The Kentucky Pharmacist January/February 2018

Vol. 13 No. 1 January/February 2018

THE KENTUCKY

PHARMACIST Official Journal of the Kentucky Pharmacists Association

INSIDE: Board Authorized Protocols Ambassador Program Board of Pharmacy Update

TABLE OF CONTENTS FEATURES Board of Pharmacy Update |4| Potential Implications of High-Risk Medication Use in the Older Adult |5|

Mission Statement:

Pharmacists’ Authority to Deliver Protocol-Driven Care Set to Impact Patient and Public Health Across the Commonwealth |38|

The mission of KPhA is to advocate for and advance the profession through an engaged membership.

Editorial Office: ©Copyright 2018 to the Kentucky Pharmacists Association. The Kentucky Pharmacist is the official journal of the Kentucky Pharmacists Association published bi-monthly. The Kentucky Pharmacist is distributed to KPhA members, paid through allocations of membership dues. All views expressed in articles are those of the writer, and not necessarily the official position of the Kentucky Pharmacists Association.

IN EVERY ISSUE President’s Perspective |3| My KPhA Rx |6| Advocacy Matters |10| Continuing Pharmacy Education |12| Pharmacy Law Brief |32| Pharmacy Policy Issues | 34|

Publisher: Mark Glasper Managing Editor: Sarah Brandenburg Editorial, advertising and executive offices at 96 C Michael Davenport Blvd., Frankfort, KY 40601.

Phone: 502.227.2303 Fax: 502.227.2258.

Email: info@kphanet.org.

Website: www.kphanet.org.

ADVERTISERS APSC|8| PTCB |18| EPIC |7 & 36| Cardinal |40| Pharmacists Mutual |41|

|2| Kentucky Pharmacists Association | January/February 2018

PRESIDENT’S PERSPECTIVE Pharmacists face new challenges and opportunities every day. We see this even more during the legislative session. The Kentucky Pharmacists Association continues to work with the leaders in the Commonwealth to ensure your voice is heard in Frankfort. We work daily to promote our profession and, in doing so, improve the value of pharmacists and the lives entrusted in our care. KPhA cares about the issues you care about, and we will continue to be the voice for all pharmacists in Kentucky.

One of the major issues facing pharmacy today is payment. Pharmacists must get adequate reimbursement for products and services rendered to ensure their continued presence in community and health systems. The strategies to accomplish this goal are complex, but I believe they are achievable. As this is a major priority for our association, and part of our strategic plan, we will overcome the barriers that decrease access to pharmacists and the services we provide.

KPhA has worked diligently to bring a new and unique opportunity for pharmacists in our State. The Kentucky Board of Pharmacy (KBOP) recently promulgated a regula“KPhA has worked diligently tion allowing pharmacists to enter into a prescriberto bring a new and unique approved protocol to manage patients with certain conditions. The KBOP considered these conditions to be serious opportunity for pharmacists public health concerns, and they acknowledged that pharin our state.” macists are willing and ready to serve in a larger capacity to get patients quicker access to care. Here at KPhA, we are actively preparing educational opportunities to meet the requirements of this regulation and refresh your knowledge and skills so you can be ready to serve your patients.

KPhA remains optimistic about the current and future opportunities for pharmacists. As we look toward the future, we continue to ask you for support of our association so we can best support you and your profession. The best way to promote yourself as an individual pharmacist is to promote the profession itself.

Donate online to the Kentucky Pharmacists Political Advocacy Council Go to www.kphanet.org and click on the Advocacy tab for more information about KPPAC and the donation form. |3| www.KPHANET.org

Board of Pharmacy Update

Larry A. Hadley Named Executive Director of Kentucky Board of Pharmacy Larry A. Hadley, Frankfort, was selected as the Executive Director of the Kentucky Board of Pharmacy. Hadley fills the vacancy left by Steve Hart's retirement. Hadley received his B.S in Pharmacy from the University of Kentucky in 1974. He has a longstanding career in community pharmacy and co-owned his own pharmacy until last year. He has many years of volunteer leadership service to the Kentucky Board of Pharmacy and the Kentucky Pharmacists Association. Please join KPhA in thanking Steve Hart for his many years of service and join us in welcoming Larry Hadley to his new role.

Larry A. Hadley Office Phone: 502-564-7910 Email: larry.hadley@ky.gov

Governor Bevin Appoints Members to the Kentucky Board of Pharmacy The following pharmacists were appointed by Governor Matthew G. Bevin to serve on the Kentucky Board of Pharmacy. The pharmacists were selected from the names supplied to the Governor by KPhA. Please join us in congratulating the following newly appointed Kentucky Board of Pharmacy members:

Peter P. Cohron, Henderson, representing licensed pharmacists, to replace Debora Lee Brewer, Sandy Hook, whose term has expired; Joe Davis Forgy, Morgantown, representing citizens at-large, to replace Brian C. DeWire, Paintsville,

Jill Rene Rhodes, Crestwood, representing licensed pharmacists, to replace Scott Andrew Greenwell, Prospect, whose term has expired.

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Feature Article Potential Implications of High-Risk Medication Use in the Older Adult Author: Kate Reeves, PharmD Candidate (2018), University of Kentucky College of Pharmacy The infamous Beers Criteria, published by the American Geriatrics Society, aims to identify potentially inappropriate medications (PIMs) in older adults. PIMs are associated with poor health outcomes when used in patients age 65 years and older. These negative outcomes could be due to falls, confusion, drug accumulation, or overall mortality. In 2015, Beers Criteria was updated to include medications that require dose adjustment based on renal function, as well as drugdrug interactions. The list of PIMs is widely utilized by healthcare professionals when prescribing medications as well as for desprescribing when medications are deemed unnecessary or a safer alternative is available. Pharmacists and technicians have an opportunity here. It is our job to be aware of what these high-risk medications are in order to educate patients, as well as other healthcare providers. As professionals at the forefront of patient safety, it is necessary to understand the potential consequences PIMs and utilize this understanding to improve the healthcare of others.

One of the most common classes of drugs targeted for deprescribing in older adults is first-generation antihistamines. Diphenhydramine, meclizine, promethazine, and hydroxyzine are just a few within this class that pose a threat to those over 65 years of age due to their anticholinergic properties. Use of these agents could increase the risk of dry mouth, constipation, and confusion. Furthermore, clearance of these drugs seems to be reduced in older adults, further exacerbating their risk.

Table 1 lists additional commonly prescribed PIMs and the rationale for their placement on the Beers list.

lead to polypharmacy in older adults, which is recognized as a serious problem due to its association with significant mortality and morbidity.

Pharmacy personnel can make a big difference in patient outcomes by recognizing high-risk medications and identifying and interfering with potential prescribing cascades. Such interventions are not easy and can be hindered by lack of access to a patient’s diagnoses, lab values, past medical history, and full medication list.

Healthcare providers should also be aware of drugs that However, gaining a better understanding of PIMs and should be avoided in patients with specific disease states being able to explain the potential consequences of rouand syndromes. For example, bupropion and tramadol tine use of these medications is necessary in optimizing should be avoided in a patient with chronic seizures or care in older adults. Pharmacists are one of the few healthcare providers that fully understand the implicaepilepsy due to the potential of these agents to lower tions of these medications in the elderly population, and seizure threshold. In patients with insomnia, pseudoephedrine and phenylephrine should be avoided it is our duty to address this growing issue and ensure quality care for our patients. due to the CNS stimulant effects these agents possess.

Awareness of drug-disease interactions can help prevent References a dangerous practice called the prescribing cascade. Pre- American Geriatrics Society 2015 Beers Criteria Update Expert Panel. “American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.” Journal of the Ameriscribing cascades occur when side effects of drugs are Geriatrics Society, vol. 63, no. 11, Aug. 2015, pp. 2227–2246., doi:10.1111/jgs.13702. misinterpreted as symptoms of a new problem, resulting can doi:10.1111/jgs.13702. in additional prescriptions. The prescribing cascade may |5| www.KPHANET.org

MY KPhA Rx Looking Forward to 2018

By Mark Glasper KPhA Executive Director/CEO The headline to this column has a couple of connotations. One, let’s look ahead to see what we’ll be doing this year. And, two, I’m really looking forward with eager anticipation to 2018! Let’s do some of both.

Legislative Session This will be my first legislative session in Kentucky and, from what I’ve heard, it’s best to expect the unexpected. My previous experience with the legislative process was in Ohio where the General Assembly met much of the year – budget or no budget. That meant there was plenty of time for legislators to get the peoples’ work done. Even then, budget discussions always pushed the process to the eleventh hour with the Governor adding his signature at the last possible minute. But, in Kentucky, the budget year is whittled down to just 60 days in session, necessitating a mad dash this year from the starting line January 2 to the finish line April 14.

I’m looking forward to the process. We had a prefiled bill by Senator Max Wise (R-District 16) which would require all outpatient pharmacy benefits to be administered directly by the Department for Medicaid Services. This would be a huge win for Kentucky pharmacists and your struggle against under reimbursements.

I pledge that KPhA will stay on top of this issue and keep you informed every step of the way. Please watch for our updates on this issue as well as the many others that will arise during session. We will seek your support in the way of letter writing, calling and e-mailing your legislators on these important issues.

As always, it’s imperative your elected officials hear from YOU, their constituents.

Ambassador Program Do you have a passion for building and growing relationships?

Do you possess knowledge of KPhA and an appreciation for the Pharmacy profession?

Are you well connected in your region?

If so, then the KPhA Ambassador Program is for you.

The Ambassador Program is a new program that will be used to build peer-to-peer relationships to strengthen KPhA Membership and Pharmacy relationships between Pharmacists, Technicians and student Pharmacists throughout the Commonwealth. KPhA is looking for volunteers who are proactive and outgoing team members who will be re|6| Kentucky Pharmacists Association | January/February 2018

sponsible for increasing awareness and excitement about the Kentucky Pharmacists Association throughout the pharmacy community.

Interested? Then we’re interested in hearing from you. Call me, send an e-mail to me but, no matter what, contact me so we can discuss how you can help us grow KPhA!

Annual Meeting & Convention I invite you all to attend the KPhA Annual Meeting & Convention June 14-17, 2018 at the Cincinnati Marriott at RiverCenter, Covington, KY. We’re planning a fun and educational event for you, including an opening reception Thursday, June 14, at the Newport Aquarium. Be sure to bring the kids to this family friendly event!

If CE is your thing, then we’ll have plenty for you to round out your 2018 requirements. Great topics, terrific speakers and the best networking opportunities you’ll have this year await you at the KPhA Annual Meeting & Convention.

Speaking of networking, you’ll want to attend our House of Delegates events, the special luncheons and the Ray Wirth Awards Banquet. You’ll be sure to rub elbows with the movers and shakers in Kentucky pharmacy!

I look forward to seeing you in Covington!

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Become a KPhA Ambassador Today!

Do you have a passion for building and growing relationships?

Do you possess a knowledge of KPhA and an appreciation for the Pharmacy profession?

Are you well connected in your region?

If so, then the KPhA Ambassador Program is for you.

Visit www.kphanet.org/ambassador-program to learn more!

Volunteer Today Pharmacist, pharmacy technician and student pharmacist recruitment is still underway for the Kentucky Pharmacists Association emergency preparedness program! Pharmacy professionals play a critical part in responding to emergency events such as a natural disaster or infectious disease outbreak.

For more information on how you can be involved in the KPhA Pharmacy Emergency Preparedness Initiative, contact KPhA 502-227-2303 or by email at jjaggers@kphanet.org.

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Advocacy Matters Ways you can support KPhA’s Advocacy efforts today! 

Participate in grassroots advocacy efforts

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Get to know your legislators—they should know your name

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Donate to the Political Advocacy Council and the Government Affairs Fund

Photo by: Matt Turner

Donate online to the KPhA Government Affairs Fund Funds contributed to KPhA Government Affairs are applied directly to our lobbying efforts in terms of staffing and contracted lobbying services. Company donations are acceptable for Government Affairs contributions, unlike contributions to Political Advocacy Funds, like KPPAC. Go to www.kphanet.org form. |10| Kentucky Pharmacists Association | January/February 2018

Sam Willett, RPh, Capital Campaign Donor

“

KPhA has always been devoted to its mission of advocating for and advancing the profession of pharmacy, a profession that has been very rewarding to me personally and financially. Donating to the capital campaign is just a small token of appreciation to the professional organization that supports all pharmacists.�

Leave a legacy by making a tax-deductible donation online at www.kypharmacyfuture.net |11| www.KPHANET.org

January CPE Article Chronic Care Management Services and the Pharmacist’s Role By: Erin N. Deja, PharmD Candidate 2018, and Joseph L. Fink III, BSPharm, JD, DSc (Hon), FAPhA The authors declare that there are no financial relationships that could be perceived as real or apparent conflicts of interest.

Goal: To discuss Chronic Care Management and identify ways in which pharmacists can be reimbursed for providing clinical services.

Universal Activity # 0143-0000-18-001-H04-P &T 1.0 Contact Hours (0.10 CEU) Expires 1/02/2021

KPERF offers all CE articles to members online at www.kphanet.org

Objectives: At the conclusion of this Knowledge-based article, the reader should be able to: 1. Define Chronic Care Management and describe the 5 core services it entails 2. Identify members of the Chronic Care Management care team and how pharmacists can engage in the provision of Chronic Care Management services 3. Discuss the various types of Chronic Care Management and corresponding billing codes 4. Illustrate the value of implementing Chronic Care Management services into patient care

The treatment of chronic health issues comprises a significant amount of American healthcare. It is estimated that half of all adult Americans – 117 million people – have at least one chronic health condition, and one in four have two or more. The care provided to these patients accounts for 84% of all healthcare spending. Two-thirds of all Medicare beneficiaries in particular have two or more chronic conditions, and 99% of all Medicare dollars are spent on these patients.1 In order to provide improved quality of care and make an effort to reduce spending, the Centers for Medicare and Medicaid Services (CMS) established guidelines and billing codes for Chronic Care Management (CCM) services in the Medicare Physician Fee Schedule (PFS) in 2015.2 This enabled physicians and other qualified healthcare providers – including pharmacists – to bill and receive reimbursement for the provision of chronic care services.

phone, but can also be delivered in alternative ways, such as online messaging.3 CCM is currently covered by traditional Medicare and select Medicare Advantage plans, as well as by an increasing number of commercial and Medicaid plans. To qualify for CCM services, beneficiaries must reside in the community and have two or more chronic medical conditions that are expected to last at least 12 months, or until death. These conditions must place the patient at significant risk of death, acute exacerbation or decompensation, or functional decline. Examples of qualifying conditions include, but are not limited to,: COPD/asthma, hypertension, Alzheimer’s, cardiovascular disease, and diabetes.2

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Structured data recording

CCM is a Medicare Part B fee-for-service program that pays providers for furnishing non-face-to-face chronic care management and coordination services. These services are typically provided via tele-

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Comprehensive care plan

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24/7 access

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Comprehensive care management

There are five core services provided as a part of CCM:2

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24/7, but simply that the means to make timely contact with the physician or their staff must be Structured data recording involves documenting available. This can be accomplished in a multitude patient demographics, problems, medications, and allergies in certified EHR technology. CMS requires of ways, one of which may be contracting with a that providers use a version of certified EHR that is 24/7 community pharmacy. The purpose of this acceptable under the EHR Incentive Programs as of requirement is to ensure continuity of care between the patient and their primary provider.2 December 31 of the calendar year preceding each Medicare PFS payment year. Once recorded, pro- Comprehensive care management encompasses viders should use this information to inform the pa- most of the services provided as part of CCM. This tient’s care plan, care coordination, and ongoing includes assessment of medical, functional, and clinical care.2 psychosocial needs; ensuring timely receipt of preventive care services; medication reconciliation Each patient receiving CCM services should have with review of adherence and potential interactions; an individualized care plan based on a “physical, mental, cognitive, psychosocial, functional, and en- and oversight of patient self-management of medications. As the experts on medications and medicavironmental (re)assessment, and an inventory of resources.” The patient or caregiver should be pro- tion management, pharmacists are perfectly qualivided a copy of the care plan, and it should be avail- fied to provide the majority of these services.2 

Transitional care management

able in a timely fashion to anyone involved in the patient’s care, such as providers from other specialties. Elements of a comprehensive care plan should include a problem list, expected outcome and prognosis, measurable treatment goals, planned interventions, and a schedule for periodic review and revision.2 Table 1

Finally, transitional care management involves overseeing a patient’s transitions between and among healthcare providers and settings. This includes follow-up after ED visits and discharges from hospitals, SNFs, or other facilities, as well as the exchange of care plan documents with other practitioners who may be involved in a patient’s care.2

These services may be provided by multiple members of a CCM care team. The leader and billing provider is referred to as the “Qualified Healthcare Professional,” or QHP. This can be a physician or non-physician practitioner (NPP), including a nurse practitioner, physician assistant, clinical nurse specialist, or certified nurse midwife. The QHP is typically a primary care or family practice provider.

CCM is not within the scope of limited license physicians, such as psychiatrists, podiatrists, or dentists, and therefore they cannot bill for these services.2 Source: “Chronic Care Management: An Overview for Pharmacists.” Pharmacists are also not considered QHPs. However, they are part of the clinical staff. Any practitionAPhA. March 2017.

Providers offering CCM services must ensure 24/7 er whose services can be billed incident to a physician or NPP, including APRNs, RNs, LSCSWs, access to urgent care management services. This does not mean that the provider must be accessible LPNs, CMAs, and pharmacists, may be part of the CCM clinical staff.4 Clinical team members still |13| www.KPHANET.org

Table 2

practice subject to state law, licensure, and scope of practice, but are reimbursed for the CCM services they provide through their relationship with a QHP, either as an employee or under contract.2 Finally, non-clinical staff, such as office managers or pharmacy support staff, do not directly deliver CCM services but may facilitate their delivery to maximize providers’ time with patients.4 Physician’s Services regulations state that clinical staff may only provide services under direct supervision, meaning that a physician must be present and immediately available throughout the entire procedure. However, CMS allows CCM services to be provided by clinical staff under general physician or NPP supervision.2 Because the physical presence of the QHP is not required, clinical staff are not required to be in the same location as the physician. This opens the door for physicians to contract with community pharmacies or lease pharmacists from their primary practice settings to provide CCM services. They may also employ fulltime pharmacists in the physician’s office.4 This is an ideal opportunity for pharmacists to form collaborative partnerships with QHPs, and may be furthered by establishing a collaborative practice agreement allowing pharmacists the authority to facilitate refill authorizations, dosage adjustments, ordering of labs, and other activities that would typically require approval from the QHP. Table 1 de-

tails the various services provided as part of CCM; notice that the QHP is only required for patient consent, initial care plan development, and billing for services. All other components of care, including managing patient care and maintaining/updating patient’s care plans, may be performed by clinical staff, including pharmacists.4 There are multiple types of CCM services that may be billed to CMS for reimbursement. Table 2 details the four different CCM billing codes. In 2015, only billing code 99490 was offered; in 2017, CMS added three new codes for additional reimbursement to account for additional time and effort spent by providers.5 Non-complex CCM (99490) involves at least 20 minutes per month spent on the provision of the five core CCM services. Comprehensive assessment (G0506) may be billed once per CCM patient as an add-on to a face-to-face visit, such as an annual wellness visit or initial preventive physical exam, during which the patient is enrolled in CCM services. To bill for this code, the QHP must provide the service, not a member of the clinical staff. Complex CCM (99487) must involve at least 60 minutes per month spent on the provision of the 5 core CCM services, in addition to complex clinical decision making and/or establishment or substantial revision of the patient’s care plan. Providers may also bill for additional complex CCM time (99489) for every 30 minutes exceeding the 60-

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minute threshold in any given month. This additional time may only be billed for complex CCM and NOT for non-complex CCM, regardless of the amount of time spent.2 The CCM service period is one calendar month.

Only one QHP per practice may bill for CCM services within any given month. Clinical staff – including pharmacists – do not directly bill CMS, but bill incident to the QHP.2 For this reason, it is important that CCM staff is well coordinated so that each member of the team takes responsibility for different components of services provided based on their scope of practice. Bills may be submitted at any time during a given month after meeting the 20-minute threshold for non-complex CCM. However, a QHP cannot bill for both non-complex and complex CCM for the same patient within the same month.2 Therefore, it may be prudent to wait until the end of each calendar month to ensure that all time dedicated to CCM services is accounted for when selecting appropriate billing codes. Additionally, certain restrictions exist for billing for other services within the same month as billing for CCM, including transitional care management, home health supervision, hospice care supervision, certain ESRD services, and patient monitoring services.2 Because these encompass much of the same or similar services as CCM, CMS will not pay for both at once.

care are numerous. First, it may have a positive impact on patients by improving the coordination of care; expanding access to care; increasing attention to patient needs; and overall improving patient health and satisfaction with their care. Second, the ability for clinical staff members to perform the majority of CCM services optimizes physician time, and takes advantage of the unique set of skills that each member of the team can provide. Third, following more closely with patients through CCM has the potential to improve key quality metrics, such as medication reconciliation post-discharge and influenza or pneumococcal immunizations.3 With the advent of new value-based payment models, it is important to perform well in these areas of care. Fourth, CCM services provide an additional source of revenue. From CMS reimbursement, a QHP may receive $40-100+ a month per patient, or $500+ annually. In large practices with a significant number of patients, this can add up quickly. Additionally, improvement of quality metrics can also lead to incentive payments from other sources.3 Finally, the provision of CCM services creates sustainable pharmacy practice positions in which qualified pharmacists may practice their clinical skills.

CCM presents a significant opportunity for pharmacists to serve as collaborators and clinical team members in the ongoing management of chronic disease.

It is also important to note that patients may be responsible for copayments and deductibles for CCM services. Medicare beneficiaries pay a 20% copay for services, which totals ~$8/month for noncomplex CCM and ~$20+/month for complex CCM. However, this is often covered by Medigap plans, and most dual-eligible beneficiaries are exempt from cost-sharing.4 For those patients who do have copays, it is important to emphasize that participating in CCM may help them avoid more costly face-to-face services by proactively managing their health.

References

The advantages of incorporating CCM into patient

3. Kunkle L, et.al. “What Can Chronic Care Management Do

1. Roulac H, et.al. “Understanding and Promoting the Value of Chronic Care Management Services.” Centers for Medicare and Medicaid Services. Medicare Learning Network. February 21, 2017. https://www.cms.gov/Outreach-andEducation/Outreach/NPC/Downloads/2017-02-21-CCMPresentation.pdf 2. “Chronic Care Management Services.” Department of Health and Human Services. Centers for Medicare and Medicaid Services. December 2016. https://www.cms.gov/Outreach-and-Education/MedicareLearning-NetworkMLN/MLNProducts/Downloads/ChronicCareManagement .pdf

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for You?” Quality Improvement Organizations. July 2017. http://www.qioprogram.org/sites/default/files/editors/141/ MedSafetyLANEvent_Slides_20170712_FNL_508.pdf 4. “Chronic Care Management: An Overview for Pharmacists.” American Pharmacists Association. March 2017. https://www.pharmacist.com/sites/default/files/CCM-AnOverview-for-Pharmacists-FINAL.pdf 5. “Chronic Care Management Services Changes for 2017.”

Department of Health and Human Services. Centers for Medicare and Medicaid Services. December 2016. https://www.cms.gov/Outreach-and-Education/MedicareLearning-NetworkMLN/MLNProducts/Downloads/ChronicCareManagement ServicesChanges2017.pdf

CPE Quiz Online www.surveymonkey.com/r/CEQuizJan18

January 2018 — Chronic Care Management Services and the Pharmacist’s Role 1. How much of Medicare spending is used on beneficiaries with 2 or more chronic conditions?

A 85% B. 50% C. 99% D. 70% 2. Chronic Care Management is: A. Medicare part B fee-for-service program B. Typically delivered via non-face-to-face methods, such as via telephone C. Only available to persons with 1 or more qualifying chronic conditions D. A and B E. All of the above 3. Which of the following is NOT a core CCM service?

A. Home health supervision B. Structured data recording C. Transitional care management D. 24/7 access 4. In order to qualify as complex CCM, services provided must: A. Exceed 20 minutes per month B. Encompass the 5 core CCM services C. Require high complexity decision making or substantial care plan revision D. Be provided as part of the initial CCM enrollment visit 5. Which of the following is NOT true regarding billing for CCM services?

A. The CCM service period is one calendar month B. A QHP may bill for both non-complex and complex CCM for the same patient within the same calendar month C. Only one QHP per practice may bill CMS for CCM per calendar month D. Bills may be submitted at any time once the 20-minute

threshold has been reached

6. Pharmacists may directly bill CMS for providing CCM services.

A. True B. False 7. Pharmacists may NOT provide which of the following components of CCM services?

A. Patient consent B. Maintaining and updating patient care plans C. Managing patient care D. Documenting CCM services 8. Clinical staff members, including pharmacists, must be under direct physician supervision in order to provide CCM services.

A. True B. False 9. Which of the following statements is TRUE? A. Community pharmacists may provide CCM services by contracting with a QHP B. To bill for CCM, the care team must provide at least 30 minutes of services per patient per month C. There is no copay for CCM services for all eligible patients D. APRNs can be a QHP and bill CMS directly for CCM services 10. Advantages of providing CCM services include: A. Positive impact on patient care B. Improved quality metrics C. Additional source of revenue D. Creates sustainable clinical pharmacy practice positions E. All of the above

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This activity is a FREE service to members of the Kentucky Pharmacists Association.

The fee for non-members is $30. Mail completed forms to: KPERF, 96 C Michael Davenport Blvd., Frankfort, KY 40601. Credit will be applied to your CPE Monitor Profile.

Expiration Date: 01/02/2021 Successful Completion: Score of 80% will result in 1.0 contact hour or .10 CEUs. TECHNICIANS ANSWER SHEET January 2018 — Chronic Care Management Services and the Pharmacist’s Role (1.0 contact hour) Universal Activity # 0143-0000-18-001-H04-T Name _______________________________________________KY Cert. # __________________________________ Address ______________________________________________Email_____________________________________ PLEASE CIRCLE THE APPROPRIATE ANSWERS: 1. A B C D 3. A B C D 5. A B C D 7. A B C D 9. A B C D 2. A B C D E 4. A B C D 6. A B 8. A B 10. A B C D E Information presented in the activity: Met my educational needs ___Yes ___No Figures and tables were useful ___Yes ___No Achieved the stated objectives ___Yes ___No Posttest was appropriate ___Yes ___No Was well written ___Yes ___No Commercial bias was present ___Yes ___No Is relevant to my practice ___Yes ___No If yes, please explain on a separate sheet.

Unmet Objectives:______________________________________________________________________________ I hereby certify that I completed this self-study program independently and without assistance from any other party.

Signature ____________________________________________Completion Date___________________________ Personal NABP eProfile ID #__________________________ Birthdate _______ (MM)_______(DD)

PHARMACISTS ANSWER SHEET January 2018 — Chronic Care Management Services and the Pharmacist’s Role (1.0 contact hour) Universal Activity # 0143-0000-18-001-H04-P Name _______________________________________________ KY Lic. # __________________________________ Address ______________________________________________Email_____________________________________ PLEASE CIRCLE THE APPROPRIATE ANSWERS: 1. A B C D 3. A B C D 5. A B C D 2. A B C D E 4. A B C D 6. A B

7. A B C D 8. A B

9. A B C D 10. A B C D E

Information presented in the activity: Met my educational needs ___Yes ___No Figures and tables were useful ___Yes ___No Achieved the stated objectives ___Yes ___No Posttest was appropriate ___Yes ___No Was well written ___Yes ___No Commercial bias was present ___Yes ___No Is relevant to my practice ___Yes ___No If yes, please explain on a separate sheet.

Unmet Objectives:______________________________________________________________________________ I hereby certify that I completed this self-study program independently and without assistance from any other party.

Signature ____________________________________________Completion Date___________________________ Personal NABP eProfile ID #_____________________________ Birthdate _______ (MM)_______(DD)

The Kentucky Pharmacy Education & Research Foundation is accredited by The Accreditation Council for Pharmacy

Quizzes submitted without NABP eProfile ID # and Birthdate cannot be accepted. |17| www.KPHANET.org

Have an idea for a continuing education article? WRITE IT! Continuing Education Article Guidelines The following broad guidelines should guide an author to  completing a continuing education article for publication in The Kentucky Pharmacist.  

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Average length is 4-10 typed pages in a word processing document (Microsoft Word is preferred).

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Articles are generally written so that they are pertinent to both pharmacists and pharmacy technicians. If the subject matter absolutely is not  pertinent to technicians, that needs to be stated clearly at the beginning of the article.

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Article should begin with the goal or goals of the overall program – usually a few sentences.

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Include 3 to 5 objectives using SMART and measurable verbs.

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Feel free to include graphs or charts, but please submit them separately, not embedded in the text of the article.

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Include a quiz over the material. Usually between 10 to 12 multiple choice questions.

Articles are reviewed for commercial bias, etc. by at least one (normally two) pharmacist reviewers.

When submitting the article, you also will be asked to fill out a financial disclosure statement to identify any financial considerations connected to your article.

Articles should address topics designed to narrow gaps between actual practice and ideal practice in pharmacy. Please see the KPhA website (www.kphanet.org) under the Education link to see previously published articles.

Articles must be submitted electronically to the KPhA director of communications and continuing education (info@kphanet.org) by the first of the month preceding publication.

|18| Kentucky Pharmacists Association | January/February 2018

February CPE Article An Overview of Current and Emerging Direct Oral Anticoagulant Reversal Agents By: Ilya Rybakov, PharmD, PGY-1 Pharmacy Resident Baptist Health Louisville The author declare that there are no financial relationships that could be perceived as real or apparent conflicts of interest.

Universal Activity # 0143-0000-18-002-H01-P & T 1 Contact Hour (0.1 CEU) Expires 1/02/2021

KPERF offers all CE articles to members online at www.kphanet.org

Goal: To educate pharmacist about current and emerging drug therapy options to reverse direct oral anticoagulants (DOACs).

Objectives: At the conclusion of this Knowledge-based article, the reader should be able to: 1. Recognize warfarin reversal strategies 2. Recognize existing options for DOAC reversal 3. Explain the mechanism of action of andexanet alfa and ciraparantag 4. Discuss the clinical literature regarding andexanet alfa and ciraparantag

Introduction Until recently the only available oral anticoagulant was warfarin.1 Briefly, warfarin is a vitamin K antagonist (VKA) that reduces the synthesis of clotting factors II, VII, IX, X, and protein C and protein S by inhibiting the vitamin K redox cycle.2 Despite widespread use and experience with warfarin, clinical challenges still remain due to warfarin’s narrow therapeutic index and propensity for drugdrug interactions.3 Figure 1: Timeline of DOAC FDA approval

[Figure 1], ushering in a new age of oral anticoagulation options.4-8 These agents, commonly referred to as direct oral anticoagulants (DOACs), are different from warfarin in that they target specific clotting factors. Rivaroxaban, apixaban, edoxaban, and betrixaban target factor Xa (FXa) while dabigatran targets factor IIa (FIIa).4-8 Their advantage over warfarin lies in their predictable pharmacokinetic and pharmacodynamic properties, thus eliminating the need for routine laboratory monitoring.2 With the approval of these agents, patients now have alternative oral options to warfarin for the approved indications listed in Table 1 (next page).

One of warfarin’s main advantages over DOACs is the availability of approved reversal strategies.9 However a new age in DOAC therapy has emerged: the beginning of targeted reversal options. In 2015, the Food and Drug Administration (FDA) approved idarucizumab, the dabigatranspecific reversal agent.10 Two other agents, andexanet alfa and ciraparantag, are currently in Phase IIIb/IV and Phase II clinical trials, respectively.

In 2010 dabigatran, the first new oral anticoaguReferred to as universal DOAC reversal options, lant, was approved. In the years following, four other oral anticoagulants were approved: rivaroxa- these agents have the ability to overcome the main limitation of DOACs: lack of approved reversal ban, apixaban, edoxaban, and betrixaban 2017 |19| www.KPHANET.org

strategies.11 This article will provide a brief overview of warfarin reversal before focusing on current and emerging options for DOAC reversal.

Warfarin Reversal Strategies As mentioned previously, one of the main advantages of warfarin over DOACs is the availability of evidence-based guidance for anticoagulation reversal and approved reversal options. The method of reversal chosen depends on the seriousness of bleeding, thrombotic risk of anticoagulation suspension, degree of reversal required, International Normalized Ratio (INR) level, and clinical circumstances.9,12 Table 1: FDA-approved indications for DOACs

Table 2. Guidance on the management of warfarin reversal.

Table 2: Warfarin Reversal Strategies INR Levels

Treatment Options

3-4.5 (without bleeding)

Hold warfarin until INR no longer supratherapeutic

4.5- 10 (without bleeding)

Use of vitamin K not recommended; hold warfarin until INR no longer supratherapeutic Administer oral vitamin K

>10 (without bleeding) Major bleeding present

Administer 5-10 mg vitamin K by slow IV infusion PLUS four-factor PCC (4F-PCC)

of warfarin. However, the need for ABO matching before transfusion, the large volume of FFP required to overcome anticoagulation, and potential for an allergic reaction or infection make FFP an option only when more effective therapies are unavailable.13 A third method used for reversal is through the use of four-factor prothrombin complex concentrate (4F-PCC). 4F-PCC contains clotting factors II Warfarin’s anticoagulation effect can be reversed through a variety of methods. In certain cases, sim- (FII), VII (FVII), IX (FIX), X (FX), protein C, and protein S. When reconstituted, it is given via IV inple dose omission can be considered sufficient if INR levels are supratherapeutic but patients do not fusion and rapidly reverses the anticoagulation efhave signs or symptoms of bleeding. If patients pre- fects of warfarin. In the most recent guideline publisent with serious bleeding, replacement of coagula- cation, the use of prothrombin complex concentrate (PCC) and/or vitamin K as reversal options is rection factors may be necessary. Select ways to re9,12 ommended.13 place coagulation factors are discussed below.

One method of reversal is through the administration of oral, intravenous (IV), or subcutaneous vitamin-K. The administration of vitamin-K bypasses the anticoagulation effects of warfarin through stimulation of endogenous clotting factor production.

The quickest method of reversal is through IV vitamin-K administration, although this isn’t without its risk as it is associated with anaphylactic reactions. Therefore, it’s only recommended in major bleeding and through slow IV infusion.13 A second method of warfarin reversal is through the use of fresh frozen plasma (FFP). FFP contains vitamin-K dependent clotting factors II, VII, IX, and X. The idea behind FFP is that replacement of these factors will bypass the anticoagulation effects

In summary warfarin reversal depends on a patient’s INR level, signs and symptoms of bleeding, and the degree of bleeding.9,12-13 Table 2 summarizes the different approaches for warfarin reversal.

Dabigatran Dabigatran is a competitive inhibitor of thrombin (factor IIa). This inhibition prevents the conversion of fibrinogen to fibrin, thereby preventing the formation of a thrombus. The half-life of dabigatran is approximately 12-17 hours in healthy subjects with 80% renal elimination. The standard dose for both nonvalvular atrial fibrillation (A.fib) and venous thromboembolism (VTE) in patients with normal renal function is 150 mg twice daily. Doses of 110 mg to 220 mg are used for VTE prophylaxis after

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hip replacement surgery. Dose reductions to 75 mg twice daily are recommended in patients with A.fib for creatinine clearance (CrCl) of 15 to 30 ml/min; dabigatran is not recommended for use in A.fib for CrCl less than 15 ml/min. For all other indications, dabigatran is not recommended if one’s CrCl is less than 30 ml/min.4 The steady-state peak and trough levels (on-therapy levels) of dabigatran in patients with A.fib are 31-443 ng/mL.4,14 Measurement of dabigatran anticoagulation effects Although not routinely used to measure efficacy, dabigatran can affect several coagulation assays: thrombin time (TT), dilute thrombin time (dTT), ecarin clotting time (ECT), and ecarin chromogenic assay (ECA). These assays are surrogate markers for dabigatran’s anticoagulation effects and are mainly used in clinical trials. Their use is not routine in clinical practice.14,15 Nonspecific dabigatran reversal strategies Prior to the approval of idarucizumab, the dabigatran-specific reversal agent, available reversal options studied for dabigatran reversal included prothrombin complex concentrate (PCC), activated PCC (aPCC), and recombinant factor VIIa (rVIIa).

However, with the approval of idarucizumab, these agents are no longer used due to lack of efficacy or lack of literature to support their use for dabigatran reversal.10,14-18 It is of interest to mention that dabigatran, unlike other DOACs, can be removed through hemodialysis because it is not as highly protein bound as the other DOACs. Hemodialysis will remove ~50% of dabigatran over 1.5-5 hours.

However, this approach is often impractical because of bleeding risk with dialysis catheter placement.14,18

followed by 20 mg daily. For renal reduction in risk of VTE recurrence, the dose is 20 mg daily and is not recommended for use if CrCl is <30 ml/min.

For deep vein thrombosis (DVT) prophylaxis following hip or knee surgery, the usual dose is 10 mg daily, with close observation recommended if CrCl is between 30 and 50 ml/min and discontinuation if CrCl is <30 ml/min. The on-therapy levels of rivaroxaban range from 6 to 419 ng/mL in patients taking 20 mg of daily rivaroxaban.5,14 Apixaban Apixaban is a selective inhibitor of free and clotbound FXa. It is metabolized by multiple routes and has little dependence on renal function. It has a half-life of approximately 12 hours. For A.fib, the usual dose is 5 mg twice daily. The dose is further reduced to 2.5 mg twice daily if any two of the following conditions are met: greater than or equal to 80 years of age, body weight less than or equal to 60 kg, or a serum creatinine greater than or equal to 1.5 mg/dL. For VTE treatment, the dose is 10 mg twice daily for the first seven days, followed by a reduction to 5 mg twice daily thereafter. Further reduction to 2.5 mg twice daily is appropriate for secondary prevention of VTE in some patients who already received at least 6 months of VTE therapy.

A dose of 2.5 mg twice daily is used for VTE prophylaxis following knee or hip replacement.

On-therapy levels range from 41 to 321 ng/mL in patients receiving 5 mg twice daily for A.fib.6,14

Edoxaban Edoxaban is a selective inhibitor of FXa. However, unlike apixaban and rivaroxaban, it does not inhibit clot-bound FXa. Its half-life is approximately 1014 hours in individuals with normal renal function with approximately 50% renal elimination. The recommended dose for A. fib is 60 mg once daily Anti-Xa agents in patients with CrCl of 50 ml/min to ≤95 ml/min, with a reduction to 30 mg once daily for a CrCl of Rivaroxaban Rivaroxaban is a selective inhibitor of free and clot- 15 to 50 ml/min. Its use in A.fib is contraindicated in patients with a CrCl greater than 95 ml/min. bound factor Xa (FXa). This inhibition prevents For the treatment of VTE, the usual dose is 60 mg thrombin formation, thereby preventing clot foronce daily, with a reduction to 30 mg once daily mation. The half-life is 5-13 hours in individuals with normal renal function with 36% renal elimina- for any of the following: CrCl 15 to 50 ml/min, tion. The dose of rivaroxaban depends on the indi- body weight less than 60 kg, or co-administration cation. For A.fib, the usual dose is 20 mg once dai- of certain P-gp inhibitors. On-therapy levels range ly. The dose is reduced to 15 mg daily when CrCl from 10 to 250 ng/mL in patients receiving 60 mg is between 15 and 50 ml/min. For VTE treatment, daily for A.fib.7,14 the usual dose is 15 mg oral twice daily for 21 days, |21| www.KPHANET.org

Table 3 (above): Summary of non-specific DOAC reversal options; Adapted from Ansell JE 24

Key: +: Yes

-: No

+?: Possible

+/-:Unclear ?: Unknown

Betrixaban Betrixaban is a selective inhibitor of FXa with a mechanism of action similar to edoxaban in that it does not inhibit clot-bound FXa. Its half-life is between 19 and 27 hours in individuals with normal renal function with approximately 11% renal elimination. Unlike the other DOACs, it has the unique indication of VTE prophylaxis in adult hospitalized patients for an acute medical illness who are at risk for VTE due to mobility restrictions. The usual dose is 160 mg as a one-time dose followed by 80 mg daily thereafter. For patients with a CrCl of 15 to 30 ml/min or with co-administration of certain P-gp inhibitors, the dose is reduced to 80 mg as a one-time dose followed by 40 mg once daily thereafter.8 Measurement of anticoagulation effects Anti-Xa assays calibrated for the specific drug (eg, an apixaban anti-Xa assay calibrated with apixaban-specific standards) show a high degree of correlation with the on-therapy range for these drugs.

However, this correlation is reduced when levels are below or above these on-therapy ranges. Most laboratories do not routinely perform these assays.14,15 Rivaroxaban and edoxaban both prolong PT in a concentration-dependent manner, however the PT is not sensitive enough to detect low on-therapy

levels of both medications. Additionally, PT reagents vary widely in their sensitivity to both medications. In terms of apixaban, the PT is not as sensitive with most PT reagents unable to detect ontherapy and above on-therapy levels of apixaban.

Therefore, this method is not used to measure levels of these drugs.14,15 APTT is less sensitive to apixaban, rivaroxaban, and edoxaban concentrations than PT. Therefore, it does not have a role in the laboratory measurement of these agents.14,15 In summary, while there are specific tests to measure on-therapy levels of DOACs, theses medications are not routinely monitored with lab values in the clinical setting.14,15 Nonspecific Anti-Xa reversal options Anti-Xa reversal options, referred to as bypass agents, are currently used for reversal in the setting of critical bleeding when supportive measures are inadequate. The data for these agents are derived from in vitro studies, ex vivo studies of healthy subjects, and animal models. High-quality evidence for their use in reversal of anti-Xa medications is lacking and the subjects in those trials may not represent real-world patients needing urgent anticoagulation reversal. Therefore the results of those trials should be taken with caution, however until the approval of specific reversal options, bypass agents may be the only drug therapy option available.14

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The reversal agent with arguably the best level of evidence is prothrombin complex concentrate (PCC). There are two types of PCCs: 4-factor PCC (4F-PCC) and 3-factor PCC (3F-PCC). The difference between these two agents is that 3-factor PCC contains factors II, IX, X, protein C, and protein S while 4-factor PCC contains factor VII in addition to those factors listed for 3-factor PCC. There are currently three randomized, placebo-controlled, in vivo human trials examining the efficacy of 4-factor PCC for the reversal of rivaroxaban, edoxaban, or apixaban.19-21 All three were cross-over studies and had a similar design. Patients in each trial received the study drug until steady state was reached. Once at steady state, subjects were given either 4F-PCC or placebo infusion. After a washout period (10-14 days depending on the trial), subjects crossed-over to the other treatment after again reaching steady state. Blood levels were taken at various intervals during 4F-PCC or placebo infusion to determine the effect on resolution of coagulation assays. Each of these studies found that 4F-PCCs were able to reverse the anticoagulation effects of apixaban, rivaroxaban, or edoxaban statistically significantly better than placebo.19-21 An important difference to note between these trials is that each trial used a different 4F-PCC. The apixaban trial used Kcentra®; the edoxaban trial used Beriplex®; the rivaroxaban trial used Cofact®. In the United States, Kcentra® is the only 4F-PCC approved for use and is considered therapeutically equivalent to Beriplex®. Additionally, formulations of 4F-PCC contain different compositions of factors II, VII, X, protein C, and protein S. Therefore, it is not appropriate to make clinical assumptions from one 4F-PCC to another.22

Recombinant activated factor VII (rFVII) is another nonspecific hemostatic agent that was thought to have clinical utility in reversing the effects of DOACs. While in vitro studies showed variable effects on DOAC-induced coagulation assays, ex vivo studies failed to show any benefit. Additionally the use of rFVII in nonhemophiliac patients is associated with an increased thrombotic risk.14-15,18, 23-24 Therefore, this agent should not be used for DOAC reversal.

Fresh frozen plasma (FFP) is not likely to have clinical utility in DOAC reversal. Its use has only been evaluated in animal models and there have been no human trials examining its use for DOAC reversal.

Additionally, it has a lower concentration of clotting factors (relative to PCC), thus limiting its effectiveness. Also, it has a higher risk of transfusion reactions and its increased volume load may precipitate a heart failure exacerbation upon administration.18, 24 Hemodialysis and hemoperfusion would not be useful in reversing the effects of apixaban, rivaroxaban, edoxaban, and betrixaban due to their high degree of protein binding.24 Table 3 summarizes the non-specific reversal options for dabigatran, apixaban, rivaroxaban, and edoxaban. As of writing this article, there are no published studies examining reversal options for betrixaban. Agents classified as possible have better evidence than those labeled as unclear.18,23-25,28

Target-specific DOAC reversal options Idarucizumab Praxbind® (Idarucizumab) is a humanized monoclonal antibody and the first target-specific DOAC Activated prothrombin complex (aPCC) is a plasreversal agent approved in 2015 by the FDA for use ma-derived concentrate of factors II, VII, IX, and in dabigatran anticoagulation reversal.10 Its bindX. These factors are activated during their manufac- ing affinity for dabigatran is higher than turing process and this product is commercially dabigatran’s binding affinity for thrombin. As a reavailable as FEIBA®. aPCC was originally develsult, idarucizumab is highly specific for dabigatran oped as a bypassing agent to treat bleeding in hemo- and has no effect on other clotting factors or platelet philia patients taking anticoagulants. aPCC has aggregation.26 shown variability in correcting DOAC-induced coagulation assays. However, aPPC use is associated The RE-VERSE AD (Reversal Effects of Idaruciwith a higher thrombotic risk than 4F-PCC. There- zumab on Active Dabigatran) study was the clinical fore, this agent should be used with caution.14-15, 18, trial that examined the safety and efficacy of ida23-24 rucizumab in reversing dabigatran’s anticoagulation effects in dabigatran-treated patients requiring ur|23| www.KPHANET.org

gent reversal due to uncontrolled bleeding or urgent surgery. Idarucizumab was administered as 2 doses of 2.5g given no more than 15 minutes apart; this was done to perform blood draws between doses.

The primary endpoint was the maximum reversal of dabigatran anticoagulation effects, as assessed by either dTT or ECT, within 4 hours after administration of the second 2.5g dose. Key secondary outcomes included time to cessation of bleeding, intraoperative hemostasis, and normalization of dTT and ECT.26

those trials are set to be completed in 2017 and 2018, respectively.28 The most recent data regarding ciraparantagâ&#x20AC;&#x2122;s efficacy comes from a Phase I study that assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of ciraparantag after edoxaban administration in health volunteers.

In this study, 80 healthy volunteers were administered either intravenous (IV) doses of ciraparantag or placebo in a double-blind, placebo-controlled fashion. Doses of ciraparantag ranged from 5 mg to 300 mg. Reversal of edoxaban was assessed The results of the study showed that the median through measurement of whole blood clotting time maximum percentage reversal of dabigatran was (WBCT). The study found that ciraparantag was 100% (95% CI 100 to 100) on the basis of dTT or able to reverse the anticoagulation effects of edoxaECT. The median time to bleeding cessation was ban within 10 minutes following injections of 100 2.5 hours. In patients requiring urgent surgery, to 300 mg of ciraparantag. This effect was sustained 93.4% had restoration to normal hemostasis with for over 24 hours after a single IV dose. Additionalmedian time to procedure initiation of 1.6 hours.27 ly, ciraparantag did not produce a procoagulant effect, as measured by D-dimer levels, prothrombin Two important observations in the RE-VERSE AD fragments, and tissue factor pathway inhibitors. trial are worth highlighting. First, there was a recur- The adverse effects in this trial were mild and inrent elevation in clotting time, which was seen 12 cluded flushing, dysgeusia, and a cool temperature and 24 hours after idarucizumab treatment. This sensation around the face.29 was thought to be due to the redistribution of dabigatran from the extravascular space to the inAndexanet alfa travascular compartment. Second, there may be Andexanet alfa (andexanet) is a reversal agent declinical utility in repeat doses of idarucizumab. In signed to reverse the anticoagulation effects of dithose patients who had recurrent elevations in clot- rect (apixaban, rivaroxaban, and edoxaban) and ting times, only 10 of those were associated with indirect (LMWH and fondaparinux) factor Xa inbleeding. Therefore, in those patients with newhibitors. Andexanet alfa is designed as an FXa deonset or recurrent bleeding, a second dose of idacoy protein that exerts its mechanism of action rucizumab may be considered.27 through sequestration of FXa inhibitors. This sequestration allows for restoration of endogenous Ciraparantag FXa activity.18, 26 Ciraparantag is a small, water-soluble molecule specifically designed as a universal anticoagulation re- The efficacy and safety of andexanet was examined versal agent. It exerts its effect through strong non- in two randomized, double-blind, placebocovalent hydrogen bonds and charge-charge inter- controlled, parallel trials conducted in healthy volactions. It is specifically designed to bind to unfrac- unteers: the ANNEXA-A (Andexanet alfa, a Novel tionated heparin(UFH), low-molecular-weight hep- Antidote to the Anticoagulation Effects of FXA Inarin (LMWH), fondaparinux, and oral factor Xa hibitors Apixaban) and ANNEXA-R (Andexanet and IIa inhibitors (apixaban, rivaroxaban, edoxaalfa, a Novel Antidote to the Anticoagulation Efban, and dabigatran). There is no binding to albufects of FXA Inhibitors Rivaroxaban) clinical trials. min or other coagulation factors, therefore there is Both trials were conducted in two phases, with each no procoagulant effect with ciraparantag. However, phase examining a different dosing strategy for anit is important to note that ciraparantag does not dexanet. In the ANNEXA-A trial, phase I involved 18, 26 bind to nor does it inhibit warfarinâ&#x20AC;&#x2122;s activity. a 400 mg IV bolus dose of andexanet versus placeCiraparantag is currently undergoing Phase II hubo; phase II involved a 400 mg IV bolus dose folman trials examining its effects on reversing the an- lowed by a 4-mg/min infusion for two hours versus ticoagulation effects of rivaroxaban and apixaban; placebo. In the ANNEXA-R trial, phase I involved |24| Kentucky Pharmacists Association | January/February 2018

Table 4: Summary of target-specific DOAC reversal options; Adapted from Ruff CT, et al.17

Table 4:Comparison of Target-Specific DOAC Reversal Agents Chemical Structure Mechanism of Action Onset Anticoagulant(s) Reversed

Idarucizumab

Ciraparantag

Andexanet alfa

Humanized monoclonal antibody

Water-soluble small molecule

Factor Xa decoy protein

Noncompetitive binding to dabigatran

Hydrogen bonds and chargecharge interactions

Sequestration of direct or indirect factor Xa inhibitors

<5 minutes

5-10 minutes

2-5 minutes

Dabigatran

Dabigatran, LMWH, UFH, apixaban, rivaroxaban, edoxaban

Direct and indirect factor Xa inhibitors

an 800 mg IV bolus dose of andexanet versus placebo; phase II involved an 800 mg IV bolus dose followed by an 8 mg/min infusion for two hours versus placebo. The primary outcome for both trials was the percent change in anti-factor Xa activity from baseline to nadir after placebo or andexanet administration. Key secondary outcomes included proportion of patients with an 80% or greater reduction in anti-factor Xa activity from baseline, change in thrombin generation from baseline, and changes in unbound apixaban and rivaroxaban concentrations from baseline.26, 30

sults to patients who require urgent anticoagulation reversal. However, it is important to mention that the ANNEXA-4 trial is currently ongoing and is designed to evaluate the efficacy and safety of andexanet in patients on factor Xa inhibitors needing anticoagulation reversal due to acute major bleeding.30 Table 4 summarizes key information regarding the three target-specific DOAC reversal options.18

Conclusion The lack of specific DOAC reversal agents has been In both phase I and phase II of the ANNEXA-A one of the main limitations of this class compared and ANNEXA-R trials, andexanet reduced apixa- to warfarin. While the use of non-specific reversal ban and rivaroxaban activity within 2-5 minutes options such as 4F-PCC have been examined, these after administration. All patients who received an- trials usually contained small sample sizes and indexanet had at least an 80% reduction in anti-factor cluded only healthy patients. Specific reversal Xa activity compared to none of the patients who agents are now being studied and have shown effireceived placebo. Thrombin generation was recacy in DOAC reversal. The approval of these tarstored within 2 to 5 minutes after andexanet admin- get-specific agents will soon change the landscape istration, and unbound concentrations of apixaban of DOAC therapy. and rivaroxaban were also reduced to a greater degree with andexanet versus placebo. Additionally, References 1. Food and Drug Administration. FDA approved drug products. the levels of unbound apixaban and rivaroxaban at: were found to be below levels considered to be ther- Available https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event apeutically significant.30 =overview.process&varApplNo=009218. Accessed September 22, Two important observations from the ANNEXA-A and ANNEXA-R trials are worth highlighting.

First, concentrations of apixaban and rivaroxaban returned therapeutic levels two hours after the end of the bolus or infusion. This timeframe is consistent with the duration of action of andexanet and these levels represent clinically significant concentrations that produce anticoagulation effects. Second, this trial was conducted in healthy volunteers.

Therefore, it may be challenging to apply these re-

2017.

2. Barnes CD, Ageno W, Ansell J, et al. Recommendation on the nomenclature for oral anticoagulants: communication from the SCC of the ISTH. J Thromb Haemost 2015;13:1154-6.

3. Lee A, Crowther M. Practicle issues with vitamin K antagonists: elevated INRs, low time-in-therapeutic range, and warfarin failure.

Jour Thromb Thrombolysis 2011;31: 249-58 4. Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2010.

5. Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2011.

6. Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2011.

7. Savaysa® [package insert]. Tokyo, JA: Daiichi Sankyo Co., LTD; 2015.

8. Bevyxxa® [package insert]. San Francisco, CA: Portola Pharmaceuticals,

|25| www.KPHANET.org

Inc.; 2017.

9. Holbrook A, Schulman S, Witt DM, et al. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2):e152S-e184S 10. Praxabind® [ package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.;2010.

11. Smythe MA, Trujillo T, Fanikos J. Reversal agents for use with direct and indirect anticoagulants. Am J Health-Syst Pharm 2016;74: s27-48.

12. Hanley JP. Warfarin reversal. J Clin Pathol 2004;57:1132-39.

13. Zareh M, Davis A, Henderson S. Reversal of warfarin-induced hemorrhage in the emergency department. West J Emergy Med 2011;12:386-92 14. Samuelson B, Cuker A. Measurement and reversal of the direct oral anticoagulants. Blood Rev 2017;31:77-84 15. Cuker A, Siegal D. Monitoring and reversal of direct oral anticoagulants. Hematology Am Soc Hematol Educ Program 2015;2015:117-24.

16. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrate (PCCs): what is the evidence? Thromb Haemost 2014;111:189-98.

17. Tummala R, Kavtaradze A, Gupta A, et al. Specific antidotes

against direct oral anticoagulants: A comprehensive review of clinical trial data. Int J Cardiol 2016;214:292-8.

18. Ruff CT, Giugliano RP, Antman EM. Management of bleeding with non-vitamin k antagonist oral anticoagulants in the era of specific reversal agents. Circulation 2016;134:248-61.

19. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate.

Circulation 2011;124:1573-79.

20. Nagalla S, Thomson L, Oppong Y, et al. Reversibility of apixaban anticoagulation with four-factor prothrombin complex concentrate in healthy volunteers. Clin Transl Sci 2016;9:176-80.

21. Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by 4-factor prothrombin complex concentrate. Circulation 2015;131:82-90.

22. Veteran’s Administration. Four-factor (II, VII, IX, X) prothrombin complex concentrate (Kcentra) national drug monograph. Available at: www.pbm.va.gov. Accessed September 28, 2017.

23. Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents.

J Thromb Thrombolysis 2015;39:395-402.

24. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012;87:s141-s145. Continued on page 35...

February 2018—An Overview of Current and Emerging Direct Oral Anticoagulant Reversal Agents 1. Patient SJ presents to your outpatient pharmacy clinic for his weekly INR check. He is taking warfarin for his atrial fibrillation and his INR today is 4.7. He does not appear to be in any acute distress and, upon questioning, does not endorse any bleeding.

Which of the following is the BEST treatment option for SJ? A. Hold his warfarin dose until his INR is no longer supratherapeutic B. Administer oral vitamin K C. Administer 5-10 mg of vitamin K by IV D. Administer 5-10 mg of vitamin K by IV and 4F-PCC 2. SJ returns to your clinic in a week and he now states that he’s having uncontrolled nosebleeds, hemoptysis, and hematochezia.

Which of the following is the BEST treatment option for SJ? A. Do nothing B. Hold his current warfarin dose.

C. Tell him to swallow a vitamin K tablet D. Tell him to report to the hospital for urgent warfarin reversal 3. Which of the following is/are not an option for reversing the anticoagulation effects of apixaban? (Select all that apply) A. 4-Factor PCC B. Idarucizumab C. FFP D. Oral activated charcoal 4. Hemodialysis is a potential reversal option for which of the following?

A. Apixaban B. Betrixaban C. Dabigatran D. Rivaroxaban 5. Which of the following is the BEST option for reversing the anticoagulation effects of dabigatran?

A. 4-Factor PCC B. Hemodialysis C. Idarucizumab D. Oral activated charcoal 6. Which of the following agents reverses the effects of DOACs through sequestration?

A. Ciraparantag

B. Andexanet alfa C. Idarucizumab D. 4F-PCC 7. Which of the following agents reverses the effects of DOACs through hydrogen bonds?

A. Ciraparantag B. Andexanet alfa C. Idarucizumab D. 4F-PCC 8. Which of the following agents reverses the effects of DOACs through noncompetitive binding?

A. Ciraparantag B. Andexanet alfa C. Idarucizumab D. 4F-PCC 9. Which of the following is/are conclusions that can be drawn from the Andexanet alfa clinical trials?

A. Phase I but not Phase II of the ANNEXA-A and ANNEXA-R trials showed significant reductions in DOAC concentrations B. Phase II but not Phase I of the ANNEXA-A and ANNEXA-R trials showed significant reductions in DOAC concentrations C. Phase I and Phase II of the ANNEXA-A and ANNEXA-R trials showed significant reductions in DOAC concentrations D. Neither Phase I nor Phase II of the ANNEXA-A and ANNEXAR trials showed significant reductions in DOAC concentrations 10. Which of the following is/are conclusions that can be drawn from the ciraparantag Phase II trial?

A. 5mg to 300mg of IV ciraparantag reversed the anticoagulation effects of edoxaban B. 100mg to 300mg of IV ciraparantag reversed the anticoagulation effects of edoxaban C. No dose of IV ciraparantag was able to reverse the anticoagulation effects of edoxaban

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This activity is a FREE service to members of the Kentucky Pharmacists Association.

The fee for non-members is $30. Mail completed forms to: KPERF, 96 C Michael Davenport Blvd., Frankfort, KY 40601. Credit will be applied to your CPE Monitor Profile.

Expiration Date: 1/02/2021 Successful Completion: Score of 80% will result in 1.0 contact hours or .1 CEUs. TECHNICIANS ANSWER SHEET. February 2018 — An Overview of Current and Emerging Direct Oral Anticoagulant Reversal Agents (1 contact hours) Universal Activity # 0143-0000-18-002-H01-T Name _______________________________________________KY Cert. # __________________________________ Address ______________________________________________Email_____________________________________ PLEASE CIRCLE THE APPROPRIATE ANSWERS: 1. A B C D 3. A B C D 5. A B C D 2. A B C D 4. A B C D 6. A B C D

7. A B C D 8. A B C D

9. A B C D 10. A B C

Information presented in the activity:

Met my educational needs ___Yes ___No Figures and tables were useful ___Yes ___No Achieved the stated objectives ___Yes ___No Posttest was appropriate ___Yes ___No Was well written ___Yes ___No Commercial bias was present ___Yes ___No Is relevant to my practice ___Yes ___No If yes, please explain on a separate sheet.

Unmet Objectives:______________________________________________________________________________ I hereby certify that I completed this self-study program independently and without assistance from any other party.

Signature ____________________________________________Completion Date___________________________ Personal NABP eProfile ID #_____________________________ Birthdate _______ (MM)_______(DD)

PHARMACISTS ANSWER SHEET February 2018 — An Overview of Current and Emerging Direct Oral Anticoagulant Reversal Agents (1 contact hours) Universal Activity # 0143-0000-18-002-H01-P Name ________________________________________________ KY Lic. # __________________________________ Address ______________________________________________Email_____________________________________

PLEASE CIRCLE THE APPROPRIATE ANSWERS: 1. A B C D 3. A B C D 5. A B C D 2. A B C D 4. A B C D 6. A B C D

7. A B C D 8. A B C D

9. A B C D 10. A B C

Information presented in the activity: Met my educational needs ___Yes ___No Figures and tables were useful ___Yes ___No Achieved the stated objectives ___Yes ___No Posttest was appropriate ___Yes ___No Was well written ___Yes ___No Commercial bias was present ___Yes ___No Is relevant to my practice ___Yes ___No If yes, please explain on a separate sheet.

Unmet Objectives:______________________________________________________________________________ I hereby certify that I completed this self-study program independently and without assistance from any other party.

Signature ____________________________________________Completion Date___________________________

Personal NABP eProfile ID #_____________________________ Birthdate _______ (MM)_______(DD)

The Kentucky Pharmacy Education & Research Foundation is accredited by The Accreditation

Quizzes submitted without NABP eProfile ID # and Birthdate will not be accepted. |27| www.KPHANET.org

Campus Corner Message from Dean Kip Guy After delivering our annual state of the college address last month, it impressed upon me once again the privilege of serving as Dean to the UK College of Pharmacy. Our students continue to go above and beyond, looking for opportunities to serve our community and each other.

Just the other day, I learned of one of our student organizations working to bring awareness about cervical cancer and the HPV vaccine.

They launched both an on-campus and digital campaign, engaging over 8,000 people in the first 24 hours while raising awareness about a lifesaving vaccine. It’s initiatives like this that make me excited to see what our students will accomplish for the profession.

It isn’t only our students who are impacting our community. Recently, alumnus Brooke Hudspeth helped secure a $7.5 million grant from the CDC. Brooke was integral in the grant application on behalf of The Kroger Company for the expansion of the Diabetes Prevention Program (DPP) and will now serve as its Director.

I’m sure there are more stories from our alumni and partners about how you are working to better the care of those in the Commonwealth. And I look forward to hearing those stories sooner than later as my team and I begin what we’re calling the “Pharmasee blue Tour.” We’ll be heading all over Kentucky to meet with and hear from local pharmacists, while also providing a free continuing education program.

For more information about dates, locations, and accreditation, please visit: bit.ly/seebluetour. I hope to see you soon.

UKCOP Student Pharmacists in the Spotlight Jessi Clark, PY3 As a third year student pharmacist, this is the busiest and most exciting semester of pharmacy school for me yet. I am fortunate to have found roles that I am passionate about in a couple of organizations within the College of Pharmacy, and we have big things in the works for this semester. I currently serve as one of the class leadership co-chairs of Phi Lambda Sigma, where we are working with faculty at the College to develop and implement a leadership course into the new curriculum for the second year student pharmacists.

My co-chair and I have created lesson plans which

will be carried out by our Phi Lambda Sigma members in small groups throughout this semester. I am excited to play a role in facilitating the growth and unveiling the leadership potential of our second year students. I have also found passion working with Operation Heart. My co-chair and I are planning a number of blood pressure screenings and heart health education events for the Spring semester, highlighting February, which is American Heart Month. Coming up, we are looking forward to being featured on WLEX News, where we will be giving a presentation on bystander CPR. We are also organizing fundraisers for the American Heart Association which will help support our team for the May Heart Walk. I am proud to report that last year we won the American Pharmacists Association Region 4 Award for Operation Heart and are

|28| Kentucky Pharmacists Association | January/February 2018

hoping to win again this year. Iâ&#x20AC;&#x2122;m looking forward dents to problem-solve using this approach. One of to an eventful last semester before I am off to APPE my favorite classes this semester was the Patientrotations.

Centered Care Lab. During our lab, we had the opportunity to interact with patient actors and pracDeAnna Stinnett, PY2 tice various clinical skills and decision-making. I "The start of the second year of believe that the curriculum will help me grow to pharmacy school means that become a confident and skilled pharmacist. your big firsts are over. The first There is a wide array of extracurricular activities day of class, the first round of and volunteer opportunities that are offered through exams, the first glimpse into the the college. This past semester, I was elected as the clinical world of pharmacy and PY1 KAPS Liaison. This position allows me to all it has to offer came and serve as the main communication point between went. Now a seasoned veteran, the KAPS officers and the PY1 student members. professors expect you to have Through this position, I have become more confiyour study methods down and to be an example to dent in my communication skills and have been those who come after you. There are still struggles. able to participate in numerous KAPS events.

Maybe you took on a leadership position within So far, the most difficult aspect of pharmacy school your college while trying to balance arguably the is balancing academics, work, extracurricular activibusiest schedule youâ&#x20AC;&#x2122;ve had in your academic caties, and spending time with friends and family. reer. Or you are taking on the challenge of those first classes in the dual degree program you chose. The faculty at the College of Pharmacy is extremely Nevertheless, you feel motivated and confident not supportive and approachable and always encouronly because of the support from your peers and faculty, but because you are secure in the knowledge that you are capable of any situation you put yourself through. You have survived and maybe even surprised yourself at how much you can handle and still succeed. Even now, every obstacle, every class completed, every challenge accepted and achieved prepares you to step out into the practicing world of pharmacy, and that is what motivates me to finish out my second year of pharmacy strong and proud."

Allison Olmsted, PY1 During my first semester at the University of Kentucky College of Pharmacy, I had the opportunity to learn about the foundations of pharmacy as a profession. The curriculum at UK puts an emphasis on patientcentered care and challenges stu|29| www.KPHANET.org

Campus Corner Author: Nathan Hughes, PharmD Candidate (2019) Sullivan University College of Pharmacy

Operation Protect Yourself In 2014 the American Pharmacist Association-Academy of Student Pharmacists (APhA-ASP) chapter at Sullivan University College of Pharmacy (SUCOP) began a community outreach educational program called Operation Protect Yourself. One-half of new cases of sexually transmitted infections (STIs) occur in individuals between the ages of 15 to 241. The SUCOP APhA-ASP chapter had a vision to educate and empower adolescents to make positive and informed sexual health decisions. The chapter developed an interactive program which provides a 50-minute educational session to high school students. This programming includes an educational presentation, a fluid exchange activity (mimicking bodily fluid transfer) to highlight how easily STIâ&#x20AC;&#x2122;s can spread, a team-based, knowledge game activity, and a question and answer session2. Student pharmacists typically spend an entire day at a high school providing these sessions for numerous classes.

This educational program has grown tremendously over the past several years. What started out as a one-day event, at one high school, has grown to multiple days at numerous high schools in the Louisville metro area. In 2016 alone, this programming educated more than 1500 high school students. Currently, the program is conducting pre-and post-program quizzes to evaluate the effectiveness of the program. Preliminary results have provided feedback that is consistent with an increase in knowledge and high satisfaction rates from both educators and students.

In 2017, at the APhA Annual Meeting, the SUCOP APhAASP chapter received the Innovative Programming Award for their efforts with Operation Protect Yourself. Moving forward, our chapter hopes to continue the expansion of this program to more local high schools and eventually other APhA-ASP student chapters.

1. Centers for Disease Control and Prevention. Sexually Transmitted Diseases (STDs). Available at: https://www.cdc.gov/std/default.htm . Accessed July 14, 2017.

2. Keeney KP. Demonstrated value in the public health arena: Operation protect yourself. Journal of the American Pharmacists Association. 2017;57(5):565-566. doi:10.1016/j.japh.2017.08.006.

KPhA sends email announcements weekly. If you arenâ&#x20AC;&#x2122;t receiving: eNews, Legislative Updates, Grassroots Alerts and other important announcements, send your email address to info@kphanet.org to get on the list. |30| Kentucky Pharmacists Association | January/February 2018

APhA Patient Counseling Competition Congratulations to Taylor Walker, winner of the Local Patient Counseling Competition at Sullivan University. On January 19th, Sullivan University’s APhA-ASP chapter hosted a local patient counseling competition. Taylor competed, along with 17 other students, for the highest scoring patient counseling session. The weekend of March 18th, Taylor will be representing SUCOP at the APhA National Patient Counseling Competition in Nashville, TN. Way to go, Taylor!

SUCOP Student Pharmacist in the Spotlight This is an exciting year for the SUCOP Chapter of APhA-ASP! Nathan Hughes (PY2), current APhA-ASP Chapter President, is the first SUCOP student pharmacist to receive an APhAASP National Standing Committee appointment.

Nathan has been appointed to the APhA-ASP National Policy Standing Committee, and will be announced in his new role at the APhA Annual Meeting and Exposition in Nashville, TN this March.

This committee is selected and appointed by the APhA-ASP National Executive Committee, based on the candidate’s application and letters of recommendation.

and providing guidance to chapter leaders and student pharmacists on policy and advocacy priorities.

In his time as SUCOP APhA-ASP Chapter President, Nathan has shown his dedication to and passion for policy. He has been an active member on the KPhA Board of Directors as the SUCOP Student Representative and organized events, such as “Policy on Tap” to get fellow student pharmacists involved in policy.

We are excited to see Nathan continue to work toward the progression of the pharmacy profession in this role, and to encourage other student pharmacists to become active in policy!

The National Policy Standing Committee is charged with multiple responsibilities regarding policy, including recommending policy issues for consideration at the APhA House of Delegates, |31| www.KPHANET.org

Pharmacy Law Brief How Courts Look at Allegations of Antitrust Violations Author: Joseph L. Fink III, BSPharm, JD, DSc (Hon), FAPhA, Professor of Pharmacy Law and Policy and Kentucky Pharmacists Association Professor of Leadership, Department of Pharmacy Practice and Science, UK College of Pharmacy Disclaimer: The information in this column is intended for educational use Question: From time to time I hear about high and to stimulate professional discussion among colleagues. It should not be profile federal cases alleging antitrust violations in construed as legal advice. There is no way such a brief discussion of an issue a variety of fields. It seems to me that the vigor or topic for educational or discussion purposes can adequately and fully with which such claims are pursued by the govern- address the multifaceted and often complex issues that arise in the course of professional practice. It is always the best advice for a pharmacist to seek ment varies greatly from one presidential admincounsel from an attorney who can become thoroughly familiar with the intriistration to another. I also hear or read about anticacies of a specific situation, and render advice in accordance with the full trust cases initiated by private parties. Can you pro- information. vide an overview of how such claims are handled when they reach the courts? preme Court, have evolved a bifurcated approach to handling cases alleging antitrust violations. CerResponse: Antitrust statutes are designed to tain activities have been deemed so clearly harmful protect competition, the cornerstone of our free market economic system in the U.S. These statutes to competition that they have been placed in a category known as “Per Se violations.” Per Se violaexist at both the federal and state levels although the federal government is much more active in this tions include activities by competitors such as price area because of greater resources to bring to bear as fixing, group boycotts, division of geographic terriwell as the fact that many anti-competitive activi- tories, or collusive bidding. If evidence establishes ties run across state borders. It should also be em- that an activity falls on the Per Se list there need be no further inquiry into the practice’s actual effect phasized at the outset that these statutes are designed to protect competition – the healthy tension on the economic market or the intentions of those that exists between economic competitors – not the who engaged in the practice; the existence of substantial harm is essentially presumed to have occompetitors themselves. curred.

The principal federal antitrust statute is the SherThe other broad category of violations is handled man Antitrust Act of 1890.1 It has been suppleunder the designation “Rule of Reason.” These are mented periodically by other Congressional acnot “automatic” violations like those on the Per Se tions. For example, the Sherman Act is aimed at preventing contracts, combinations or conspiracies list; rather, some business activities at time constitute anticompetitive behavior while at other times that restrain trade. The Clayton Antitrust Act of encourage competition within the marketplace, 1914 was designed to address some of the perceived shortcomings of the Sherman Act with par- and hence, they must be evaluated individually. ticular emphasis on nipping in the bud nascent or For these cases the courts apply a “totality of cirevolving anti-competitive practices at their earliest cumstance” standard and focus on whether the challenged practice promotes or suppresses market stages.2 competition. Here are some broad descriptions of Over the 125 years the Sherman Act has been in how this “comes alive” in the context of a specific place the federal courts, especially the U.S. Su-

|32| Kentucky Pharmacists Association | January/February 2018

case. The following discussion is based on the court’s opinion in the very high profile lawsuit addressing legal issues with name, image and likenesses of intercollegiate student-athletes – O’Bannon, et al v. National Collegiate Athletic Association, et al.3

“pay-for-delay” cases where a brand name pharmaceutical manufacturer approaching impending patient expiration on a popular product will pay a generic firm to delay or defer introduction of a competing product. Courts have wrestled with those cases with decisions usually turning in the specifics of the arrangement between the firms.8 The Federal A restraint on free economic activity violates the Rule of Reason “if the restraint’s harm to competi- Trade Commission takes a very dim view of such arrangements and legislation has been introduced in tion outweighs the pro-competitive effects.”4 Courts use a burden shifting framework to evaluate Congress to outlaw such practices.9 Thus, all three branches of the federal government have focused at the claims in such cases. Under that approach the one time or another on these pay-for-delay agree“plaintiff bears the initial burden of showing that the restraint produces ‘significant anti-competitive ments. effects’ within a ‘relevant market.’”[5] If the plainSubmit Questions: jfink@uky.edu tiff satisfied this initial burden the defendant must come forward with evidence of the restraint’s “proReferences: competitive effects.”5 15 U.S.C. §§1-7.

Finally, if the defendant meets this burden of estab- [1] lishing a pro-competitive impact, the focus shifts [2] 15 U.S.C. §12 et seq. back to the plaintiff who must show that “any legiti[3] Case No. C-09-3329, U.S.D.C. Northern District mate objectives can be achieved in a substantially of California (August 8, 2014). less restrictive manner.”4 [4] Tanaka v. University of Southern California, 252 Proof that the defendant’s activities had an impact F.3d. 1059, at 1063 (9th Cir. 2001). upon competition in the relevant market is an [5] Hairston v. Pacific 10 Conference, 101 F.3d 1315, “absolutely essential element of a Rule of Reason case.”6 In this context the term “relevant market” is at 1319 (9th Cir. 1996). more broad and encompassing than one might [6] Supermarket of Homes, Inc. v. San Fernando think. It “encompasses notions of geography as well Valley Bd. of Realtors, 786 F.2d 1400, at 1404 (9th as product use, quality and description. The geoCir. 1986). graphic market extends to the area of competition [7] Oltz v. St. Peter’s Community Hospital, 861 F.2d …where buyers can turn for alternative sources of 1440, at 1446 (9th Cir. 1988). supply. The products market includes the pool of [8] Fink III JL. “Pay for Delay” agreement reviewed goods or services that enjoy reasonaTimes, ble…interchangeability of use and cross-elasticity of by federal appeals court. Pharm 2016(Aug);82:62. demand.”7 If the facts of a case are somewhat ambiguous and could fall into either category – Per Se or Rule of Reason – a presumption exists in favor of using the Rule of Reason.

[9] Cecka CH, Fink III JL. Will U.S. Senate address pay-for-delay agreements? Pharm Times.

2017(Feb);83:61.

One category of pharmacy-related cases that bring the federal antitrust laws into play is the so called |33| www.KPHANET.org

Pharmacy Policy Issues Biosimilars and “Follow On’s” Arrive in the Marketplace Author: William Cody Johnson is a fourth year PharmD student at the University of Kentucky College of Pharmacy. A native of Topmost, KY, he completed his pre-professional studies at Alice Lloyd College while earning at Bachelor of Science degree in biology. is accomplished through required components of the application: analytical studies showing that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, animal studies (including the assessment of toxicity), and clinical studies (assessing immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency. The bioDiscussion: Biologics accounted for 13 of the top similar product and reference product must also 25 drugs with the highest expenditures in 2015; inutilize the same mechanism for labelled indicacluding 3 of the top 5 products. The appeal of biotions. A biosimilar can be approved only for those similars lies in their potential for savings in this exindications and conditions previously approved for pensive sector of medication spending. The Patient the reference product, but may be approved for Protection and Affordable Care Act (Affordable fewer. Health care providers should review the Care Act) amended the Public Health Service Act product labeling to determine those indications and (PHS Act) to create an abbreviated licensure pathroutes of administration for which the product was way for biological products that are demonstrated approved. The route of administration, dosage to be “biosimilar” to or “interchangeable”. This form, and strength of the biosimilar product are pathway is provided in the part of the law known also the same as those of the reference product. as the Biologics Price Competition and Innovation Act (BPCI Act), which is sometimes called the 351 An “interchangeable” product is biosimilar to an FDA-approved reference product and meets addi(k) application pathway. tional standards for interchangeability. The key Under the BPCI Act, biosimilars are products additional standards are that the biosimilar product deemed to be “highly similar” with a demonstrais expected to produce the same clinical result as tion of no clinically meaningful differences to an the reference product in any given patient and approved biological product (known as a reference when the product is administered more than once product) by the FDA. “Highly similar” and “no to an individual, the risk in terms of safety or diclinically meaningful differences” are separate minished efficacy of alternating or switching bestandards, which need to be met to support a tween use of the product and its reference product demonstration of biosimilarity. This determination is not greater than the risk of using the reference Issue: The FDA approved Basaglar (insulin glargine) by an abbreviated 505(b)(2) application, labeling this product as a “follow-on” and not as a biosimilar. This approach has generated some confusion in practice regarding what constitutes a biosimilar. Can you shed some light on this definition along with the approval criteria for biosimilars and interchangeable products?

|34| Kentucky Pharmacists Association | January/February 2018

product without such alternation or switch. ProdHave an Idea? ucts meeting this definition may be interchanged for This column is designed to address timely and practical issues of interest to pharmacists, pharmacy interns the reference product by a pharmacist without the and pharmacy technicians with the goal being to enintervention of the health care provider who precourage thought, reflection and exchange among pracscribed the reference product. Currently as of this titioners. Suggestions regarding topics for considerawriting, the FDA has given no approved biosimilar tion are welcome. Please send them to jfink@uky.edu. product a designation as interchangeable. Draft guidance from the FDA on considerations for demonstrating interchangeability was released in FDA. “Biosimilars: Additional Questions and AnJanuary 2017. swers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009” The terms biosimilar and interchangeable are reserved for biologics licensed under a provision of the Public Health Service Act (PHSA). This involves the use of the 351(k) application pathway.

The FDA “Purple Book” serves as a resource to locate these products and their designation as biosimilar or interchangeable. Biologically similar products developed based on reference products approved under the Federal Food, Drug, and Cosmetic Act (FD&C Act), which includes all currently available insulin products, are not labeled as biosimilar or interchangeable. Biologically similar products in this category may be approved via 505(b)(2) or 505 (j) application pathways. These products are included in the FDA “Orange Book” for reference.

Interest in biosimilars will likely continue to grow as health care providers and industry spearhead efforts to help control rising health care costs. The FDA, as of the date this article was written (May, 2017), has approved four biosimilar products through the 351(k) application pathway. These numbers are likely to continue to increase as patents on biologics expire. Pharmacists as the medication experts, and often as the gatekeepers of cost, are posed to receive numerous questions regarding this growing field of pharmaceuticals. Therefore, it is crucial to have an understanding of the terminology that may be used with these agents.

Christl, Leah. “FDA’s Overview of the Regulatory Guidance for the Development and Approval of Biosimilar Products in the US” Web.

References: 1 Schumock, Glen T., et al. "National trends in prescription drug expenditures and projections for 2015." American Journal of Health-System Pharmacy 72.9 (2015): 717-736.

2 FDA: Information on Biosimilars 3 Lemery, Steven J., Francisco J. Esteva, and Martina Weise. "Biosimilars: Here and Now." American Society of Clinical Oncology Educational Book 36 (2016) Web. 4 42 U.S.C. §262(k)(2)(A).

5 Christl, Leah. “FDA’s Overview of the Regulatory Guidance for the Development and Approval of Biosimilar Products in the US” Web. 6 FDA. “Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009” Continued from page 26...

25. Ansell JE. Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants. J Thromb Thrombolysis 2016;41:248-52.

26. Smythe MS, Trujillo T, Fanikos J. Reversal agents for use with direct and indirect anticoagulants. Am J Health-Syst Pharm 2016;73:s27-s48.

27. Pollack C, Rilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal---full cohort analysis. N Engl J Med 2017;377:431-41.

28. Ciraparantag. Available at: https://clinicaltrials.gov/ct2/results? cond=&term=ciraparantag+&cntry1=&state1=&recrs=. Accessed October 7, 2017.

29. Ansell JE, Bakhru SH, Laulicht BE, et al. Singe-dose of ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost 2017;117:23845.

30. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015;373:2413-24.

|35| www.KPHANET.org

|36| Kentucky Pharmacists Association | January/February 2018

Welcome to KPhA! We’re so happy to have you!

The list reflects new memberships received from November 1, 2017— December 31, 2017 Rick Dunn Lexington

Brittany Sullivan Boaz

Jami Dutton Lexington

Nicholas Sullivan Boaz

David Gresham Louisville Mark Mlburn Louisville

If you see one of these new members, please welcome them to the KPhA family!

Jimmy Tucker Bon Aqua, TN Heath Wentzel Lexington

MEMBERSHIP MATTERS: To YOU, To YOUR Patients To YOUR Profession!

|37| www.KPHANET.org

Feature Article Pharmacists’ Authority to Deliver Protocol-Driven Care Set to Impact Patient and Public Health Across the Commonwealth Author: Patricia R. (Trish) Freeman, RPh, PhD, Chair, Kentucky Pharmacists Association Board of Directors, Director, Center for the Advancement of Pharmacy Practice On Wednesday, December 13, 2017 the culmination of almost two years of collaborative effort was achieved when the Health & Welfare & Family Services Interim Joint Committee of the Kentucky Legislature approved regulation 201 KAR 2:380, Board authorized protocols.

of non-controlled or over-the-counter-medications and related professional services. There must be a prescriber-approved protocol in place that is based on current clinical guidelines, meets minimum requirements, and has been approved by the Board of Pharmacy. Additionally, the regulation stipulates that pharmacists must document they have received education and training in the subject matter of the These efforts were spearheaded protocol prior to initiating care under the protocol. by the Advancing Pharmacy Similar to the protocol used for naloxone dispensPractice in Kentucky Coalition ing, medications dispensed under protocol must be (APPKC), an advocacy group documented in the dispensing system as required comprised of the key pharmacy under 201 KAR 2:170. stakeholder organizations in Kentucky, including the Kentucky Pharmacists Association, the KenWhy is this important? tucky Society of Health-System Pharmacists, the In Kentucky, as in many states, access to care is an Kentucky Board of Pharmacy, the American Pharimportant issue. The Health Resources and Service macy Services Corporation, the Sullivan University Administration’s Healthcare Workforce Analysis College of Pharmacy and the University of Kenestimates that by 2025, Kentucky is expected to extucky College of Pharmacy’s Center for the Adperience close to a 30% shortfall in primary care vancement of Pharmacy Practice, working together provider adequacy. to advance the practice of pharmacy, in Kentucky And, evidence shows that pharmacists providing and the nation. protocol-driven direct patient care can improve both patient and public health. Many organizaThe regulation was promulgated in response to tions, including the Centers for Disease Control 2016 legislation that amended KRS 315.010(25) to (CDC), Centers for Medicare and Medicaid Serdefine valid prescription orders to include those isvices (CMS) and the National Governor’s Associasued as a result of Board authorized protocols. tion, have recognized the value that pharmacistThis legislation set the stage for the Kentucky provided care can bring to our nation’s health.

Board of Pharmacy to establish procedures for Board authorized protocols by which pharmacists, How does this regulation help? acting under the direction of a prescriber, can proPharmacists have long collaborated with physicians vide mutually agreed-upon services as outlined in a and other prescribers to provide immunization serspecific care protocol. vices via protocol, and, more recently, with physicians to initiate the dispensing of naloxone under What does the regulation say? protocol. With the implementation of this regulaThe regulation outlines the procedures that must be tion, the Kentucky Board of Pharmacy is now able in place for a pharmacist to initiate the dispensing |38| Kentucky Pharmacists Association | January/February 2018

to review and approve protocols for 12 authorized conditions.

Pharmacists ability to provide care under a prescriber-approved protocol differs from that provided under a collaborative care agreement in that protocoldriven care can be provided to any person who requests care and meets the criteria for care as outlined in the Board authorized protocol. In contrast, pharmacists may only provide care to patients under a collaborative care agreement upon prescriber referral. Collaborative care agreements, therefore, are best used for chronic care management where continued follow-up communication with the referring prescriber is needed. Protocol-driven care provided in pharmacies can eliminate potential delays in treatment as anyone who walks into a pharmacy in need of acute care for the conditions authorized by the regulation, and who meets criteria for care as outlined in the specific protocol, can be treated.

Prioritizing efforts to address Kentucky’s most pressing health issues According to the CDC, Kentucky has the unenviable distinction of having the overall highest rate of lung cancer incidences and deaths in the nation (https://www.cdc.gov/cancer/lung/statistics/state .htm). Cigarette smoking is the #1 cause of lung cancer, and is linked to 80% to 90% of all lung cancers. In response to this pressing health concern in Kentucky, the first Board authorized protocol approved on December 20, 2017 was the Tobacco Cessation Therapy Protocol, which specifies the criteria and procedures for pharmacists to initiate the dispensing of tobacco cessation therapies to individuals who have tobacco use disorder. The protocol can be found on the Board of Pharmacy’s website: https://pharmacy.ky.gov/Pages/default.aspx.

More care to come In the Kentucky Board of Pharmacy’s administrative regulations, protocols may also be established for the following authorized conditions:

Acute mucocutaneous fungal infection Allergic rhinitis Anaphylaxis HIV infection prevention through pre-exposure prophylaxis (pursuant to recommendations by the CDC Nutritional supplementation with vitamins and minerals Opioid use disorder (pursuant to recommendations by the American Society of Addiction Medicine) Travelers health (pursuant to recommendations by the CDC) Tuberculosis prevention and control through skin testing and referral as necessary (pursuant to recommendations by the CDC) Self-care conditions appropriately treated with overthe-counter medications and products Protocols for tuberculosis skin testing, opioid use disorder and self-care with diabetes testing supplies were approved on January 17, 2018 by the board and will be available on the board’s webpage soon.

Protocols for other authorized conditions are under development.

Plans for developing education and training to prepare pharmacists for delivery of protocol-driven care for the 12 authorized conditions are underway.

Public Health Impact Pharmacists are highly trained healthcare providers who stand ready and willing to help improve public health by serving as care extenders. Given the opportunity to provide additional patient care services through evidence-based, prescriber-driven, Board authorized protocols, pharmacists can improve the health of Kentucky’s citizens by providing needed access to care.

Acute influenza (pursuant to recommendations by the CDC) Acute streptococcal pharyngitis infection Acute, uncomplicated urinary tract infection |39| www.KPHANET.org

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|41| www.KPHANET.org

KPhA BOARD OF DIRECTORS Trish Freeman, Lexington trish.freeman@uky.edu

Chair

Tyler Stephens, Lexington Vice Speaker of the House stevens.tyler@uky.edu

Chris Harlow, Louisville cpharlow@gmail.com

President

KPERF BOARD OF DIRECTORS

Chris Palutis, Lexington chris@candcrx.com

President-Elect

Brooke Hudspeth, Lexington brooke.hudspeth@kroger.com

Secretary

Duane Parsons, Richmond dandlparsons@roadrunner.com

Treasurer

Jessika Chinn, Beaver Dam jessikachilton@ymail.com

Past President Representative

Directors

Clark Kebodeaux, Lexington clark.kebodeaux@uky.edu

Secretary

Duane Parsons, Richmond dandlparsons@roadrunner.com

Treasurer

Chris Harlow, Louisville cpharlow@gmail.com

President

Paul Easley, Louisville rpeasley@bellsouth.net

Sarah Lawrence, Louisville slawrence@sullivan.edu

Matt Carrico, Louisville* matt@boonevilledrugs.com University of Kentucky Student Representative

Kelly Smith, Lexington ksmit1@email.uky.edu

KPERF ADVISORY COUNCIL

Chad Corum, Manchester pharmdky21@gmail.com

Matt Carrico, Louisville matt@boonevilledrugs.com

Cassy Hobbs, Louisville cbeyerle01@gmail.com Nathan Hughes, Louisville nhughe1030@my.sullivan.edu

Chair

Melinda Joyce, Bowling Green MBJoyce@chc.net

Angela Brunemann, Union Angbrunie@gmail.com

Jaclyn Ochsner, Lexington jaclyn.Ochsner@uky.edu

Bob Oakley, Louisville rsoakley21@gmail.com

Sullivan University Student Representative

Chris Killmeier, Louisville cdkillmeier@hotmail.com Don Kupper, Louisville donku.ulh@gmail.com Jeff Mills, Louisville jeff.mills@nortonhealthcare.org Richard Slone, Hindman richardkslone@msn.com Sam Willett, Mayfield willettsam@bellsouth.net

Kim Croley, Corbin kscroley@yahoo.com Kimberly Daugherty, Louisville kdaugherty@sullivan.edu Mary Thacker, Louisville mary.thacker@att.net

KPhA/KPERF HEADQUARTERS 96 C Michael Davenport Blvd., Frankfort, KY 40601 502.227.2303 (Phone) 502.227.2258 (Fax) www.kphanet.org www.facebook.com/KyPharmAssoc www.twitter.com/KyPharmAssoc www.twitter.com/KPhAGrassroots www.youtube.com/KyPharmAssoc

*At-Large Member to Executive Committee

HOUSE OF DELEGATES Amanda Jett, Louisville Speaker of the House ajett@sullivan.edu

|42| Kentucky Pharmacists Association | January/February 2018

K.PH.A. BREAKS GROUND FOR BUILDING Coleman Friedman R, Ph., Louisville, has been elected President of the Kentucky Board of Pharmacy, succeeding Vernon Stubblefield, R. Ph., Murray.

- From The Kentucky Pharmacist, February 1968, Volume XXXI, Number 2

Frequently Called and Contacted Kentucky Pharmacists Association 96 C Michael Davenport Blvd.

Frankfort, KY 40601 (502) 227-2303 www.kphanet.org Kentucky Board of Pharmacy State Office Building Annex, Ste. 300 125 Holmes Street Frankfort, KY 40601 (502) 564-7910 www.pharmacy.ky.gov Pharmacy Technician Certification Board (PTCB) 2215 Constitution Avenue Washington, DC 20037-2985 (800) 363-8012 www.ptcb.org

Kentucky Society of Health-System Pharmacists P.O. Box 4961 Louisville, KY 40204 (502) 456-1851 x2 (502) 456-1821 (fax) www.kshp.org info@kshp.org Kentucky Regional Poison Center (800) 222-1222 American Pharmacists Association (APhA) 2215 Constitution Avenue NW Washington, DC 20037-2985 (800) 237-2742 www.aphanet.org

National Community Pharmacists Association (NCPA) 100 Daingerfield Road Alexandria, VA 22314 (703) 683-8200 info@ncpanet.org Drug Information Center SUCOP 2100 Gardiner Lane Louisville, KY 40205 (502) 413-8638 www.sullivan.edu

KPhA Staff Mark Glasper Executive Director mglasper@kphanet.org Sarah Brandenburg Director of Communications & Continuing Education sbrandenburg@kphanet.org Angela Gibson Director of Membership & Administrative Services agibson@kphanet.org Jody Jaggers, PharmD Director of Pharmacy Emergency Preparedness jjaggers@kphanet.org Elizabeth Ramey Receptionist/Office Assistant eramey@kphanet.org

KPhA Remembers KPhA desires to honor members who are no longer with us. Please keep KPhA informed by sending this information to eramey@kphanet.org.

Deceased members for each year will be honored permanently at the KPhA office.

|43| www.KPHANET.org

THE

Kentucky PHARMACIST 96 C Michael Davenport Blvd.

Frankfort, KY 40601

www.kphanet.org |44| Kentucky Pharmacists Association | January/February 2018