be downgraded by states in their inspection survey, which grades facilities on providing adequate patient pain control.

Pharmacist-Physician Dyad While DEA allows for verbal authorization from the “prescribing individual practitioner” to the pharmacist for a schedule II medication on an emergency basis, it also requires the prescriber to follow up with a written or faxed “Authorization for Emergency Dispensing” within seven days, with the date of the oral order written on its face.7 While this may seem reasonable to the policymaker, this is a significant change in practice from a few short years ago when chart orders were accepted as valid prescriptions for controlled substances for long-term care facility residents.8 This new requirement complicates—and potentially interferes with—the ability of the facility to provide appropriate patient care. In addition, another requirement that the pharmacist must notify the nearest DEA office of the prescribers who failed to follow up with a valid prescription within seven days, also can disrupt relations with physicians; providers may be less than thrilled to work collaboratively with pharmacists who have reported them to DEA for such administrative failures.

In addition to the paperwork requirements, many physicians serving a long-term care facility can expect an increase in phone calls from facilities and pharmacies. Since most nurses have no legal agency relationship with the physician, they are not recognized by the DEA as an “agent” of the physician to authorize any controlled- substance prescription.8 This forces both the nurse and pharmacist to communicate with the prescriber about the care plan for a patient instead of the prescriber giving the order to the nurse who in turn can communicate to the pharmacy, turning a two-way process into a three-way process. This has become an issue with all controlled substances since the shift from the practice of using chart orders as prescriptions, but the rescheduling of HCPs may amplify the problem. This is a problem both because of the number of patients currently prescribed these products and other ‘ regulatory requirements, outlined below.

Impact on Operations No Refills A major consideration for practitioners implementing the HCP rescheduling is the inability to refill a schedule II substance. After October 6, 2014, when this ruling took effect, all prescriptions written for HCPs may not be refilled. Prescriptions issued before October 6, 2014, may be treated as a schedule III as long as the refills are dispensed before April 8, 2015.1 In other words, it would FEATURES

have been possible for a prescription for norco (acetaminophen and hydrocodone), for example, to have been called in to a pharmacy on October 5 (which happens to be a Sunday) by an authorized prescriber or agent of the prescriber, with six months of refills. However, after October 6, 2014, refills for an HCPs prescription required additional communication among prescribers, nurses, and pharmacies to ensure no lapse in treatment for long-term care facilities residents, delaying needed medications for patients.

Shorter Prescription life In addition to the refill restrictions, schedule II prescriptions may now only be written up to a 90-day supply.

Patients in long-term care facilities may also receive partial quantities on schedule II prescriptions, but the prescription is only valid for 60 days. By contrast, if a patient is prescribed a schedule III-V, noncontrolled substance, the prescriber may write the prescription or verbally authorize a twice-a-year refill to maintain therapy. If the patient is prescribed a schedule II substance, however, to maintain the same length of therapy, the prescriber must physically write the prescription from four to six times a year. Several states have more specific requirements regarding expiration dates on schedule II prescriptions. Many long- term care pharmacies and facilities have implemented reporting processes to alert the staff when a resident is nearing the end of a controlled-substance prescription. Residents vary in their clinical severity and need for pain control. Patients with “as needed” orders for HCPs to treat mild-to-moderate pain may not require frequent dosing, but will still need the “as needed” order renewed more frequently, requiring the nurse to reorder the medication from the pharmacy.

Ordering Schedule II Drugs: DEA Form 222 The ordering and transfer of schedule II drug inventory between “registered entities,” which are approved to handle these drugs, require a more detailed and labor-intensive process involving DEA Form 222 or through the Controlled Substance Ordering System (CSOS).9 From an operational perspective, this process is drastically different than the supply-chain regulations for schedule III-V non- controlled drugs. Pharmacies that are not set up on CSOS for schedule II ordering must obtain, prepare, and execute the DEA Form 222 (a triplicate form). A pharmacy that is ordering schedule II substances from the supplier must submit the top two copies of the DEA Form 222 and retain the third copy in the pharmacy purchasing records. The supplier fills the order, recording the number of items filled, and retains Copy 1.

The sup- plier ships the filled order back to the pharmacy with Copy 2 containing what was actually shipped. The receiving pharmacy records receipt of the order on Copy 2 and Copy 3 and forwards Copy 2 to the area DEA office.

Spring 2015 • Arizona Journal of Pharmacy • 21

Remote Automated Dispensing Systems New technologies and board of pharmacy regulations in various states have allowed long-term care facilities to use onsite automated dispensing systems (ADSs) to increase access to medication. In these cases, the medication contained within the ADS is still considered a part of the pharmacy inventory until it is dispensed. States are currently evaluating the use of ADSs, and practice varies widely across the country. According to the CFR, separate registrations are required for each location. For a pharmacy to replenish stock within the ADS, it must complete the DEA Form 222.10 Inventory and Recordkeeping Another major difference in the schedule II versus sched- ule III classification involves the inventory requirements in the federal code. Pharmacies are required to maintain an “exact count” of schedule II substances while “estimated count(s)” are allowed for schedule III, IV, or V.11 In prac- tice, this means pharmacy staff handling schedule II drugs must maintain a perpetual log and manually record inven- tory exact counts. The sheer volume of HCPs dispensed from long-term care pharmacies will have a significant budget impact on pharmacy directors and personnel. Many pharmacies purchase larger bottle quantities forhigh-volume drugs (500 or 1,000 count) to reduce per-unit cost. However, with the need to record exact counts, the additional staff time to back count a 1,000-unit stock bottle will eliminate any cost savings.

Beyond DEA The federal change regarding HCPs may have further implications for pharmacists practicing in states with more stringent schedule II requirements. For example, in a state that does not allow fax transmission of schedule II prescriptions, physicians must mail the written prescriptions to the long-term care pharmacy within seven days. States also vary in how they regulate ADSs and emergency dose kits that store controlled substances. Boards of pharmacy may want to revisit any additional requirements specific to practice in their state regarding schedule II prescriptions and evaluate how the addition of HCPs to the list will impact patient care and business development. While a board’s primary responsibility is the safety of the consumer, small differences in pharmacy practice across state lines may affect a company’s decision to open in a specific location and operate in a highly regulated environment.

Discussion Cost of Care The objective of this article is not to dispute the validity of the recommendation to reschedule HCPs because of their abuse potential and risk of diversion or to judge FEATURES

DEA’s decision. Rather, it is to shed light on the potential repercussions that may be expected in the wake of this change. Recently, investigators reported that the median operational cost to dispense (CTD) for the typical independently owned, closed-door, long-term care pharmacy was $13.54 for each prescription.12 The measurement of CTD does not include the cost of the drug itself. Carroll, Rupp, and Holdford also found that more than half of this dispensing cost for long-term care pharmacies was labor.12 One may expect the additional personnel time required to comply with the new DEA regulations could have an impact on the overall CTD. The Centers for Medicare & Medicaid Services (CMS) clarified existing policy regarding dispensing fees to reflect additional requirements and recognized the increased costs in a billing cycle from more short-cycle dispenses.13 This recognition from CMS is encouraging in that it leaves flexibility for third-party sponsors of Medicare Part D and Medicaid plans to increase dispensing fees, but this does not require the third-party sponsors to do so. negotiating pharmacy reimbursement between two profit-maximizing entities (the pharmacy and the health insurance company) is beyond the scope of this article, but pharmacy owners are going to face difficult business decisions if revenues remain unchanged as costs rise. If third-party insurance companies agree to pay pharmacies more to dispense to long-term care facility, this will affect the per-memberper-month amount required for the managed care organization to remain profitable. The end result is a higher cost to deliver health care services to long-term care facilities residents.

Moving Forward Prescribers, nurses, facilities administrators, and pharmacists will need to work collectively to identify ways to become more efficient to counter some of the additional costs and patient-related issues anticipated from the DEA reschedul- ing. Additional incentives for hospital systems to reduce readmissions and improve transitions of care— including drug therapy—can also address the prescribing process for schedule II medications. Further progress to implement electronic prescribing and health records may improve communication and address some of the challenges in transferring prescriptions during admission and discharge into a facility. ADSs may also reduce labor costs for phar- macies, allowing the shift of pharmacist and technician efforts to account for increased labor on controlled- substance prescriptions. Practitioners must continue to adapt to the regulatory environment to operate sustainable business models, all while advocating policy changes to improve patient care.

Disclosure: no funding was received for the development

of this manuscript. The author has no potential conflicts of interest. Consult Pharm 2015;30:13-19.

Reprinted with Permission of the American Society of Consult Pharmacists, Alexandria, Virginia, www.ascp.com © 2015 American Society of Consultant Pharmacists, Inc. All rights reserved.

References 1. Drug Enforcement Administration. Schedules of controlled substances: rescheduling of hydrocodone combination products from schedule III to schedule II. Available at https://federalregister. gov/a/2014-19922. Accessed August 22, 2014.

2. IMS Institute for Healthcare Informatics. Medicine use and shifting costs of healthcare: a review of the use of medicines in the united States in 2013. Available at http://www.imshealth. com/portal/site/ imshealth/menuitem.762a961826aad98f53c753c71ad8c22a/?vgnext oid=2684d47626745410VgnVCM10000076192ca2RCRD. Accessed August 22, 2014.

3. Office of Diversion Control, Drug and Chemical Evaluation Section. Placement of hydrocodone combination products into schedule II background, data, and analysis: eight factors determinative of control and findings pursuant to 21 u.S.C. 812(b). Washington DC: 2014.

4. Drug Enforcement Administration. DEA publishes proposal to reschedule hydrocodone. Available at http://www.justice. gov/dea/ divisions/hq/2014/hq022714.shtml. Accessed August 22, 2014.

5. King BJ, Gilmore-Bykovskyi AL, Roiland RA et al. The consequences of poor communication during transitions from hospital to skilled nursing facility: a qualitative study. J Am Geriatr Soc 2013;61:1095-102.

6 .Popejoy L, Galambos C, Vogelsmeier A. Hospital to nursing home transition challenges: perceptions of nursing home staff.

J nurs Care Qual 2014;29:103-9.

7. Requirement of a prescription, 21 C.F.R. Sect. 1306.11 (2010).

8. Turner SA. Medication chart orders and the DEA: longterm care facility residents caught in the middle. Geriatr nurs 2010;31:212-3.

9. Orders for Schedule I and II Controlled Substances, 21 C.F.R. Sect.

1305 (2014).

10. Separate registrations by retail pharmacies for installation and operation of automated dispensing systems at long term care facilities, 21 C.F.R. Sect. 1301.27 (2005).

11. Inventory requirements, 21 C.F.R. Sect. 1304.11 (2003).

12. Carroll nV, Rupp MT, Holdford DA. Analysis of costs to dispense prescriptions in independently owned, closed-door longterm care pharmacies. J Manag Care Pharm 2014;20:291-300.

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Spring 2015 • Arizona Journal of Pharmacy • 23

DRUG INFORMATION QUESTION What evidence is available on the use of ondansetron for the treatment of IBS-associated diarrhea?

By Zubair Afzal, Pharm.D., PGY1 Resident, and Virginia Boomershine, Pharm.D., BCACP, CDE, RPD, Walgreens and Midwestern University College of Pharmacy-Glendale

Introduction Irritable bowel syndrome (IBS) is a chronic condition characterized by abdominal pain and altered bowel movements without an identifiable cause.1 It is one of the most common gastrointestinal disorders affecting anywhere from 5-15% of the population. Diagnosis is based on the Rome III criteria which require the presence of recurrent abdominal pain or discomfort at least 3 days per month within the past 3 months with at least 2 of the following: improvement with defecation, change in stool frequency, or change in appearance of stool. IBS is subtyped as IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), mixed type (IBS-M), and unclassified (IBS-U). IBS-D patients will generally have increased bowel movements and shorter colonic transit times.

Treatment of IBS is symptomatic as there currently is no cure for the condition.2 The goal of treatment is to enhance quality of life by providing symptom relief using lifestyle interventions (e.g., exclusion diets, fiber supplementation) and, if necessary, pharmacotherapy.

Pharmacotherapy specific to IBS-associated diarrhea includes the use of 2 agents, loperamide, an anti-diarrheal, and alosetron, a serotonin subtype 3 (5-HT3) receptor antagonist. According to the American College of Gastroenterology (ACG) guidelines, there is insufficient evidence to recommend loperamide for use in IBS.1 While the ACG guidelines state alosetron is effective in females with IBS-D, its use is limited as it has been associated with serious complications of severe constipation and ischemic colitis.1,3 The pathophysiology of IBS remains unclear; however, serotonin is thought to play a role as IBS-D is associated with an increase in postprandial plasma serotonin, proposed to occur either due to an increase in release or a decrease in uptake by serotonin transmitters.4 Antagonism of the 5-HT3 receptors has been shown to decrease painful sensations in the gut and slow intestinal transit.1 Hence, ondansetron, another 5-HT3 receptor antagonist, may possibly also be of benefit in IBS-D, but without the serious adverse events of alosetron. Ondansetron is FDA-approved for the prevention of chemotherapy-induced nausea

and vomiting.5 A search of PubMed identified 4 randomized, controlled, clinical outcome trials of ondansetron in patients with IBS. Clinical Trials Three small trials of ondansetron in patients with IBS were published in the 1990s; the first of which was a pilot study by Steadman et al. published in 1992.6 It was a randomized, double-blind, placebo-controlled, crossover trial performed to determine ondansetronâ&#x20AC;&#x2122;s effect on colonic and small bowel transit and subsequent symptom improvement in patients with IBS. Patients diagnosed with diarrhea-predominant IBS, having more than 3 stools per day, abdominal pain, and at least 3 of 6 symptom criteria for IBS, were included in the study. Fourteen patients, age 28-61, were enrolled. The trial consisted of 2 treatment periods, each 28 days long, in which patients were randomized to receive either ondansetron 16 mg 3 times daily or placebo. The treatment periods were separated by a minimum washout of at least 4 weeks. The length of the washout period was determined by the time it took for the patientâ&#x20AC;&#x2122;s symptoms to return to baseline. No significant difference in colonic transit time was found; however, ondansetron demonstrated significant improvement in stool consistency compared to placebo (P<0.05). The median number of pain episodes was decreased by ondansetron, but the difference was not statistically significant. An order effect for pain was found for the first period; however, no significant difference was found between drug and placebo. The authors concluded that ondansetron provided relief from watery or liquid stools in patients with diarrhea-predominant IBS. Maxton et al. published the next study of ondansetron in IBS.7 It was a randomized, double-blind, placebo-controlled, crossover study to assess the effects of ondansetron on the classic symptoms of IBS (abdominal pain, distension, and disordered bowel habit) and functional dyspepsia.

DIQ To be included, patients had to meet the Rome criteria for the diagnosis of IBS and have normal hematological and biochemical indices and no abnormal findings on either barium enema or colonoscopy. Fifty patients ranging from 22-65 years of age were enrolled; 28 of whom had diarrhea-predominant IBS, 20 had constipation-predominant IBS, and 2 could not be classified into either subgroup. The trial consisted of an initial 2-week baseline period, followed by 2 distinct 4-week treatment periods, in which patients were randomized either to placebo or ondansetron 4 mg 3 times daily, separated by a 2-week washout phase. All patients were assessed by the same clinician at 14-day intervals throughout the study. Patients recorded their bowel habits daily on diary cards. Compared to placebo, ondansetron significantly improved postprandial discomfort, heartburn, and flatulence (P=0.008, P=0.003, P=0.022, respectively). Ondansetron was also associated with significant improvement in stool consistency, P <0.001; however, this was mainly due to its effects in the diarrhea-predominant subgroup. No statistically significant improvements in abdominal pain or distension were noted. The authors concluded that ondansetron did have a beneficial effect on the bowel habits in diarrhea-predominant IBS patients.

In 1996, Goldberg et al. published another randomized, double-blind, placebo-controlled, crossover study evaluating the effect of ondansetron on visceral sensation and rectal compliance.8 Twelve healthy volunteers, age 20-59, and 9 symptomatic patients with IBS, age 26-64, were studied. To be randomized, patients with IBS had to have been experiencing symptoms at least 3 times per week for 3 months. Symptoms included abdominal pain and distension along with 1 of the following: unexplained diarrhea, unexplained constipation, or fluctuating bowel habits. The study had an initial 2-week run-in period after which patients were randomized to receive either ondansetron 16 mg 3 times daily or placebo for 2 weeks and then crossed over treatment arms for an additional 2-week period, with a 2-week washout in between. Assessment was completed by daily symptom and bowel function diaries. A statistically significant increase in stool consistency was noted for ondansetron compared to placebo for combined healthy subjects and IBS patients (P<0.01) and healthy volunteers alone (P<0.02). However, there was only a trend toward statistical significance (P<0.07) in the IBS patient group alone. Compared to placebo, ondansetron significantly

decreased the number of episodes of abdominal pain in IBS patients (P<0.03), although the severity of the episodes was not altered. The authors concluded that ondansetron modifies motor function and may lead to symptom improvement in patients with IBS. The most recent and largest study of ondansetron in IBS was published in 2014 by Garsed et al.9 The randomized, double-blind, placebo-controlled, crossover study assessed if ondansetron improves symptoms of frequent loose stools in patients with IBS-D. One hundred twenty patients, 18-75 years of age, meeting the Rome III criteria for IBS-D, were enrolled in the study. Patients were randomized to receive either ondansetron or placebo for 5 weeks and then crossed over treatment arms for an additional 5-week period, with a 2-week washout in between. Ondansetron was administered as 4 mg tablets. Patients started with 1 tablet daily and increased by 1 tablet every 2 days to a maximum of 2 tablets 3 times per day. The primary endpoint was average stool consistency in the last 2 weeks of treatment. Patients attended a total of 7 visits throughout the study in which stool diaries were assessed and colonic transit time was evaluated by plain X-ray. Ondansetron significantly improved stool consistency with a mean difference in stool form between ondansetron and placebo of -0.9 (95% CI -1.1 to -0.6, P<0.001). Patients with less severe diarrhea benefitted more from ondansetron (-1.0, 95% CI -1.3 to -0.7, P<0.001) than those with severe diarrhea (-0.7, 95% CI -1.0 to -0.4, P<0.001) in terms of stool form difference. Gut transit time was increased for ondansetron compared to placebo, with a difference of 10 hours, 95% CI 6 to 14 h, P<0.001. The authors concluded that ondansetron can be used to treat loose stools, frequency, and urgency in IBS-D. Discussion Overall these 4 clinical trials show beneficial results with the use of ondansetron in the treatment of IBS-D.6-9 Specifically, all 4 studies highlight improved stool consistency with the use of ondansetron. In theory this improvement in stool consistency may be due to a delayed colonic transit time which is supported by the fact the serotonin receptor agonists have been shown to decrease colonic transit time.4 In both the Maxton Spring 2015 â&#x20AC;˘ Arizona Journal of Pharmacy â&#x20AC;˘ 25

DIQ et al. and Goldberg et al. study the ondansetron dose was 4 mg 3 times daily; in Steadman et al. the ondansetron dose was 16 mg 3 times daily; and in Garsed et al. the median ondansetron dose was 4 mg daily. Based on the studies a reasonable dose for ondansetron in the treatment of IBS-D is 4 mg daily titrated by 4 mg every 2 days based on symptom control. A large limitation of all the studies is their small sample size. None of the studies were powered leading to potentially false negative results; in addition, the small sample size leads to difficulty in determining less frequent side effects. Another major limitation of the studies is that all trials used a crossover design which may cause carryover and order effects. Due to the fluctuating nature of IBS, even with washout periods, it is difficult to ensure there is no carryover between treatment periods. In Garsed et al. it was noted that there was a higher dropout rate in patients receiving active treatment first, suggesting that there may have been an order effect.

The safety profile of ondansetron has proven to be favorable. Ondansetron has not been associated with ischemic colitis and has been used over 20 years without reports of any serious adverse events. The most common side effect experienced in all trials was constipation.6-9 In the trial by Garsed et al. constipation generally subsided within 4 days after a decrease in dose or discontinuation of the medication. Other commonly observed side effects in the studies were headache and abdominal pain. According to the patient package insert for ondansetron, more serious side effects include arrhythmias and elevated liver enzymes.5 Ondansetron itself does not appear to induce or inhibit CYP450 enzymes, but because it is metabolized by these enzymes, CYP3A4, CYP2D6, and CYP1A2, inducers and inhibitors may affect the clearance of ondansetron.

Ondansetron is commercially available without restrictions, has a favorable safety profile compared to alosetron, and is available as a generic. The studies discussed have shown that ondansetron may be beneficial in patients with IBS-D; however, further studies with larger sample sizes are needed to elucidate its long term efficacy and safety.

References 1. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109:S2-S26.

2. Wald A. Treatment of irritable bowel syndrome in adults. In: Talley N, Grover S, eds. UpToDate. 2014 Oct 02. (accessed 2015 January 10).

3. Food and Drug Administration. Lotronex tablets.

Safety labeling changes approved by FDA Center for Drug Evaluation and Research. http://www.fda.gov/ Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm117693.htm. (accessed 2015 January 10).

4. Spiller RC. Targeting the 5-HT(3) receptor in the treatment of irritable bowel syndrome. Curr Opin Pharmacol. 2011;11:68-74.

5. Zofran (ondansetron) package insert. Research Triangle Park, NC: GlaxoSmithKline Inc; 2014 Sep. 6. Steadman CJ, Talley NJ, Phillips SF, et al. Selective 5-hydroxytryptamine type 3 receptor antagonism with ondansetron as treatment for diarrhea-predominant irritable bowel syndrome: a pilot study. Mayo Clin Proc.

1992;67:732-8.

7. Maxton DG, Morris J, Whorwell PJ. Selective 5-hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia? Aliment Pharmacol Ther. 1996;10:595-9.

8. Goldberg PA, Kamm MA, Setti-Carraro P, et al. Modification of visceral sensitivity and pain in irritable bowel syndrome by 5-HT3 antagonism (ondansetron). Digestion. 1996;57:478-83.

9. Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63:1617-25.

AzPA Presents: Arizona Pharmacy Law and Public Policy Course The ideal preparation for the MPJE! Available on-demand at the Arizona Center for Professional Education website. Registration is available online only at: www.azpharmacy.org/ Pharmacy_Law

Academy News American College of Clinical Pharmacy Arizona Chapter Academy News We are excited to announce that The ACCP Board of Regents has voted to approve the application of the Arizona College of Clinical Pharmacy as a regional chapter of ACCP. This new chapter is already off to a fast start with plans for a variety of activities to meet the needs of chapter members. Our focus will be on clinical education through the creation of continuing education programs and board certification exam prep groups working in collaboration with local colleges of pharmacy. Partnering with AzPA, we will provide certified, clinically focused, continuing education seminars on a biannual basis. These clinical education efforts will begin this Fall under the direction of the newly formed Clinical Meeting Planning Committee. Lastly, there are plans for regular outreach events to support our local community through medication education while promoting the importance of pharmacy services.

For more information on the Arizona College of Clinical Pharmacy or if you are interested in joining the Clinical Meeting Committee, please contact us.

M. Scott Hardy, PharmD, BCACP ACCP Arizona Academy Chair accp@azpharmacy.org

Community Pharmacy Academy News Thank you for your continuous commitment and support for AzPA. In the Community Practice Front, we continue to receive questions from our patients regarding gluten-free diets, prescriptions, and over-the-counter (OTC) products.

A growing trend in our society today, people are preferring gluten-free foods, medications, and OTC products. Gluten is a protein found in wheat, barley, rye and triticale. While whole grains are an essential component of a healthy diet, many whole grains contain gluten. Some people are less tolerant of it as it is blamed for certain health problems. It has been established that autoimmune reaction to gluten causes inflammation and damage to gastrointestinal (GI) tract resulting in symptoms like abdominal pain, bloating, and interferes with absorption of nutrients in the system. Gluten also has a profound negative effect on the quality-of-life of patients with Celiac disease. For the majority of people, gluten is not a problem, but the hype about gluten-free foods continues to rise. Gluten has developed a reputation that has produced tremendous marketing opportunities for all sorts of businesses – the public continues to receive information tailored for profit motives. It’s incumbent upon the pharmacist to step in and play a role in providing supportive information to individuals in need of gluten-free products.

How do we help ensure that our patients make choices suitable for their purposes? We should encourage our patients to see their dietician or nutritionist for proper evaluation and recommendation of gluten- free foods; in combinations that ensure a balanced and nutritive diet for that individual. As pharmacists, we can help evaluate, educate, and direct our patients to appropriate gluten-free medications and OTC products. Some helpful resources include: Facts and Comparison, Martindale, Clinical Pharmacology, Manufacturer Packet Inserts (PI), www.dailymed. nlm.nih.go (an FDA site), and www.glutenfreedrugs.com, a site run by a clinical pharmacist. This particular site gives detailed listings of select products that are gluten-free, lactose-free, and soy-free. When calling manufactures be sure to provide the lot number of the product in question.

We are looking forward to, and hope you will join us for our annual conference from June 25th-28th in Tucson. For more information, please visit the AzPA website at www. azpharmacy.org Once again, thank you for support this year and we look forward to a very productive 2015 for both our organization and our profession.

Grace Akoh-Arrey, Pharm.D., CDE, BCACP Community Pharmacy Academy Chair cpa@azpharmacy.org

Spring 2015 • Arizona Journal of Pharmacy • 27

Geriatric Care Academy News The GCA ended 2014 on a high note. The first edition of the Geriatric Care Academy Newsletter was released in December 2014. We will be trying to use the newsletter to reach out to our members who are unable to join us for our monthly conference calls. Look for the second edition in early summer 2015.

We are also really excited for the upcoming AzPA Annual Convention, which is scheduled for June 25-28th at the Westin La Paloma in Tucson, Arizona. We hope that you will be able to join us for a wide variety of continuing education sessions and networking.

As a reminder, the GCA meets via monthly conference calls on the second Wednesday of the month at 12:30 pm. Since we know not everyone is able to attend these calls, keep an eye out for additional e-mails and updates from the GCA. I invite everyone that is interested in geriatrics to get more involved!

We currently have a couple positions open on the executive board. If you are interested in getting more involved in the GCA or have any questions, please e-mail me at gca@azpharmacy.org Nicole K. Kitts, PharmD, BCPS, CGP Geriatric Care Academy Chair gca@azpharmacy.org

Health-System Academy News The New Year has been busy for our academy. Please congratulate Christi Jen who will be assuming the role of the 2015-2018 as one of Arizona’s representative for the ASHP House of Delegates. She will be inducted at the ASHP Summer Meeting in June 2015. She will join our two current delegates, Carol Rollins and Mindy Burnworth.

I would also like to thank our Health System Academy Planning Committee for making this year’s Southwest Clinical Meeting a success! This was a conference in collaboration with the University of Arizona, which was held in February. If you wish to participate in the planning for next year’s conference, please contact the HSA leadership (hsa@azpharmacy. org) if you have any questions, comments, or suggestions.

Also, we are continuing our Mentor-Mentee Program. The purpose of this program is to provide an opportunity for students to be assigned to a seasoned pharmacist to serve as a resource for professional development. This program has been very successful thanks to the leadership of Marce Honkonen, Jon Merchen and Tony Rondinella. Please visit azpharmacy.org/mentor for more information about the program.

The Health-System Academy of the Arizona Pharmacy Association is the Arizona affiliate of the American Society of Health-System Pharmacists (ASHP).

Mitchell Buckley, FASHP, FCCM, BCPS Health-System Academy Chair hsa@azpharmacy.org

Managed Care Academy News The academy has had a great beginning. Ideas and future topics abound for upcoming conferences along with suggestions on holding our first networking event for fellow Managed Care Partners.

The Managed Care Academy will hold another meet and greet event in San Diego this coming April. Please join us for an exciting and fun conference to learn more of upcoming trends in our field. We are very excited. Watch for emails for more information.

We look forward to hearing from our AzPA members for your suggestions, ideas and topics that will help our association grow in improving our healthcare. So don’t forget to join us, Managed Care Academy for our monthly phone conferences every 3rd Thursday of the month at 7am.

Paul Lynne, Pharm.D., Managed Care Academy Chair mca@azpharmacy.org ACADEMY NEWS

Student Pharmacist Academy News After a relaxing winter break, the UA student chapter of AzPA welcomed its members back to the semester in style.

A letter writing campaign--hosted along with APhA’s student chapter--continued from December until the middle of January with students writing their legislators to try and get them to the Pharmacy Day at the Capitol event. At the end of January the Pharmacy Day at the Capitol happened with students from UA joining Midwestern students and pharmacists in the state to advocate for their profession. This was a great opportunity especially for first year students to feel their hand in the democratic process.

Students also attended the Southwest Clinical Symposium in February. Change for Change was also done in February with the different classes competing with each other to see who could raise the most money for the PharmPAC. The Annual Meeting Planning Committee also started meeting to help plan the student track for this year’s AzPA Annual Meeting to be held at the end of June in Tucson.

Nicole Runge, SPA Co-Chair, Midwestern University of College of Pharmacy Glendale nrunge21@midwestern.edu Pearce Engelder, SPA Co-Chair University of Arizona College of Pharmacy engelder@pharmacy.arizona.edu

Technician Academy News Happy spring! It was great to see you all at the Pharmacy Day at the Capital and the Southwestern Clinical Pharmacy Seminar! The Arizona Pharmacy Association’s continuing education committee has done a great job to provide interesting and educational CE’s to meet the Pharmacy Technician Certification Board requirements for pharmacy technician-specific subjects and 1 hour in the subject of patient safety. When you see AzPA Staff at the next conference, please be sure to thank them for their efforts on our behalf!

Your Technician Academy has been focusing on developing interesting CE topics and expanding our communication through a technician-specific Facebook page. If you haven’t seen it yet, search for “AzPA Technician Academy” and join the conversation!

If you see us at upcoming conferences with a video camera, don’t be shy. We will be collecting footage to use in a YouTube video (or two). It might be your big break!

Reginald Roy, C.Ph.T. Technician Academy Chair tech@azpharmacy.org

JOIN AN ACADEMY TODAY! • • • • • • •

Visit azpharmacy.org Login on the right hand side of website Select Manage Profile (on right) Select Edit Bio Scroll to ‘AzPA Academy Affiliation’ field Select the appropriate academy You may also choose a secondary academy

Arizona Pharmacy Association

Once you have selected an academy, you will begin to receive academy meeting emails / invites.

Questions? Please contact the AzPA Office 480.838.3385

ACADEMY NEWS

Spring 2015 • Arizona Journal of Pharmacy • 29

CONTINUING EDUCATION Drug-induced Cardiotoxicity of Oncological Agents: Monitoring Parameters, Prevention, and Future Chemotherapy

By Sarah Nguyen, Pharm.D. Candidate 2015; Mary Nguyen, PharmD Candidate 2015; Laura Tsu, Pharm.D., BCPS; Midwestern University College of Pharmacy - Glendale Goal: The goal of this article is to educate pharmacists of the impact of cardiotoxicity on chemotherapy regimens including key cancer agents, monitoring parameters, prevention, and the future of chemotherapy..

Objectives for Pharmacists: At the conclusion of this lesson, successful participants should be able to: 1. Determine the clinical significance of cardiotoxicity in cancer therapy.

2. Describe the mechanism of action and cardiotoxic effects of anthracyclines, mitoxantrone, trastuzumab, 5-fluorouracil, and bortezomib.

3. Compare the cardiotoxicity safety profiles of the different HER2 inhibitors and their roles in HER2 positive breast cancer 4. Evaluate the treatment options, monitoring parameters, and prevention of anti-cancer drug-induced cardiotoxicity.

Objectives for Technicians: #1-3 above (same as pharmacists) 4. Describe the treatment options, monitoring parameters, and prevention of anti-cancer drug-induced cardiotoxicity.

Introduction Cancer is the second leading cause of death in the United States, with a 5 year survival rate of 68%. This accounts for 1 in 4 deaths in the US. In 2013, 1.6 million Americans were diagnosed with cancer, and approximately 585,720 Americans are expected to die in 2014 from cancer.1 Due to developments in early diagnosis and therapies, cancer survival rates have greatly improved. Emerging anti-cancer drugs have been increasingly valuable in treatments of many cancers and have made significant advances in the field of oncology. However, a caveat of many of the widely used, highly effective agents is that they are associated with cardiotoxic effects; this increases cardiovascular morbidity in patients on these regimens.

Anti-cancer drugs target cell signaling pathways, which inadvertently affect myocardial cells. Because of this, there has been a development of cardio-oncology, which is aimed at cardiovascular care for oncology patients. This new focus is highly relevant in the treatment of cancers as the cardiotoxic effects have led to the discontinuation of many regimens, which have been shown clinically to slow tumor growth and lead to remission otherwise. Drugs which are highly associated with cardiotoxic side effects include anthracyclines, mitoxantrone, trastuzumab, and 5-fluorouracil. The cardiotoxic effects of these agents differ based on their target and mechanism

of action. Hence, pharmacists must be aware of these myocardial toxic effects to effectively monitor cardiac function of oncology patients under their care. As the incidence of myocardial side effects increases and are taken into account in the treatment of many cancers, promising developments of newer anti-cancer agents have arisen for the discipline of cardio-toxicity including: lapatinib, pertuzumab, and trastuzumab emtansine.

Anthracyclines Anthracyclines are a class of cytotoxic antibiotic commonly used to treat cancer. The class includes the drugs: daunorubicin (DaunoXome, Cerubidine), doxorubicin (Doxil, Adriamycin, Lipodox), epirubicin (Ellence), idarubicin (Idamycin), and valrubicin (Valstar).

They work by inhibiting DNA and RNA synthesis through direct binding to DNA in addition to inhibiting DNA repair.2 Consequently, the lack of functional DNA and RNA deprives malignant cells of basic resources for survival, a useful property of an anti-cancer agent.

Liposomal formulations of anthracyclines, such as Doxil and Lipodox, are generally the preferred analogue due to its accumulation and releasing properties. Their advantages stem from their properties of preferential accumulation and prolonged release within the tumor environment; thus, lowering accumulation in healthy tissue and adverse effects.3 Although anthracyclines are beneficial in cancer treatment, it also has concerning adverse effects such as cardiotoxicity, cardiomyopathy, declined left ventricular ejection fraction (LVEF), and congestive heart failure (CHF).4 An alarming factor is that anthracycline-induced cardiotoxicity is dose-related and tends to be progressive and irreversible, which can add undesirable complications to vulnerable cancer patients.5 Therefore, cardiotoxicity is a major limitation in the usage of anthracycline in the treatment of cancer, requiring critical monitoring and evaluation within an interdisciplinary setting of pharmacists and oncologists.

Anthracycline-induced cardiotoxicity can be categorized into three types. The first type is the acute or sub-acute injury that may occur immediately after treatment. This type is more rare and includes conditions such as transient arrhythmia, pericarditis-myocarditis syndrome, or acute failure of the left ventricle.6 The second type is chronic cardiotoxicity,

Cardiotoxicity the more common and clinically important form of damage, which includes cardiomyopathy.6 The third type of cardiotoxicity manifests years after treatment, leading to late-onset arrhythmia and ventricular dysfunction.6 The exact cause of anthracycline-induced cardiotoxicity is uncertain but the proposed mechanisms include reactive oxygen species (ROS) leading to membrane damage, lipid peroxidation, cardiomyocyte apoptosis or necrosis, disruption of sarcomere structure, or altered ability of cardiac myocyte contraction.5 When the anti-cancer benefits of anthracycline outweigh the risks of cardiotoxicity, the common methods to monitor patient’s conditions throughout treatment include an echocardiography (ECHO) and multiple gated acquisition (MUGA) scan. ECHO measures LVEF and indicates cases of left ventricle dysfunction (LVD) that denotes anthracycline-induced cardiotoxicity. However, ECHO may be regarded as insensitive in detecting cardiotoxicity at an early stage due to the fact that significant changes in LVEF usually presents upon substantial myocardial damage. On the other hand, a normal LVEF does not exclude the possibility of cardiotoxicity in the future. Usually, an LVEF less than 50% or a LVEF decrease of 10% or greater from baseline constitutes for discontinuation of the anthracycline. On the other hand, the MUGA scan measures cardiac function but it has the disadvantage of radioactivity exposure and limited information on cardiac structure and diastolic function.7 There are many risk factors for anthracycline-induced cardiotoxicity that pharmacists and oncologists should be aware of. The biggest risk factor is exceeding the recommended maximum cumulative lifetime dose of anthracyclines. Others include prior anthracycline treatment, concurrent use of other cardiotoxic agents, history of cardiovascular disorders, older and younger age, and female gender.5 As anthracycline cardiotoxicity is progressive and irreversible, it is critical to know the maximum cumulative dose of the specific anthracycline utilized. The recommended lifetime cumulative doses according to the package inserts are 550 mg/m2 for doxorubicin8, 400 mg/m2 for daunorubicin9, and 900 mg/m2 for epirubicin in adults.10 However, pediatrics is a special vulnerable population that even the smallest dose of anthracycline may induce cardiac complications.11 In addition, cardiotoxicity of anthracyclines is peak-related. Therefore, utilizing continuous infusions (24-48 hours) as opposed to bolus administration (5-15 minutes) will lower peak serum concentration and decrease the risk of acute cardiotoxicity.11 Once anthracycline-induced cardiotoxicity is present in a patient, preventative care should be implemented to prevent the condition from worsening and recurring. A common secondary prevention measure is a cardioprotective intravenous agent, dexrazoxane (Totect, Zinecard). The proposed mechanism of dexrazoxane is the metal chelation that reduces anthracycline-induced free radical damage.

CONTINUING EDUCATION

Two meta-analyses have shown that dexrazoxane significantly decreases the risk of anthracycline-induced cardiotoxicity in cancer patients by approximately 75% compared to no treatment.12 Dosing of dexrazoxane to anthracycline is a 10:1 ratio, respectively. Although dexrazoxane is a common cardioprotective agent, there is insufficient evidence to recommend its use for pediatric patients.12 Mitoxantrone Mitoxantrone (Novantrone) is an anthracenedione derivative, a relative of the anthracyclines. Its mechanism of action is similar to anthracyclines in that it intercalates into DNA and causes DNA strand break in addition to inhibiting DNA topoisomerase II and prevents DNA replication.2 Mitoxantrone is also associated with dose-related cardiotoxicity such as tachycardia, arrhythmia, and CHF. The risk of cardiotoxicity increases with increased cumulative lifetime dose of mitoxantrone, prior anthracycline treatments, prior mediastinal radiotherapy and pre-existing cardiovascular disease.13 Therefore, mitoxantrone treatment is not recommended in patients with LVEF < 50% or with clinically significant reduction in LVEF while on treatment.14 Mitoxantrone is indicated for multiple sclerosis and has a maximum lifetime cumulative dose of 140 mg/m2.14 It is administered every 3 months as a short IV infusion (5-15 minutes) as opposed to subcutaneous, intramuscular, intrathecal, and intra-arterial administrations, which are contraindicated.14 Baseline LVEF should be obtained prior to initiation of mitoxantrone therapy and continually monitored throughout treatment. Mitoxantrone is metabolized by the liver and reduces the amount of leukocytes. Therefore, it is not recommended in hepatic insufficiency with three-fold elevated enzymes or when neutrophil count is < 1500 mm3. Consequently, complete blood count and liver function tests should be done prior to each administration. Mitoxantrone’s side effects include blue-green urine days after infusion, sterility, and birth defects, which warrant for contraception throughout treatment and contraceptive test prior to each administration.15 Similar to anthracycline, dexrazoxane may be utilized to reduce free radical damage of mitoxantrone-induced cardiotoxicity with a dosing of dexrazoxane to mitoxantrone at 50:1 ratio.16 Human Epidermal Growth Factor Receptor 2 Protein (HER-2) receptor antagonist: trastuzumab HER-2 receptor antagonists are humanized IgG1 kappa monoclonal antibodies that target the human epidermal growth factor receptor tyrosine kinase HER-2/ ErbB2 for use in chemotherapy. Their effect on the overSpring 2015 • Arizona Journal of Pharmacy • 31

Cardiotoxicity expression of HER-2 is due to their selective binding to the extracellular HER-2. In recent years, these agents have been widely used in the treatment of women with HER2-positive breast cancer. However, while useful, their implications in cardiomyopathy and other cardiotoxic effects have limited their use. Trastuzumab is a HER-2 receptor inhibitor that has the most implications with cardiotoxicity in patients.18 Trastuzumab is one of the older HER-2 receptor antagonists that have been associated with cardiotoxicity. Using the classification system from the New York Heart Association (NYHA) to classify heart failure, the American Heart Association (AHA) found that HER-2 receptor antagonists have been associated with cardiotoxicity as its most debilitating side effect.18 The use of trastuzumab in HER2-positive breast cancer patients revealed cardiac dysfunction to a large extent shown in a large phase III trial.18 The incidence of cardiac dysfunction ranged between 4% to 7% when trastuzumab is used in monotherapy. However, if combined with anthracyclines, this number can reach up to 27%.18 Cardiac dysfunction in trastuzumab includes decreased LVEF and LVD. The rate of heart failure in patients treated with trastuzumab was significantly higher than those with regimens which did not include trastuzumab.19 Risks of cardiotoxicity of trastuzumab increases when anthracyclines are used in conjunction with or prior to the administration of trasuzumab.18 Hence, more careful monitoring for cardiac function is required for patients on these combinations.

While it is clear that the use of trastuzumab is related to cardiac failure, the mechanism of cardiotoxicity is unclear.

Erb2 is associated in a pathway that is essential for cardiomyocyte growth, repair, and survival. The mechanism of trastuzumab is currently thought to be related to its inhibition of the signaling cascade of the epidermal growth factor that includes cardiomyocyte HER-2 signaling and its ligand neuregulin-1. Neuregulin-1 and ErbB4 binding increases the activity of the tyrosine kinase, leading to hetero-dimerization with Erb2. This increases the signaling potency, which controls the survival of cardiomyocytes. Interruption of this signaling cascade can result in an ineffective mounting of a stress response.18 Unlike anthracyclines, cardiotoxicities of HER-2 receptor antagonists has not been linked to cell death. Rather, cardiotoxic stress from these agents is more closely associated with cardiac dysfunction. Moreover, it is important to note that the cardiotoxic effects of HER-2 receptor antagonists is not cumulative-dose related. Upon observation using electron microscopy, typically ultrasound changes were not present. This indicates that the cardiotoxic effects are reversible upon discontinuation of the agents. However, patients do not demonstrate recovery by a full 100%.19 To ensure patient safety on trastuzumab, baseline cardiac function is performed prior to therapy using chemotherapeutic medication. Assessment of this is completed using MUGA and ECHO. Patients with normal cardiac function will CONTINUING EDUCATION

be allowed to proceed with therapy with trastuzumab.

These are patients with normal LVEF (55-70%). Those with intermediate risk factors may begin treatment, but must be under increased observation of their healthcare provider to determine the risk-benefit relationship.

Intermediate risk factors are those with borderline LVEF (40-50%), advanced age, and increased cardiac risk.19 During treatment, patientsâ&#x20AC;&#x2122; LVEF is closely monitored and their treatment is based on the decrease of LVEF. In patients exhibiting a normal ejection fraction (EF) with an absolute decrease of greater than 16%, it is recommended for the treatment to be held for four weeks. If EF falls below the normal range, any decrease greater than 10% from baseline is indicative that treatment should be held for four weeks. It is noted that these decreases are symptomatic decreases of LVEF.19 Promising HER-2 inhibitors: lapatinib (Tykerb), pertuzumab (Perjeta), and trastuzumabemtansine (Kadcyla) HER-2 positive breast cancers are associated with a poorer prognosis. Because of the high cardiotoxicity of trastuzumab that limits its use in chemotherapy, there are several recent developments in the treatment of HER-2 positive breast cancers. Newer agents used after failure or discontinuation of trastuzumab include lapatinib (Tykerb), pertuzumab (Perjeta), and trastuzumab emtansine (Kadcyla). These agents are accompanied with a lower rate of cardiotoxicity.

Lapatinib is a reversible inhibitor of HER-2 and epidermal growth factor receptor (EGFR). Its approved indication is in combination with capecitabine (Xeloda) following trastuzumab failure.20 Lapatinib therapy is associated with a significantly lower rate of heart failure.

While cardiotoxicity is seen in animal trials, the bright outlook of lapatinib in terms of cardiotoxicity remains that its mechanism does not affect the ErbB2-ErbB4 signaling pathway, which is activated by cardiac cells via neuregulin-1. Because of this, lapatinib has exhibited a low cardiotoxic profile in comparison to trastuzumab, as seen in preliminary data from clinical trials.21 Pertuzumab is a newer agent in the anti-ErbB2 family of drugs, which is indicated for HER2-positive breast cancer in patients who cannot tolerate or have failed trastuzumab. Similar to lapatinib, pertuzumabâ&#x20AC;&#x2122;s mechanism does not involve the ErbB2-ErbB4 signaling pathway, which plays a role in its lower cardiotoxicity when compared to trastuzumab.14 Additionally, the mechanism of action of pertuzumab differs from that of trastuzumab in that they recognize different epitopes distant from one another, which is thought to play a role in their difference in cardiotoxic safety profile.21 Trastuzumab emtansine (T-DM1) is a combination drug, which includes trastuzumab and mertansine (DM1). Mertansine is a potent cytotoxic derivative of

Cardiotoxicity the antimicrotubule agent maytasine.22 The promising cardiotoxic profile of T-DM1 is linked with the stability of the tioether linker (N-maleimidomethyl) cyclohexan-1-carboxylate (MCC), which covalently binds trastuzumab and DM1.22 T-DM1’s more favorable safety profile is associated with its mechanism of action. The agent is initially internalized into its target cell, where it covalently binds to a lysine, creating a positively charged Lys-MCC-MD1. Lys-MCC-MD1 is unable to diffuse past the membrane into nearby normal cells. Because of this, T-DM1 exudes lower cardiotoxicity than trastuzumab.23 In addition to its free drug counterpart, trastuzumab, T-DM1 shows a higher cytotoxicity by delivering a higher drug concentration into the HER-2 positive tumor. In a phase II clinical trial, T-DM1 exhibited low cardiotoxicity, with no dose reduction due to decreased cardiac function. While it is noted that the pre-screened patient study population had low cardiotoxic potential, they continued receiving the agent for longer than one-year span. This is indicative of a tolerable long-term administration of T-DM1. In both phase I and phase II studies, cardiotoxicity was not reported with T-DM1.23 Because of its lower cardiotoxic profile, T-DM1 is a promising new agent in HER-2 positive breast cancers in patients who discontinue trastuzumab regimens due to its toxic effect on the heart.

However, T-DM1 show dose-limiting thrombocytopenia, which should be monitored in patients with moderate to high risk.23 5-Fluorouracil 5-fluorouracil (Adrucil) and its pro-drug capecitabine, are pyrimidine antagonist antineoplastic agents under the anti-metabolite family indicated in cancers of the breast, colorectal, gastric, pancreas, anal, bladder, cervix, bladder, esophagus, head and neck, and hepatobiliary pathway. While used for many indications, 5-fluorouracil (5-FU) has a several cardiac complications, including heart failure, arrhythmia, and myocardial ischemia.11 The cardiotoxic effects of 5-FU is seen more in patients with a history of cardiac event and is reversible upon discontinuation of the agent.24 Similar to trastuzumab, the mechanism of toxicity of 5-FU is unknown. It is theorized that 5-FU induces coronary spasms and direct vasoconstriction on smooth muscle cells.25 However, regardless of this theory, calcium channel blockers and nitrates were not seen as beneficial preventative agents for the cardiotoxic events. Another theory for 5-FU’s cardiac adverse effects is that it is catabolized to fluoroacetate, which is a known cardiotoxic substance.26 One important study by Lamberti et al. showed cardiotoxic effects not only in cancer patients, but also in their providing healthcare workers who were exposed to the chemo-agents.

The cause of the providers’ decreased cardiac function was not studied, but a correlation exists between their level of myocardial dysfunction and the drug concentration of their working tables, floors, and air-conditioning. This indicates safety and prevention should be performed in both patients and their health care providers handling the drug.26 CONTINUING EDUCATION

Additionally, the direct cardiotoxic effects of 5-FU are administration dose and frequency related. While continuous infusion and bolus dosing are both cardiotoxic, bolus dosing is associated with a lower cardiotoxic risk when compared to a prolonged continuous infusion regimen.25 24-hour 5-FU continuous infusions was associated with increased cardiac-related events when administered for 5 days, when compared to a shorter 5-FU administration regimen.26 Regardless of the dosing differences and mechanism of cardiotoxicity, all findings in the Lamberti study indicates 5-FU increases oxidative stress on cardiomyocytes, which can further lead to apoptosis of cardiac cells. Thus, the close cardiac monitoring must be considered in all patients on a cancer regimen utilizing 5-FU. Proteasome Inhibitors Bortezomib (Velcade) is a reversible dipeptide boronate-proteasome inhibitor used for hematological malignancies. Bortezomib has been shown to cause cardiotoxicity in patients, and thus studies have recently been performed to test for these toxic events. While these studies do not show this agent to induce cardiac myocyte death, it does show to cause impairment in cardiac function. Studies suggest that bortezomib impairs the ubiquitin-proteasome function, which is crucial in the vitality of cardiac myocytes. Thus, the inhibition of this proteasome pathway leads to cardiac dysfunction. The mechanism involves increased cardiac stress due to the accumulation of poly-ubiquinated proteins. Additionally, this agent impacts the heart possibly due to its induction of mitochondrial defects, leading to mitochondrial protein translocation. Further studies are needed to confirm this mechanism of toxicity. In a systematic review and meta-analysis by Xiao et al, there was no significant all-grade or high-grade cardiotoxicity risk with bortezomib.21 Regardless, the cardiotoxicity of bortezomib has not been shown to be reversible, therefore monitoring should be performed in these patients with a high baseline cardiac toxicity risk.27 Conclusion Oncologic drug-induced cardiotoxicity is a culprit in the premature halt of oncologic treatment regimen and induction or worsening of preventable cardiotoxicity. It not only hinders the treatment and progress of vulnerable oncologic patients, but it can potentially cause fatal or irreversible cardiac adverse events.

Therefore, pharmacists uphold the crucial responsibility in recognizing high-risk patients, screening patients prior to treatment, monitoring ECHO and MUGA, documenting cumulative dose when necessary, and Spring 2015 • Arizona Journal of Pharmacy • 33

Cardiotoxicity utilizing cardioprotective agents when applicable, in an effort to avert drug-induced cardiotoxicity. Oncologic patients are already in a highly vulnerable state; therefore, hopeful goals of pharmacologic treatment and management should be to improve patients’ quality of life and/or disease state, and at the very minimum to not harm the patients. As drug experts, pharmacists can make an impactful difference in preventing drug-induced cardiotoxicity in oncologic patients to optimize patients’ treatment outcome and quality of life.

Acknowledgement: We would like to acknowledge Ngoc Tran, PharmD, BCOP for her review of this manuscript.

References 1. American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.

2. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; 2014; July 30, 2014.

3. Minotti G, Menna P, Salvatorelli E et al. Anthracyclines:molecular advances and pharmacologic developments in antitumor activity andcardiotoxicity. Pharmacol Rev. 2004;56(2):185-229.

4. Daunorubicin Hydrochloride. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2005.

5. Colombo A, Cipolla C, Beggiato M et al. Cardiac toxicity of anticancer agents.CurrCardiol Rep. 2013;15(5):362.

6. Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med. 1996;125(1):47-58.

7. Cardinale D, Bacchiani G, Beggiato M et al. Strategies toprevent and treat cardiovascular risk in cancer patients. SeminOncol. 2013;40(2):186-98.

8. Doxorubicin package insert. Horsham, PA: Janssen Products; 2013.

9. Daunorubicin package insert. Auckland, New Zealand: Pfizer; 2014.

10. Epirubicin package insert. Irvine, CA: Teva Medical Inc; 2013.

11. Lipshultz SE, Adams MJ, Colan SD et al. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation.

2013;128(17):1927-95.

12. 2013 Oncology Pharmacy Preparatory Review Course. 2013 edition. Chicago: American Society American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy, Inc.; 2013.

13. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; 2014; July 30, 2014.

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14. Ghalie RG, Edan G, Laurent M et al. Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS. Neurology. 2002;59(6):909-13.

15. Scott LJ, Figgitt DP. Mitoxantrone: a review of its use in multiple sclerosis.CNS Drugs. 2004;18(6):379-96.

16. Rommer PS, Zettl UK, Kieseier B et al. Requirement for safety monitoring for approved multiplesclerosis therapies: an overview. ClinExpImmunol. 2014;175(3):397-407.

17. Cohen BA, Mikol DD. Mitoxantrone treatment of multiple sclerosis: safety considerations. Neurology.

2004;63(12Suppl6):S28-32.

18. Barth AS, Zhang Y, Li T et al. Functional impairment of human resident cardiac stem cells by the cardiotoxic antineoplastic agent trastuzumab. Stem Cells Trans Med. 2012;1:289-297.

19. Schlitt A, Jordan K, Vordermark D, Schwamborn J, Langer T, Thomssen C: Cardiotoxicity and oncological treatments. Dtsch Arztebl Int 2014; 111(10):161-8.

20. Gradishar WJ. Emerging approaches for treating HER2-positive metastatic breast cancer beyond trastuzumab. Annals of Oncology. 2013:24:2492-2500.

21. Fedele C, Riccio G, Malara AE et al. Mechanism of cardiotoxicity associated with ErbB2 inhibitors. Breast Cancer Res Treat. 2012;134:595-602.

22. Burris III HA, Rugo HS, Vukelja SJ et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) – positive breast cancer after prior HER2-directed therapy. J ClinOnc. 2011;29(4):398-405.

23. Diéras V, Bachelot T. The success story of trastuzumab emtansine, a targeted therapy in HER2-positive breast cancer. Tag Oncol. 2013. DOI 10.1007/s11523-013-0287-4.

23: Diéras V, Bachelot T. The success story of trastuzumab emtansine, a targeted therapy in HER2-positive breast cancer. Target Oncol. 2014;9(2):111-22.

24. Steingart RM, Yadav N, Manrique C et al. Cancer survivorship: cardiotoxic therapy in the adult cancer patient; cardiac outcomes with recommendations for patient management. Semin Oncol. 2013;40:690-708.

25. Astasopoulos P, Stebbing J. Molecular bassis of 5-fluorouracil-related toxicity: lessons from clinical practice. Anticancer Research. 2014;34:1531-1536.

26. Lamberti M, Porto S, Zappavigna S et al. A mechanistic study on the cardiotoxicity of 5-fluorouracil in vitro and clinical and occupational perspectives. Toxicology Letters.

2014;227:151-156 27. Xiao Y, Yin J, Wei J et al. Incidence and risk of cardiotoxicity associated with bortezomib in the treatment of cancer: a systematic review and meta-analysis. PLoS ONE. 2014;9(1) e87671.

ACPE UAN# 0100-0000-15-022-H04-P 0100-0000-15-022-H04-T

Geriatric Clinical Pearls

CONTINUING EDUCATION II

By Elizabeth Pogge, Pharm.D., BCPS, MPH, FASCP, Shana Walker, Pharm.D. and Paul Nguyen, Pharm.D. Midwestern University College of Pharmacy-Glendale Goal: This home-study CPE article is intended to provide pharmacists and pharmacy technicians with clinical pearls regarding medication dosing, monitoring, and appropriateness in the geriatric population.

Objectives for Pharmacists & Technicians: 1. Describe the differences in pharmacokinetics and pharmacodynamics in the elderly; elucidate some of the etiologies of the divergence in dosing, adjusting, and monitoring in the elderly.

2. Describe some of the currently relevant and/or significant medications with lower maximum doses for the elderly.

3. Describe some of the currently relevant and/or significant medications that require renal-adjustments and are of particular concern in the geriatric population.

4. Describe some of the currently relevant and/or significant drug-drug interactions that are commonly seen in the geriatric population.

5. Understand some miscellaneous clinical pearls that are helpful to know for optimal care in the geriatric population.

Background: Pharmacists are responsible for ensuring medication regimens are appropriate, safe, and optimal for each patient. In this endeavor, pharmacists are trained to review a plethora of information including, but not limited to, dosing, monitoring parameters, and criteria for special populations in which medications may need to be adjusted or used with caution. The elderly should be considered one of these special populations.

As the body ages, changes in pharmacokinetics (absorption, distribution, metabolism, and excretion of medication) and pharmacodynamics (the medication’s effect on the body) can occur. Two of the major pharmacokinetic changes that provide reasoning for alternative dosing strategies in the elderly are: age-related declines in renal function resulting in decreased drug clearance, and changes in fat to lean body mass ratio, leading to increased volume of distribution and larger drug storage reservoirs.1,2 The combination of these two changes in elderly patients can result in prolonged half-lives and ultimately higher plasma drug concentrations. If healthcare professionals are not aware of these changes or actively monitoring for these issues, they may expose elderly patients to toxicities at doses that are otherwise optimal in younger patients.2 In terms of pharmacodynamics changes, elderly are often more sensitive to the effects of medications, particularly adverse effects.

In addition to these changes, the geriatric population is more likely to be affected by at least one chronic disease state, and is therefore more likely to use prescription medCONTINUING EDUCATION

ications, over-the-counter medications, or dietary supplements. A recent survey of community-residing individuals from 57 to 85 years of age, found that 81% of adults in this age group used at least 1 prescription medication, 42% used at least 1 over-the-counter medication, and 49% used as least 1 dietary supplement.3 Furthermore, 29% of these individuals used at least 5 prescription medications concurrently. As a result, drug-drug interactions are more likely in the setting of polypharmacy, and are of particular importance considering the aforementioned pharmacodynamic and pharmacokinetic changes in these patients that may further exacerbate this issue.2 Maximum doses in the elderly: A typical reaction to the age-related changes that effect medication use in the elderly is a decrease in dose compared to younger patients. The adage “start low, go slow” in geriatrics applies to all medications and is something that can help healthcare providers avoid excessive dosages in the elderly. In response to the pharmacokinetic and pharmacodynamic changes that occur with aging, several medications have maximum doses that are specific to, and recommended for, the geriatric population. Some of these commonly used medications include citalopram, escitalopram, ketorolac, digoxin, zolpidem, zaleplon, and eszopiclone. See Table 1 for maximum doses in adult versus geriatric populations.

Selective serotonin reuptake inhibitors (SSRIs) In patients over 60 years of age, the maximum dose of citalopram, escitalopram, and paroxetine is lower. 5-7 These recommendations for reduced maximum doses in this population are due to increased risk for QT prolongation and symptom of inappropriate antidiuretic hormone secretion (SIADH).

Ketorolac (Toradol®) In the elderly (≥ 65 years of age), the maximum dose of ketorolac is reduced.8 This is delineated as: Intravenously (IV): 30 milligrams (mg) as a single dose or 15 mg every 6 hours Intramuscularly (IM): 15 mg as a single dose or 15 mg every 6 hours Oral: 10 mg, then 10 mg every 4 to 6 hours as needed8 Oral dosing should be restricted to a continuation of parenteral therapy, with the maximum combined duration of treatment (for parenteral and oral) being 5 days for any age. This dosing recommendation for a Spring 2015 • Arizona Journal of Pharmacy • 35

Geriatric reduced maximum dose in this population is due to age-related declining renal function and increased sensitivity to adverse events such as gastrointestinal bleeding and peptic ulcer disease.4,8 Digoxin (Lanoxin®) In patients who are > 70 years of age, have decreased renal function, and/or have low lean body mass, doses of 0.125 mg daily or every other day are recommended.9 This medication has a narrow therapeutic window and must be dosed appropriately with the knowledge that the elderly may have increased drug concentration levels at doses higher than the recommended 0.125 mg once daily or every other day due to their decreased renal function and lean body mass.10 Geriatric patients are also more likely to display signs and symptoms of toxicity at lower drug concentration levels.

Non-benzodiazepine hypnotics: In the elderly, the maximum dose of all the non-benzodiazepine hypnotics should be lower.11-15 All non-benzodiazepine hypnotics are recommended to be limited to short-term use (< 90 days) in older adults.4 These dosing recommendations for a reduced maximum dose in this population are due to the increased sensitivity to the related CNS adverse events such as confusion, impaired cognition, and impaired motor ability. Not only are the elderly more at risk for these adverse events, but their effects are more detrimental in this population due to increased risk for fall, fracture, and subsequent complications.4 Renal dosing adjustments: This topic is very broad and the following pearls are not inclusive, however, they detail some of the most common and newer renally-dosed medications that are used in the elderly. In addition to decreased renal clearance, serum creatinine levels may be misleading in this population due to the changes in lean muscle mass.2 Traditionally, drug dosing is based on pharmacokinetic studies where kidney function is assessed using creatinine clearance levels estimated from the Cockcroft-Gault equation.16 For this reason, most professionals recommend using the creatinine clearance estimation from the Cockcroft-Gault equation to determine medication dosing.17 In elderly patients with a low serum creatinine, most likely due to a decrease in muscle mass, some professionals recommended rounding this level up to 0.8 mg/dL or even 1 mg/dL, although this is not a practice that has been substantiated in clinical trials.18 Furthermore, use of ideal, adjusted, or actual body weight is another controversial issue that may affect the estimated creatinine clearance. A recent meta-analysis showed that adjusted body weight with a correction factor of 0.3 or 0.4 may be the most accurate in obese individuals, with the use of actual body weight for those close who are not obese.18 For all of these reasons, pharmacists must utilize clinical judgment, CONTINUING EDUCATION

Table 1. Maximum recommended doses for the geriatric population4-15 Agent SSRIs ketorolac digoxin (Lanoxin®) (Toradol®) Standard citalopram (Celexa®) 120mg IV, IM Maintenance: maximum 40mg once daily 40mg orally 0.125-0.25mg daily dose once daily escitalopram (Lexapro®) 20mg once daily paroxetine (Paxil®) IR: 50mg once daily CR: 62.5 mg once daily

Geriatric maximum daily dose

citalopram (Celexa®) 20mg once daily

eszopiclone (Lunesta®) 3mg once daily zaleplon (Sonata®) 20mg once daily 60mg IV, IM 40mg orally

escitalopram (Lexapro®) 10mg once daily

Maintanence: 0.125mg once daily or every other day

paroxetine (Paxil®) IR: 40mg once daily CR: 50 mg once daily

Risk in geriatric population

QT prolongation, symptom of inappropriate antidiuretic hormone secretion

Non-benzodiazepine hypnotics zolpidem (Ambien®) IR: 10mg ER: 12.5mg SL: 10mg Intermezzo: females – 1.75mg males – 3.5mg

IR: 5mg ER: 6.25mg SL: 5mg Intermezzo: 1.75mg (regardless of sex) eszopiclone (Lunesta®) 2mg once daily zaleplon (Sonata®) 10mg once daily

Gastrointestinal bleed, peptic ulcer disease

Digoxin toxicity

Central nervous system adverse events

taking into account the muscle mass of the patient, the clinical status of the patient, the therapeutic index of the medication, the severity of the patient’s illness, as well as the consequences of underdosing verses overdosing a particular medication when making decisions about rounding weight and/or serum creatinine.

Target Specific Oral Anticoagulants (TSOAC) The use of anticoagulant agents are indicated for many disease states including but not limited to stroke prevention in atrial fibrillation, stroke prevention in mechanical heart valve replacement, prophylaxis of venous thromboembolism (VTE) and treatment of VTE. Until recent years, the standard of care has been warfarin; however, in light of recent Food and Drug Administration (FDA) approvals and guideline recommendations—the usage of the TSOAC agents have been on the rise. The TSOAC agents include dabigatran (Pradaxa®), apixaban (Eliquis®), and rivaroxaban (Xarelto®). Dabigatran works as a direct thrombin inhibitor while both apixaban and rivaroxaban are factor Xa inhibitors.19-21 All of the TSOACs have FDA approved indications for non-valvular atrial fibrillation. Dabigatran and rivaroxaban are both approved for the treatment and reduction in the risk of VTE while apixaban and rivaroxaban are indicated for VTE prophylaxis following hip or knee replacement surgery.

The newer agents have demonstrated comparable efficacy and are generally well-tolerated. Some of the benefits for using the TSOACs over warfarin include fixed daily dosing, the lack of routine monitoring, and less drug-food interactions. Despite these benefits, the TSOACs are not without their risks. Due to the short half-lives of TSOACs, compliance is of paramount importance; as a missed dose may put the patient at

Geriatric an increased risk of a clot or stroke. Since the TSOACs are cleared mostly renally and/or hepatically, there may be issues with high systemic drug levels in the elderly populations, which can lead to an increased risk of adverse drug events. Dabigatran is 80%, rivaroxaban is 66%, and apixaban is 25% renally excreted.19-21 Additionally, patients with severe renal dysfunction were often excluded during the clinical trials for each of the medications, resulting in a lack of clinical trial data in renal dysfunction. As such, warfarin may be the preferred agent in this specific population since the dose can be titrated and adjusted in those with hepatic or renal impairment. Recommendations for renal adjustment are listed in Table 2.

Table 2. Target Specific Oral Anticoagulant FDA Approved Dosing Regimens Dabigatran19 Rivaroxaban20 Standard Dose VTE treatment: 150 mg VTE treatment: 15 twice daily (after 5-10 mg twice daily for the days of parenteral first 21 days, anticoagulation); followed by 20 mg nonvalvular atrial once daily; VTE fibrillation: 150 mg prophylaxis: 10 mg twice daily once daily; nonvalvular atrial fibrillation: 20 mg once daily Nonvalvular 75 mg twice daily: 15 mg once daily: atrial CrCl 30-50 mL/min with CrCl 15-50 mL/min fibrillation concomitant use of P-gp inhibitors ketoconazole Avoid use: or dronedarone OR CrCl <15 mL/min CrCl-15-30 mL/min Avoid co-administration: CrCl <30 mL/min with concomitant use of P-gp inhibitors OR with p-gp inducers Reduced Dosing

No recommendation: CrCl <15 mL/min or on dialysis

VTE treatment

Postoperative VTE prophylaxis

Avoid co-administration: CrCl <50 mL/min with concomitant use of P-gp inhibitors OR with p-gp inducers No recommendations: CrCl <30 mL/min or on dialysis Not FDA approved

Avoid use: CrCl <30 mL/min

Avoid use: CrCl <30 mL/min

Apixaban21 VTE prophylaxis: 2.5 mg twice daily; nonvalvular atrial fibrillation: 5 mg twice daily

2.5 mg twice daily: Patients with at least 2 of the following: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL OR taking dual strong CYP3A4 and P-gp inhibitors Avoid co-administration: Patients with at least 2 of the following: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL AND taking dual strong CYP3A4 and P-gp inhibitors Not FDA approved

No recommendations: Consider avoiding use with CrCl <30 mL/min

Nitrofurantoin (Macrobid®) Nitrofurantoin is currently FDA approved for the treatment of urinary tract infections when caused by susceptible strains of Escherichia Coli, enterococci, Staphylococcus aureus, and certain susceptible strains of Klebsiella and Enterobacter species.22 Both the safety and efficacy of the agent are highly dependent on the patient’s renal function. Contraindications for nitrofurantoin include anuria, oliguria, and/or significant impairment of renal function (elevated serum creatinine or CrCl<60 mL/min).

Elderly patients who have decreased renal function may have a lack of efficacy due to the inadequate drug concentration in the urine, thus hampering the medications bactericidal activity. Additionally, elderly patients that are unable to clear the drug are at an increased potential for pulmonary toxicities.4 Recommendations include avoiding CONTINUING EDUCATION

long-term usage or choosing a different antibiotic based on local susceptibilities and patient characteristics.

Glyburide (Diabeta®, Glynase®) Although sulfonylureas are not recommended as first line monotherapy for the treatment of type 2 diabetes mellitus, it is still a widely used agent due to its efficacy and low cost.23 Sulfonylureas are often used in combination with other oral antihyperglycemics in order to obtain greater glycemic control. Due to its pharmacokinetic profile, glyburide is known to have a longer duration of action, which is prolonged in patients with renal or hepatic dysfunction.24 In older patients, this may pose an increased risk for prolonged hypoglycemia since the patients may metabolize and renally excrete the medication at a slower rate. As such, it is recommended to avoid glyburide in the elderly population due to a greater risk of severe and prolonged hypogylcemia.4 A different sulfonylurea, such as glipizide or glimepiride, is recommended in the elderly.20 Canagliflozin (Invokana®) and Dapagliflozin (Farxiga®) Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a novel drug class approved as adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. SGLT2 channels are expressed in the proximal renal tubule and are responsible for the reabsorption of filtered glucose from the tubule lumen. Canagliflozin and dapagliflozin work by inhibiting the SGLT2 channels, thus reducing the reabsorption of filtered glucose, which causes an increase in urinary glucose excretion.25-26 Inherent to its mechanism of action, the SGLT2 inhibitors are dependent on renal function for proper efficacy and metabolism. For patients with normal renal function, the maximum doses of canagliflozin is 300 mg daily, while dapagliflozin is 10 mg daily.25-26 In those with decreased renal function, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min, these agents are recommended at a decreased dose or their use is not recommended.

Dapagliflozin is not recommended with an eGFR < 60 mL/ min, while canagliflozin should not be used when the eGFR <45 mL/min (maximum dose of 100 mg daily if eGFR 45-60 mL/min). Patients with impaired renal function will likely experience increased serum SGLT2 concentrations and reduced efficacy. Patients on these medications may also experience increased serum creatinine and decreased eGFR, with a greater probably in patients that are hypovolemic.25-26 It is recommend that renal function be monitored periodically and that the medications should be discontinued if the eGFR is persistently lower than the aforementioned thresholds.

Drug-drug Interactions: Polypharmacy is a common complication that is seen in Spring 2015 • Arizona Journal of Pharmacy • 37

Geriatric the geriatric population. Geriatric patients often time have multiple disease states and comorbidities that require complex treatment. Furthermore, necessary medications may have side effects that interfere with the patient’s quality of life, often resulting in the addition of mediations to treat these side effects.27 At times it is difficult to tell if a certain symptom that is being treated is indeed based within a newly acquired disease state that requires treatment, or if it is actually a side effect of another drug masquerading as a comorbidity. It is imperative to determine the indication for each medication so that the patient is exposed to the minimum amount of medications necessary to adequately treat their disease states.27 In addition to increased incidence of side effects with polypharmacy, patients are naturally at risk for more drug-drug interactions secondary to the fact that more medications are involved in the patient’s regimen. As pharmacists, we are responsible for determining the clinical significance of these interactions. It is important to note that drug-drug interactions are ubiquitous in nature and numerous in quantity; this list is not inclusive and outlines only some of the important and common drug-drug interactions seen in the geriatric population.

increased risk of myopathy and/or rhabdomyolysis and are dose-adjusted to avoid these adverse events.30-31 The elderly, in particular, are at higher risk for myopathies and should be monitored for these drug-drug interactions due to the fact that they are more likely to be exposed to these combinations and more likely to develop adverse events.

A recent dosing limitation in light of the FDA’s Drug Safety Communication titled “Ongoing safety review of high-dose Zocor (simvastatin®) and increased risk of muscle injury” recommends that doses of simvastatin 80 mg no longer be used, with the caveat that patients currently treated for > 12 months on this dose without evidence of myopathy or potential drug interactions may continue treatment.31 Table 3. Simvastatin and lovastatin dose limitations30-31 Agents Strong CYP3A4 inhibitors: ketoconazole, itraconazole, posaconazole, erythromycin, telithromycin, clarithromycin, HIV protease inhibitors, nefazodone, gemfibrozila, cyclosporinea Recommended maximum dose a b

Avoid

danazol diltiazem dronedarone verapamil

amiodarone amlodipineb ranolazineb

10 mg of simvastatin or 20 mg of lovastatin

20 mg of simvastatin or 40 mg of lovastatin

Avoid with lovastatin; maximum dose of 10 mg with simvastatin Maximum dose via package insert of simvastatin. Use caution with lovastatin.

Clopidogrel (Plavix®) and proton pump inhibitors Clopidogrel is a pro-drug that is activated primarily by cytochrome P450 (CYP) 2C19 to the active metabolite that produces its antiplatelet effects.28 Omeprazole and esomeprazole are CYP2C19 inhibitors, which results in decreased production of and exposure to clopidogrel’s active metabolite when given concomitantly.29 In the presence of this drug-drug interaction, the use of a different acid-suppressive therapy that does not have effects on CYP2C19, such as histamine type-2 receptor antagonists, is recommended.

It is important to note that poor metabolizers of CYP2C19 have reduced antiplatelet effect when given clopidogrel alone, and this drug-drug interaction may be more important in those who have poor CYP2C19 activity.28 If the patient is required to continue on a proton pump inhibitor, it may be more logical to choose pantoprazole, lansoprazole, or dexlansoprazole due to their reduced effects on CYP2C19 when compared with omeprazole and esomeprazole.28

Some miscellaneous pearls: Benzodiazepines Benzodiazepines have a wide array of usages, including anxiety, panic disorders, insomnia, and seizures. Benzodiazepines are typically recommended for short-term use, although this is not always what occurs in clinical practice. Besides the potential for addiction, benzodiazepines have many negative adverse effects including central nervous system depression, cognitive impairment, confusion, delirium, and falls. These adverse effects may be more pronounced in the elderly due to increased sensitivity to benzodiazepines and slower metabolism.4 Higher dosages of benzodiazepines have also been associated with an increased for adverse events, especially falls.4 If possible, it is recommended to avoid benzodiazepines in the elderly for the treatment of insomnia, agitation, or delirium.4

Statin medications Simvastatin and lovastatin are commonly used cholesterol lowering statin medications. Both agents are substrates of CYP3A4, causing the agents to have drug-drug interactions with several commonly used medications. One of the major adverse events that require safety monitoring with statin medications is the increased incidence of myopathies/ rhabdomyolysis. As a result of the CYP3A4 metabolism of these agents, there are several clinically significant drugdrug interactions with strong CYP3A4 inhibitors that require either a dose decrease or are should not be used with these agents (Table 3). These interactions are all associated with

Antipsychotics In April 2005, the FDA issued a statement that elderly patients with dementia-related psychosis who are treated with atypical antipsychotic medications are at an increased risk of mortality. This statement for atypical antipsychotics came from a meta-analysis of 15 randomized placebo-controlled trials that examined the use of atypical antipsychotics for the treatment of behavioral disturbances secondary to dementia or Alzheimer’s Disease.33 This meta-analysis included studies on aripiprazole, olanzapine, quetiapine, and risperidone.

The authors found that death occurred in 3.5% patients

CONTINUING EDUCATION

Geriatric receiving an atypical antipsychotics when compared to 2.3% of the patients randomized to placebo. The pooled odds ratio for death was 1.54; 95% CI: (1.06-2.23); P=0.02.33 Further observational and epidemiological studies also demonstrated an increased risk of death in elderly dementia patients that were using atypical or typical antipsychotics.34-35 In 2008, the FDA extended their statement to include the black box warning for both atypical and typical antipsychotics. When encountering older patients with dementia, the use of antipsychotics should be avoided whenever possible. Antipsychotics should only be considered if non-pharmacological options have failed and the patient is a threat to themselves or others.4 Conclusion: The geriatric population is a special population with pharmacologically evident changes in their response to medications that are typically predictable and somewhat avoidable with the knowledge and awareness of these changes. Pharmacists should be aware of these changes and can play a key role in making sure that the dosing, along with the medication, is appropriate for the patient.

References:

1. Rowe JW, Andres R, Tobin JD, et al. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol. 1976;31(2):155.

2. Corsonello A, Pedone C, Incalzi RA. Age-related pharmacokinetic and pharmacodynamic changes and related risk of adverse drug reactions. Curr Med Chem. 2010;17(6):571-584.

3. Qato DM, Alexander GC, Conti RM, et al. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA. 2008,300(24):2867-2878.

4. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am GeriatrSoc. 2012;60(4):616-31.

5. Celexa® [package insert]. St Louis, MO. Forest Pharmaceuticals Inc; 2013.

6. Lexapro® [package insert]. St. Louis, MO. Forest Pharmaceuticals, Inc; 2012.

7. Paxil® [package insert]. St. Louis, MO. Forest Pharmaceuticals, Inc; 2012.

8. Ketorolac Tromethamine [package insert]. Lake Forest, IL. Hospira; 2005.

9. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-e327.

10. Lanoxin® [package insert]. Greenville, NC. DSM Pharmaceuticals Inc; 2011.

11. Ambien® [package insert]. Bridgewater, NJ. Sanofi-Aventis LLC; 2013.

12. Intermezzo® [package insert]. Stamford, CT. Purdue Pharma L.P; 2014.

13. Ambien CR® [package insert]. Bridgewater, NJ. Sanofi-Aventis LLC; 2013.

14. Lunesta® [package insert]. Marlborough, MA. Sunovion PharmaCONTINUING EDUCATION

ceuticals Inc; 2014.

15. Sonata® [package insert]. Philadelphia, PA. Wyeth Pharmaceuticals Inc; 2006.

16. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41.

17. National Kidney Foundation. Frequently asked questions about GFR estimates. http://www.kidney.org/professionals/ kls/pdf/12-10-4004_KBB_FAQs_AboutGFR-1.pdf Accessed July 9, 2014.

18. Wilhelm SM, Kale-Pradhan PB. Estimating creatinine clearance: a meta-analysis. Pharmacotherapy. 2011;31:658664.

19. Pradaxa® [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals Inc; 2014.

20. Xarelto® [package insert]. Titusville, NJ. Janssen Pharmaceuticals Inc; 2014.

21. Eliquis® [package insert]. Princeton, NJ. Bristol-Myers Squibb Company; 2014.

22. Lexi-Comp online. Nitrofurantoin. Hudson, Ohio: LexiComp, Inc; Accessed July 9, 2014.

23. American Diabetes Association. Standards of medical care in diabetes - 2014. Diabetes Care. 2014; 37(1):S14-S74.

24. Lexi-Comp online. Glyburide. Hudson, Ohio: Lexi-Comp, Inc.; Accessed July 9, 2014.

25. Invokana® [package insert]. Titusville, NJ. Janssen Pharmaceuticals Inc; 2013.

26. Farxiga® [package insert]. Princeton, NJ. Bristol-Myers Squibb Company; 2014.

27. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. Guiding Principles for the Care of Older Adults with Multimorbidity; An Approach for Clinicians. J Am Geriatr Soc. 2012;60(10):E1-E25.

28. Plavix® [package insert]. Bridgewater, NJ. Sanofi-Aventis LLC; 2013.

29. Prilosec® [package insert]. Wilmington, DE. AstraZenica Pharmaceuticals LP; 2014.

30. Zocor® [package insert]. Whitehouse Station, NJ. Merck and Company Inc; 1999-2014.

31. Lovastatin [package insert]. Sellersville, PA. Teva Pharmaceuticals; 2014.

32. US Food and Drug Administration. FDA Drug Safety Communication: Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. http:// www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm. March 19, 2010. Accessed July 21, 2014.

33. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia. JAMA. 2005;294(15):1934-43.

34. Gill SS, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med. 2007;146(11):775-786 35. Schneeweiss S, Setoquchi S, Brookhart A, et al. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ. 2007; 176(5):627-632.

ACPE UAN# 0100-0000-15-021-H04-P 0100-0000-15-021-H04-T Spring 2015 • Arizona Journal of Pharmacy • 39

I.

CONTINUING EDUCATION QUIZ QUESTIONS

Drug-induced Cardiotoxicity of Oncological Agents: Monitoring Parameters, Prevention, and Future Chemotherapy ACPE UAN# 0100-0000-15-022-H04-P; 0100-0000-15-022-H04-T 1. What is the significant impact of oncologic drug-induced cardiotoxicity on cancer treatment? a. It may warrant a delay or discontinuation of cancer treatment b. It can potentially cause fatal or irreversible cardiac adverse events c. It may worsen the treatment outcome d. All of the above 2. Which of the following is TRUE regarding anthracyclines? a. Anthracycline-induced cardiotoxicity is dose-related and potentially irreversible b. Anthrancycline should be discontinued when LVEF is less than 50% or when it is decreased greater than 10% from baseline c. ECHO and MUGA are generally used to monitor anthracycline-induced cardiotoxicity d. All of the above 3. Which of the following is FALSE regarding dexrazoxane? a. It is an intravenous cardioprotective agent b. It reduces anthracycline-induced free radical damage c. Dosing of dexrazoxane to anthracycline is a 10:1 ratio, respectively d. It is recommended in the pediatric population 4. Which of the following is FALSE? a. Mitxoxantrone is an anthracenedione derivative with similar mechanism of action as antracyclines b. Dosing of dexrazoxane of mitoxantrone is also a 10:1 ratio, respectively c. Mitoxantrone has a maximum lifetime cumulative dose of 140 mg/m2 d. Mitoxantrone requires a CBC, thrombocyte, and liver function test prior to administration 5. Which of the following statement is accurate ? a.The maximum lifetime cumulative dose for doxorubicin is 800-900 mg/m b. The cardiotoxicity of lapatinib is irreversible upon discontinuation c. Dexrazoxane is an important preventative agent for trastuzumabcardiotoxicity d. An LVEP < 50% warrants discontinuation from anthracycline chemotherapy

6. Of the following agents, which has been shown to cause cardiac cell death? a. Anthracyclines b. HER-2 inhibitors c. HER-2 and EGFR inhibitors d. Proteosome inhibitors 7. What is the theorized mechanism of cardiotoxicity of trastuzumab? a. Trastuzumab binds to Neuregulin-1, inhibiting the heterodimerization with Erb2 and Erb4 b. Trastuzumab inhibits the signaling cascade involving the heterodimerization of neuregulin-1 ErbB4 with Erb2, inhibiting cardiomyocyte stress response c. Trastuzumab interferes with the signaling cascade involving neuregulin-1, ErbB4, and ErbB2 in cardiomyocytes, leading to lower LVEF d. B and C 8. The incidence of cardiotoxicity increases significantly when trastuzumab is combined with which of the following chemotherapeutic agent? a. Lapatinib b. Doxorubien c. Bortezomib d. Emtansine 9. Which of the following is FALSE regarding lapatinib? a. Lapatinib is a reversible inhibitor of HER2 and EGFR b. Lapatinib affects a different epitope from trastuzumab, leading to a lower cardiotoxic profile c. It can be considered in combination with capecitabine in patients who have failed trastuzumab d. It is indicated for HER2 positive breast cancer e. All of the above are true 10. Which of the following is TRUE regarding the cardiotoxicity safety profile different between pertuzumab and trastuzumab? a. Pertuzumab and trastuzumab recognize different epitopes from one another b. Pertuzumab is highly selective for HER2 positive tumer cells c. Once entered into the tumor cell, pertuzumab cannot diffuse into nearby

cardiac cells. d. Pertuzumab is a newer cardioprotective HER2 inhibitor 11. Which of the following is TRUE regarding T-DM1? a. T-DM1 is less cytotoxic than trastuzumab due to the stability of the linker MCC b. T-DM1 should not be used for longer than 1 year c. The dose limiting adverse effect of T-DM1 is ventricular dysfunction d. MCC binds to Lysine, preventing drug diffusion into nearby cardia ccell, lowering cardiotoxicity of T-DM1 12. Which oncologic agent has been shown to affect healthcare workers treating patients on its regimen? a. 5-Fluorouracil b. Doxorubicin c. Trastuzumab d. Bortezomib e. Pertuzumab 13. The cardiotoxicity of which agents are reversible upon discontinuation? a. Trastuzumab b. Doxorubicin c. 5-Fluorouracil d. A and B e. A and C 14. What is the suggested pathways involved in the cardiotoxicity of Bortezomib? a. Erb2 pathway of cardiomyocytes b. Ubiquitin-proteosome function which vital for cardiomyocytes c. Direct vasoconstruction d. All of the above e. Bortezomib does not show any cardiotoxicity in patients

PLEASE COMPLETE THE ANSWER SHEET ON PAGE 42

II.

Geriatric Clinical Pearls

ACPE UAN# 0100-0000-15-021-H04-P; 0100-0000-15-021-H04-T

1. Example(s) of possible pharmacokinetic differences that may present in the elderly are? a. Decreased drug clearance due to age-related declines in renal function b. Decreased drug absorption due to declines in GI function c. Increased plasma drug concentrations due to changes in volume of distribution d. A and C e. All of the above 2. Typical reasons for dose adjustments in the elderly include: a. Increased sensitivity to adverse events b. Decreased renal clearance c. Increased incidence of drug interactions d. Increased plasma drug concentration due to changes in body mass ratios e. All of the above 3. Citalopram/escitalopram/paroxetine have reduced maximum doses in the elderly du to their increased risk for which of the following adverse events: a. Diarrhea b. QT prolongation c. Tremor d. SIADH e. B and D 4. The maximum does of digoxin in the elderly is: a. 0.25 mg by mouth once daily b. 0.25 mg by mouth every other day c. 0.125 mg by mouth once daily or every other day d. 0.0625 mg by mouth once daily e. There is no maximum dose of digoxin in the elderly 5. What is the recommended maximum daily dose for canagliflozin (Invokana ®) if a patient’s eGRF is ~ 40 mL/min? a. 5 mg daily b. 10 mg daily c. 100 mg daily d. 300 mg daily e. Canagliflozin should not be used

6. A prescriber wants to start apixaban for a patient who has nonvalvular atrial fibrillation. The patient is 75 years old, weighs 50 kg, and has a serum creatinine of 1.7 mg/dL. What dose do you recommend for this patient? a. 5 mg twice daily b. 5 mg once daily c. 2.5 mg twice daily d. 2.5 mg once daily e. Apixaban is not indicated for non-valvular atrial fibrillation 7. Concern for a significant drug interaction with clopidogrel in the elderly is warranted with concomitant use of which of the following: a. Proton pump inhibitors b. Histamine2 Receptor Antagonists c. Antacids d. None of the above e. All of the above 8. A maximum dose of simvastatin 20 mg by mouth once daily is appropriate with concomitant use of all of the following EXCEPT: a. Amiodarone b. Amlodipine c. Ranolazine d. Verapamil 9. TRUE or FALSE. Benzodiazepines are recommended for the treatment of insomnia in the elderly due to the medication’s sedating effects? a. True b. False 10. What is the black box warning associated with atypical antipsychotics for the elderly? a. Increased mortality in elderly patients with dementia-related psychosis b. Increased mortality in all elderly patients c. Decreased mortality in elderly patients with dementia-related psychosis d. Decreased mortality in all elderly patients e. None of the above

PLEASE COMPLETE THE ANSWER SHEET ON PAGE 42

CONTINUING EDUCATION

Spring 2015 • Arizona Journal of Pharmacy • 41

Continuing Education Answer Sheet:

I.

Drug-induced Cardiotoxicity of Oncological Agents: Monitoring Parameters, Prevention, and Future Chemotherapy

ACPE UAN#0100-0000-15-022-H04-P

0100-0000-15-022-H04-T

Activity accredited date: 03/01/2015 Expiration date: 03/01/2018. This activity is accredited for 1 hour of CPE credit (CEUs 0.10) In order to qualify for ACPE credit, participants must achieve a grade of 70% or above on the quiz and submit a completed activity evaluation. Complete the quiz / eval below or take the quiz online at Pharmacists: azpharmacy.org/ajp_spring/cardiotoxicityRPh

Technicians: azpharmacy.org/ajp_spring/cardiotoxicityCPhT

CE Assessment Answers - Please circle your answers (one answer per question.)

1. a. b. c. d.

8. a.

2. a. b. c. d.

9. a.

3. a. b. c. d.

10. a.

4. a. b. c. d.

11. a.

5.

6.

7.

a. a. a.

b. b. b.

c. c. c.

d. d. d.

12.

13.

14.

a. a. a.

Questions on page 40. b. c. d. b. c. d. e. b. c. d. b. c. d. b. b. b.

c. c. c.

d. d. d.

e. e. e.

ACTIVITY EVALUATION – Must be completed to receive credit.

1. The activity met the stated learning objectives. (Full list of learning objectives in article.)

AGREE DISAGREE 2. Please rate the activity based on the following (please circle one): • Overall evaluation of the article content:

Poor 1 2 3 4 5 Excellent • Relevance to pharmacy practice Poor 1 2 3 4 5 Excellent • Value of the content Poor 1 2 3 4 5 Excellent 3. The information presented (check all that apply):

Reinforce my current practice/treatment habits Will improve my practice/patient outcomes Provided new ideas or information I expect to use Adds to my knowledge 4. Will the information presented cause you to make any changes to your style or method?

Yes No 5. Will the information presented cause you to make any changes in your practice?

Yes No 6. How committed are you to making these changes?

Not committed 1 2 3 4 5 Very committed 7. Do you feel future activities on this subject matter are necessary and/or important?

Yes No

II.

Geriatric Clinical Pearls ACPE UAN#0100-0000-15-021-H04-P

0100-0000-15-021-H04-T

Activity accredited date: 03/01/2015 Expiration date: 03/01/2018. This activity is accredited for 1 hour of CPE credit (CEUs 0.10) to qualify for ACPE credit, participants must achieve a grade of 70% or above on the quiz and submit a completed activity evaluation.

In order

Complete the quiz / eval below or take the quiz online at Pharmacists: azpharmacy.org/ajp_spring/geriatricRPh Technicians: azpharmacy.org/ajp_spring/geriatricCPhT \ C

CE Assessment Answers - Please circle your answers (one answer per question.)

1. a. b. c. d. e.

6. a.

2. a. b. c. d. e.

7. a.

3. a. b. c. d. e.

8. a.

4. a. b. c. d. e.

9. a.

5.

a.

b.

c.

d.

e.

10.

a.

Questions on page 41 b. c. d. e. b. c. d. e. b. c. d. b. b.

c.

d.

e.

ACTIVITY EVALUATION – Must be completed to receive credit.

1. The activity met the stated learning objectives. (Full list of learning objectives in article.)

AGREE DISAGREE 2. Please rate the activity based on the following (please circle one): • Overall evaluation of the article content:

Poor 1 2 3 4 5 Excellent • Relevance to pharmacy practice Poor 1 2 3 4 5 Excellent • Value of the content Poor 1 2 3 4 5 Excellent 3. The information presented (check all that apply):

Reinforce my current practice/treatment habits Will improve my practice/patient outcomes Provided new ideas or information I expect to use Adds to my knowledge 4. Will the information presented cause you to make any changes to your style or method?

Yes No 5. Will the information presented cause you to make any changes in your practice?

Yes No 6. How committed are you to making these changes?

Not committed 1 2 3 4 5 Very committed 7. Do you feel future activities on this subject matter are necessary and/or important?

Yes No PARTICIPANT INFORMATION: Name ________________________________________ Phone _______________________________________

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