North Carolina Pharmacist Volume 103 Number 3

North Carolina Pharmacist Volume 103 Number 3

Advancing Pharmacy. Improving Health.

Celebrate With Us! October is American Pharmacists Month National Pharmacy Week - October 16-22 Women Pharmacist Day - October 12 Pharmacy Technician Day - October 18

Official journal of the North Carolina Association of Pharmacists ncpharmacists.org

Call for Articles North Carolina Pharmacist (NCP) is currently accepting articles for publication consideration.

We accept a diverse scope of articles, including but not limited to: original research, quality improvement, medication safety, case reports/case series, reviews, clinical pearls, unique business models, technology, and opinions.

NCP is a peer-reviewed publication intended to inform, educate, and motivate pharmacists, from students to seasoned practitioners, and pharmacy technicians in all areas of pharmacy.

Articles written by students, residents, and new practitioners are welcome. Mentors and preceptors – please consider advising your mentees and students to submit their appropriate written work to NCP for publication.

Don’t miss this opportunity to share your knowledge and experience with the North Carolina pharmacy community by publishing an article in NCP. Click on Guidelines for Authors for information on formatting and article types accepted for review.

For questions, please contact Tina Thornhill, PharmD, FASCP, BCGP, Editor, at tina.h.thornhill@ gmail.com.

North Carolina Pharmacist is the official journal of the North Carolina Association of Pharmacists Located at: 1101 Slater Road, Suite 110 Durham, NC 27703 Phone: (984) 439-1646 Fax: (984) 439-1649 www.ncpharmacists.org

Official Journal of the North Carolina Association of Pharmacists 1101 Slater Road, Suite 110 Durham, NC 27703 Phone: (984) 439-1646 Fax: (984) 439-1649

North Carolina Pharmacist Volume 103 Number 3

www.ncpharmacists.org EDITOR-IN-CHIEF Tina Thornhill LAYOUT/DESIGN Rhonda Horner-Davis

EDITORIAL BOARD MEMBERS Anna Armstrong Jamie Brown Lisa Dinkins Jean Douglas Brock Harris Amy Holmes John Kessler Angela Livingood Bill Taylor

BOARD OF DIRECTORS EXECUTIVE DIRECTOR Penny Shelton PRESIDENT Matthew Kelm PRESIDENT-ELECT Ouita Gatton PAST PRESIDENT Elizabeth Mills TREASURER Ryan Mills SECRETARY Paige Brown Shane Garrettson, Chair, SPF Carrie Baker, Chair, NPF Trish Mashburn, Chair, Community Mary-Haston Vest, Chair, Health-System Amber M Lussier, Chair, Chronic Care Holly Canupp, Chair, Ambulatory Macary Weck Marciniak, At-Large Vinay Patel, At-Large Riley Bowers, At-Large North Carolina Pharmacist (ISSN 0528-1725) is the official journal of the North Carolina Association of Pharmacists.

An electronic version is published quarterly. The journal is provided to NCAP members through allocation of annual dues. Opinions expressed in North Carolina Pharmacist are not necessarily official positions or policies of the Association. Publication of an advertisement does not represent an endorsement. Nothing in this publication may be reproduced in any manner, either whole or in part, without specific written permission of the publisher.

A Few Things Inside • From the President..................................................................................................4 • From the Executive Director...................................................................................5 • Integration of Well-Being and Resilience Training................................................7 • Low-Dose Naltrexone.........................................................................................15 • Adolescent and Adult Chlamydial Infections.......................................................18 • Anti-NMDAR Encephalitis: A Case Series............................................................24 • Case Report: Over-the-Counter Codeine Use in a SeniorAdult................................29 • Comparison of Glycemic Control.........................................................................31 • New Drug Monographs....................................................................................37 • NCAP News.......................................................................................................45

North Carolina Pharmacist is supported in part by: • Pharmacy Quality Commitment ...........................................................14 • Pharmacy Technician Certification Board (PTCB) ..............................17 • NCAP Career Center ............................................................................23

• EPIC Pharmacies Inc ............................................................................28 • Pharmacists Mutual Companies ...........................................................30 • Pharmacy Audit Assistance Service .....................................................35 • VUCA Health .......................................................................................36 • Alliance for Patient Medication Safety ................................................40

• Your Community Health Plan ..............................................................48 CORRECTIONS AND ADVERTISING For rates and deadline information, please contact Rhonda Horner-Davis at rhonda@ncpharmacists.org

Connect With Us!

•From the President• Matt Kelm, PharmD

With the return of pumpkin spice lattes to Starbucks and gourds on display at the front of grocery stores, signs of fall are certainly returning to North Carolina. This fall is a quiet period legislatively with the state house and senate in recess for the short session, but NCAPs efforts to prepare legislation for the coming long session are well underway. Exciting progress is being made with the department of labor to create a portal to receive complaints about pharmacy benefit manager (PBM) practices that our regulatory leaders need to learn about and investigate. Our advocacy committee is doing excellent work to organize our legislative priorities for the year and continuing conversations with our supporters in the legislature.

During this downtime in legislative action, I wanted to highlight the last year’s legislative win with the passage of House Bill 96, creating standing orders for pharmacists to provide hormonal contraception, tobacco cessation, HIV prevention, prenatal vitamins, and glucagon. Additionally, medication administration was expanded to self-administered injectable drugs, including long-act-

ing injectables. NCAP has created excellent programming for each of these expanded authorities. I highly encourage pharmacists interested in providing these services to register for the training content via our website.

In addition to the training opportunities mentioned previously, the organization continues to provide on-demand, streaming, and live continuing education (CE). The 24th Annual NC Anti-Infective Conference will be held on Friday, October 28th, at the Greensboro Country Club. This program provides 5 hours of CE programming.

Please consider registering today.

Also, keep a close eye on our website or your email for a coming announcement about the site of our next residency conference.

Recently, the board of directors was able to hear a report on the

success of our annual meeting.

The event was a welcome return to in-person CE, networking, and knowledge development. We experienced strong attendance and support for our vendor partners.

Recently, NCAP staff visited the site of our 2023 annual convention in Beaufort, NC. If you have not already had a chance to see the convention website, I encourage you to do so. The venue is outstanding and will create a unique setting for the convention.

Room blocks are open currently, and this is certainly an event you will not want to miss.

Lastly, I would be remiss if I did not use this opportunity to wish every NCAP member a very happy National Pharmacy Week. From October 16th through the 22nd, we celebrate our profession and all it does for the patients of our communities.

#pharmacyweek

National Pharmacy Week October 16–22, 2022

ncpharmacists.org Page 4

•From the Executive Director• Penny Shelton, PharmD, BCGP, FASCP

Carolina Association of Pharmacists, like so many other ‘membership organizations,’ is highly dependent upon our members as volunteers.

Inside NCAP Operations: A Membership Organization and the Call to Serve

In 2022, I set out the year to devote each of my columns in the journal to a behind-the-scenes peek into various operations for the North Carolina Association of Pharmacists (NCAP). This issue publishes during the time of year when our Association is also seeking individuals to run for a number of different leadership roles among our practice academies and our Board of Directors.

Therefore, I thought it would be fitting to write about the role of volunteer leaders within the Association’s overall operations.

Our member volunteers are essential for strong governance, smooth operations, and forward-thinking progress.

NCAP exists for and because of our members. The work of the Association is carried out on behalf of pharmacists, pharmacy technicians, and student pharmacists.

At the same time, we need member volunteers to help by serving on our committees, task forces, special project teams, forum and practice academy leadership teams, and the Board of Directors.

In L. David Marquet’s book “Leadership is Language,” he frequently refers to the concept of embracing variability and that decision-making is enhanced by variable thinking. When I was hired to serve as the Executive Director for NCAP, I shared with the search committee and later with the staff that no one enjoys conflict, but conflicting ideas can be good. If everyone thought the same way, change would never occur, and the organization would fall victim to the status quo. NCAP’s governance structure and operations are bettered by the inclusion of volunteers who bring their variability of thought, which helps spark creativity and innovation for the Association.

Here in North Carolina, we are fortunate that our state is large enough to have a pharmacy association with part- and full-time employed staff. It is the NCAP staff that enables the Association to provide important information, carry out an active legislative agenda, produce valuable resources and toolkits, and offer educational programming throughout the year. Our staff also provides many other services and benefits for members, and they collectively support the work of The Oath of a Pharmacist, recentour volunteer leaders. The North Page 5

ly revised in late 2021, still has its opening statement: “I promise to devote myself to a lifetime of service to others through the profession of pharmacy.” Each year, I am asked to speak with various student groups on advocacy, leadership, and service to the profession. During these presentations, I frequently share that we are taught in pharmacy school how to advocate for patients across the care continuum. Still, very little time is devoted to teaching us how to advocate for our profession. This represents a different, yet still appropriately applicable, interpretation of ‘the Oath’ we all take when entering the profession. We, too, have a duty to serve and advocate for the profession of pharmacy to protect and advance our profession; if we don’t do it, who will?

One way to serve or advocate for your profession, and to set an example for others, is to volunteer for NCAP. Each year, we do a ‘call to action’ to run for elected positions in the fall.

Also, in the fall and occasionally throughout the year, we call for volunteers to serve on specific committees, task forces, and special projects. These ‘calls’ run in our weekly news, eNCAPsulated, but we also welcome and receive members’ interest in serving through our ‘how to get involved’ webpage. The NCAP Nominations Committee is currently working on slating the ballot for elected positions; see

page 45 in this issue of the journal.

If you’ve read many of Adam Grant’s leadership books, he postulates that “highly successful people have three things in common: motivation, ability, and opportunity.” I would surmise the same is true for a highly successful organization. NCAP provides the opportunity to serve and lead.

We all know that pharmacists, technicians, and student pharmacists are loaded with talent and ability. But the motivation to serve must come from within the hearts of our members. Our humanity and compassion are evident in our personal lives when we say to others in need, “I’m thinking of you, and if you need anything, all you have to do is ask.” Oftentimes, we don’t know what to do or how to help, but we genuinely want to be there for the person in need.

“Whatever you need, just ask!”

The same is true for your pharmacy association. The ‘calls to volunteer’ are times when your association is reaching out to ask for help. Do you feel called to serve?

Are you motivated to step up?

Pharmacy Proud, Penny

Integration of Well-Being and Resilience Training Into the Curriculum of a Pharmacy Residency Program By: Dr. Anne C. Carrington Warren, Dr. Gwen J. Seamon, and Dr. Rebecca Grandy Background and Purpose Burnout is defined by the Agency for Healthcare Research and Quality as a “long-term stress reaction marked by emotional exhaustion, depersonalization, and a lack of sense of personal accomplishment.”1 In 2019, the World Health Organization classified burnout as an “occupational phenomenon” in the 11th Revision of the International Classification of Diseases (ICD-11).2 While previous research on rates of burnout focused primarily on physicians and nurses; emerging data shows that pharmacists experience the phenomenon at similar rates. A 2017 nationwide study of hospital clinical pharmacy practitioners found a burnout rate greater than 60%, largely driven by emotional exhaustion.3 As the profession continues to embrace advanced practice roles, rates of burnout are expected to increase with increasing clinical responsibilities.4 The American Society of Health-System Pharmacists (ASHP) Foundation Pharmacy Forecast 2019 found that the increasing pressure of clinical roles and the complexity

of healthcare will increase the annual turnover rate amongst frontline pharmacists to at least 15%, an expected increase from 6.8% in 2014.4 In response, numerous pharmacy organizations including ASHP, the American Association of Colleges of Pharmacy, and the American Pharmacists Association developed well-being initiatives and task forces to address these concerns.5-7 The National Academy of Medicine (NAM) is currently addressing the issue of clinician well-being through the Action Collaborative on Clinician Well-Being and Resilience, or “Action Collaborative.”8 This initiative was launched in response to the expanding body of evidence that burnout is widespread and ultimately affects patient outcomes. The focus of the action collaborative goes beyond addressing the negative outcome effects of burnout. A key result is “to understand the broader phenomenon of clinician well-being, and to help clinicians achieve a state of personal fulfillment and engagement that leads to joy in practice, and ultimately, a Page 7

connection to why one went into health care in the first place.”8

A new conceptual model for understanding the complexity of clinical well-being was proposed

by NAM in 2018, titled “Factors Affecting Clinician Well-Being and Resilience” [Figure 1].8 Patient well-being is the center of the model, as, without a patient, there is no clinician.9 Patient well-being is enveloped by the clinician-patient relationship, followed by clinician well-being.

Surrounding clinician well-being are a myriad of factors, divided into either external or individual, which are known to affect clinician well-being and resilience.

The external factors are defined as “Society & Culture; Rules & Regulations; Organizational Factors; Learning/Practice Environment; and Health Care Responsibilities.” Individual factors are defined as “Personal Factors; and Skills & Abilities.” The 2019 Society for Academic Emergency Medicine Consensus Conference notably utilized this framework to further identify areas of needed study amongst physician wellness, identifying the distinct

impact of organizational factors on physician well‐being.10

The purpose of this paper is to describe a Well-Being and Resilience Curriculum developed for a Post-Graduate Year 1 (PGY-1) Pharmacy Residency in an Ambulatory Care Setting, utilizing NAM’s “Factors Affecting Clinician Well-being and Resilience” model as a framework.

Educational Activity and Setting

This PGY-1 pharmacy residency was established in 2018 within a family medicine clinic that serves a largely rural population. The main clinic includes family medicine physician and dental residency programs as well as PGY-2 pharmacy residency programs in ambulatory care and geriatrics.

The PGY-1 residency program is taking a unique approach to addressing resiliency and potential burnout. Utilizing the innovative model from NAM as a framework, preceptors ensure that each internal and external factor is considered to provide a comprehensive resiliency experience. The ways each component is addressed and tasks the residents complete during residency are described in further detail below.

Wellness Components External Factors

External factors are those influences, circumstances, or situations that may be beyond one’s control. External factors have also been shown to carry more weight in contributing to burnout

than internal factors.9 These factors can be difficult for residents to navigate and usually depend significantly on the culture of the organization and the patient populations that are served. The pharmacy residency program directors and staff worked to address these factors for their residents within the curriculum.

As a Family Medicine residency site within an Area Health Education Center (AHEC), the organization has a long-standing tradition of training the next generation of healthcare professionals in various disciplines such as medicine, pharmacy, behavioral health, nursing, dentistry, and nutrition.

The organization supports a “Culture of Civility,” which operates under three foundational principles: Civility, Inclusivity, and Empowerment. The human resources department has an Inclusion and Diversity Team to ensure all people are treated with respect and kindness, and the contribution of people of different backgrounds is valued.

As part of the “Culture of Civility” initiative, seminars are held throughout the year on varying topics, including microaggression and systemic racism. Although not required, pharmacy residents are encouraged to embrace this culture and utilize the support throughout the year. Including a “Culture of Civility” at an organization or department level may provide the foundation necessary to introduce a Well-Being and Resilience Curriculum in outside programs.

The pharmacy residency aligns the healthcare responsibilities of the PGY-1 with their current Page 8

abilities and scope. Initial training within this residency program emphasizes teaching the residents to “practice at the top of their license” and to define their role on the healthcare team.

Throughout the year, residency preceptor roles move from modeling to coaching to facilitating to grant timely autonomy and independence to residents.

This process intentionally follows ASHP guidance on the roles of a preceptor so that residents will feel comfortable entering independent practice post-residency.13

The residency program director provides another level of support for residents by including weekly informal check-ins called “Coffee Rounds,” generally lasting around one hour on a weekday morning and involving all residents simultaneously. The aim is to promote an open-door policy for residents to seek advice whenever needed.

The organization also encourages using an error reporting system to promote a culture of safety and transparency. Pharmacy residents, overseen by the residency program director and nursing manager, are responsible for evaluating and implementing at least one process change resulting from a reported error.

Additionally, for many new practitioners, the financial burden of maintaining licensure, accumulating required CE, and malpractice insurance are considered stressors. Pharmacists registered in North Carolina are required to earn 15 hours of CE per year for license maintenance. The organization offers free CE for their employees, including phar-

macy residents, when utilizing programs provided through the organization. Annual pharmacy state licensure fees and malpractice insurance are also covered.

The residency program created Primary Care Clinical Meetings (PCCM) for residents to feel more comfortable with various topics.

These meetings are once-weekly, one-hour sessions led by a topic expert from the state. Attendees include all ambulatory care pharmacy residents in the area, and the meeting place is a conference room within this residency location. Topics include pharmacotherapy in chronic disease states; interdisciplinary topics including mental health, nutrition, and social determinants of health; transitioning from residency to pharmacy practice; and the business models associated with pharmacy administration and advocacy. Residents also gain insight through discussions about National/State Policies, litigation, and accreditation. The inclusion of periodic financial wellbeing seminars as well as advocacy discussions facilitated by state and local level organizations throughout the residency year may be a tangible way to assist residents in transitioning from a learner into a full-time career.

Individual Factors

While clinician burnout is widely viewed as a systems issue, NAM acknowledges the role individual factors can play in building capacity for resilience.8 This includes thoughtfulness around personal factors, as well as skills and abilities, to help individuals navigate changing landscapes

and relationships. The residency curriculum intentionally incorporates personal and professional activities to support strengthening these individual factors.

Residents are supported in individual goals related to residency as well as that outside of pharmacy through creating a personalized development plan at orientation. At this time, an actionable plan for goal achievement is developed. The RPD meets quarterly with residents to support them in completing their goals and to update goals as needed. Additionally, time is spent throughout the year learning about various topics related to resilience, worklife integration, and well-being goals to support personal and professional goals.

Relationships and social support are known to be protective against burnout.1 This is especially important in a residency program, where many residents relocate and move away from friends and family. On day one of orientation, each resident is given “wellness coupons” that include coupons to trade in for items like emergency lunch delivery, a get-out-of-clinic pass for a half-day of administrative time, and group excursions for activities like pedicures and tubing the river (Table 1).

An annual retreat is held in July for the Pharmacotherapy Department. This allows the incoming residents to begin understanding their role and meaning within the care provided to patients in the organization. The retreat also sets the stage for building organic relationships with preceptor Page 9

mentors. Following orientation, monthly opportunities to connect with preceptors and co-residents are scheduled throughout the year (Table 2).

To further expand the residents’ social network and opportunities for connection, residents from all other regional programs are incorporated into longitudinal opportunities to foster relationships (Table 3). Incorporating all residents within the region into required longitudinal learning activities was an intentional residency design to promote peerto-peer relationships both within and outside the program. When considering the inclusion of a Well-Being and Resilience Curriculum in one’s residency program, the authors strongly recommend allocating time on a regular basis for social and team-building activities.

In addition to relationships, NAM stresses the importance of personality traits, personal values, ethics, and morals contributing to well-being. Residency training allows individuals to reflect on these personal factors and how they affect their work. The leadership curriculum offered within the program formally incorporates these principles during once-monthly sessions and individualized, one-on-one leadership coaching. Residents are assigned a leadership coach at the beginning of the year and meet with them every other month for one hour. Leadership curriculum sessions meet monthly for three hours, and topics include personal leadership assessment, advocacy, servant leadership, interdisciplinary

communication, balance and time management, leadership book discussion, women in leadership, managing conflict, managing departments, supervising others, resiliency/burnout, and emotional intelligence. Sessions are led by leadership curriculum preceptors and pharmacy leaders within the community. Relevant skills and abilities are taught in this curriculum to familiarize residents with each topic and provide strategies for implementation in day-to-day life. Additional sessions on financial planning, transitioning from residency to practice, and best practices for job hunting are included in the PCCM curriculum.

To promote physical well-being, residents are encouraged to participate in local intramurals or running groups. Additionally, the organization’s health plan includes discounts on local gym classes. Recognizing that mental health is just as important, the organization contracts with a local Employee Assistance Program to provide free behavioral healthcare services to employees. Sick time for residents can include both physical and mental illness.

Discussion

No previous publications described the creation of a Well-Being and Resilience Curriculum within a pharmacy residency utilizing a recognized framework to ensure both the internal and external components of wellness were addressed. While residents provide feedback for the Well-Being and Resilience Curriculum periodically throughout the year and during exit surveys, no for-

mal evaluation currently occurs.

Additional study is needed to determine the extent of perceived benefit to residents and the overall impact on feelings of burnout.

The authors of this manuscript believe there is usefulness in both modeling new curricula on a validated framework as well as continual re-evaluation of current curricula to determine if all components are met. This process may be a promising strategy to meet the evolving needs of residents entering the healthcare workforce.

Little research has focused on the impact of stress and burnout on pharmacy residents. A nationwide study conducted in March 2016 found that roughly 40% of pharmacy residents who responded to the survey reported moderate-to-severe depressive symptoms, as measured by Patient Health Questionnaire – 9 scores, and the rate of severe depressive symptoms increased from around 3% in September to nearly 8% by March (p<0.05).11 Additionally, previous research identified discrepancies in perceptions of well-being between residents and residency program directors (RPDs). In one study, less than half of residents reported a “good” or “great” level of well-being as compared with 80% of RPDs assessing their resident’s well-being as “good” or “great” (p < .001).12 Given the known impacts of burnout on professional well-being, quality of patient care, and increased healthcare costs, it is prudent to develop strategies addressing well-being and resilience within not only health-systems but also residency programs to better Page 10

prepare residents for lifelong careers in pharmacy.

Only one previous study evaluated resident perceptions of a resilience curriculum in a PGY1 pharmacy residency program utilizing a quarterly survey.14 Results of these surveys showed that most residents (90%) rated the Well-Being and Resilience curriculum as highly or extremely valuable and that the most valuable component was the creation of a sense of community. While the resilience curriculums within these two programs are modeled differently, the authors plan to adapt portions of this survey for longitudinal use within the curriculum. In the future, a formal, quantitative assessment of the Well-Being and Resilience Curriculum will be created to identify the most valuable components, opportunities to improve the curriculum, and significant sources of stress within the residency year.

This initial research was designed to discuss creating a Well-Being and Resilience program that utilizes an evidence-based framework to ensure all external and internal components of well-being are addressed. Research has shown that student pharmacists often do not acknowledge nor recognize health-system factors as impactful on well-being.15 Thus, the authors postulate that a baseline discussion of NAM’s framework should be introduced during residency orientation alongside the Well-Being and Resilience Curriculum so that residents may be better educated and understand the interplay between external

and internal factors on well-being. Recognition of the “Factors Affecting Clinician Well-Being and Resilience” may result in better articulation of feedback and needs amongst residents, particularly as stress and workload rise throughout the year.

Plans for this research include utilizing the information from this informal research to create a formal exit survey evaluating the impact of the Well-Being and Resilience curriculum on residents’ attitudes and overall wellness. Quantitative data to collect include yearlong attendance to optional “Culture of Civility” and CE sessions.

Education at the Mountain Area Health Education Center, Inc., UNC Eshelman School of Pharmacy in Asheville, NC. Rebecca. grandy@mahec.net References 1.

2.

3.

Summary

As multiple leading pharmacy organizations take a stand to address well-being, residency programs should consider incorporating training strategies to manage internal and external factors that impact resilience.

This PGY-1 Pharmacy Residency is taking steps to address these factors by integrating a Well-Being and Resilience Curriculum.

Clinician well-being is important and should be a component of pharmacy residency training.

Authors: Anne C. Carrington Warren, PharmD, BCPS, CPP, is an Assistant Professor of Clinical Education at the Mountain Area Health Education Center, Inc., UNC Eshelman School of Pharmacy in Asheville, NC. Gwen J. Seamon, PharmD, CPP is a Clinical Pharmacist at St Elizabeth Healthcare in Edgewood, KY. Rebecca Grandy, PharmD, BCACP, CPP (corresponding author) is an Assistant Professor of Clinical

4.

5.

6.

7.

8.

Agency for Healthcare Research and Quality. Physician Burnout (2017).

Accessed 4 March 2020. https:// www.ahrq.gov/prevention/clinician/ahrq-works/burnout/index. html World Health Organization. Burnout an “occupational phenomenon”: International Classification of Diseases (2019). Accessed 6 July 2020. https://www.who.int/mental_health/evidence/burn-out/en/ Jones GM, Roe NA, Louden L, et al. Factors associated with burnout among US hospital clinical pharmacy practitioners: results of a nationwide pilot survey. Hosp Pharm. 2017;52(11):742-751. doi: 10.1177/0018578717732339 Vermeulen LC, Eddington ND, Gourdine MA, et al. ASHP pharmacy forecast 2019: strategic planning advice for pharmacy departments in hospitals and health systems. AJHP. 2019;76(2):71-100. doi: 10.2146/ sp180010 American Society for Health-Systems Pharmacists. Wellbeing & You. Accessed 4 Mar 2020. https://wellbeing.ashp.org/ American Association of Colleges of Pharmacy. Wellness and Resilience in Pharmacy Education. Accessed 4 March 2020. https://www.aacp. org/resource/wellness-and-resilience-pharmacy-education American Pharmacists Association.

Well Being. Accessed 4 March 2020. https://www.pharmacist.com/ well-being National Academies of Sciences, Engineering, and Medicine. 2019.

Taking Action Against Clinician

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9.

10.

11.

12.

13.

14.

15.

Burnout: A Systems Approach to Professional Well-Being. https:// doi.org/10.17226/25521. Reproduced with permission from the National Academy of Sciences, Courtesy of the National Academies Press, Washington, D.C. Brigham T, Barden C, Dopp AL, et al.

A journey to construct an all-encompassing conceptual model of factors affecting clinical well-being and resilience. NAM Perspectives (2018). Discussion Paper, National Academy of Medicine, Washington, DC. doi: 10.31478/201801b Sikora RD, Manfredi RA, Chung A, et al. Wellness for the future: cultural and systems-based challenges and solutions. Academic Emergency Medicine. 2020;27(4):317-332. doi:10.1111/acem.13937 Williams E, Martin S, Fabrikant A, et al. Rates of depressive symptoms among pharmacy residents. Am J Health-Syst Pharm. 2018;75(5):2927. doi: 10.2146/ajhp161008 LeDoux H, Bowers R, Shapiro M, et al. Perceptions of well‐being among pharmacy residents and residency program directors. JAACP. 2020;3(3):623-629. doi: 10.1002/ jac5.1197 document for the ASHP accreditation standard for postgraduate year one (PGY1) pharmacy residency programs. Accessed 4 March 2020. https://www.ashp.org/-/media/ assets/professional-development/ residencies/docs/guidance-document-PGY1-standards.ashx Swanson S, Schweiss S. Resident perceptions of a resilience curriculum in a postgraduate year 1 (PGY1) pharmacy residency program.

Currents in Pharmacy Teaching and Learning. 2019;11:949-955. doi: 10.1016/j.cptl.2019.05.004 Babal JC, Abraham O, Webber S, et al. Student pharmacist perspectives on factors that influence wellbeing during pharmacy school.

AJPE. 2020.84(9). Article 7831.

Doi:10.5688/ajpe7831

Tables Table 1: Wellness Coupon Template

Welcome Wellness Coupons Class of 2023 - Ambulatory Care PGY1 ***Be sure to plan ahead and coordinate schedules for redeeming group wellness coupons

Mani, Pedi, or Facial Courtesy of ____

Lunch at the School of Pharmacy Courtesy of ___

Redeemable as time with preceptor or as preceptor-free time – based on resident preference

Redeemable for one lunch on campus

One free admin half-day Courtesy of your MAHEC RPDs

“I forgot my lunch?!”

Courtesy of __

Redeemable x 1 (please provide 1 day heads up to your preceptor)

Redeemable for one lunch at MAHEC (please notify __ by 11:30am if same day)

One home-cooked meal Courtesy of ___

Coffee and breakfast treat from Starbucks Courtesy of ___

Redeemable for 1 dinner

Redeemable x 1

Raid office chocolate drawer Courtesy of ____

***

“Float or Hike the Stress Away” Courtesy of ____

Redeemable for 1 tube, paddleboard, or hike excursion

Redeemable for repeated PRN use (no need to present coupon at time of transaction) ***Evening

Lake Cruise with Wine OR Waterfall Hike (weather dependent) Courtesy of _____

Decorate your space!

Courtesy of ____ Redeemable for one piece of office “flare” of your choosing (send link to item and she will order)

Redeemable for 1 activity above ***Wine

and Cheese Night Courtesy of ____

Treats from Free Clinic Courtesy of ____

Redeemable for an outing to the Biltmore Wine Bar for wine and cheese

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A Free Friday off to start an early weekend/ holiday or self-care day (no PTO necessary) A free breakfast from McFarlands.

Table 2. Monthly Social Engagement Schedule (optional attendance)

Month July August September October November December January February March April May June

Event Pharmacy Department Retreat Baseball Game Beach Trip (includes former residents) Halloween Party Self-Care Sunday ASHP Midyear Networking Dinner (includes former residents) Holiday Party Galentine’s Day Dinner Game Night Regional Residency Conference Outing Bowling River Float Trip

Table 3. Required Learning Activities to Promote Regional Networking Among Residents Learning Activity Primary Care Clinic Meeting (PCCM) Evidence-Based Medicine (EBM) Diabetes Didactics

Teaching and Learning Curriculum (TLC) Global Health Curriculum

Description

Residency Programs Included One hour, weekly lunch Regional outpatient-fomeetings focused on topics cused residencies pertaining to ambulatory care One hour, monthly journal Regional outpatient-foclubs cused residencies Four hour, monthly intenRegional outpatient-fosive review of recent litercused residencies ature related to diabetes care All regional residencies Four hour, monthly sessions as part of the teaching certificate curriculum Two week experience in Pharmacy students and Honduras residents Medical students and residents

Dual publications: Yes, some portion of the results/data/figures in this manuscript has been published and written permission to reproduce or adapt previously published material has been obtained from the original copyright holder.

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Low-Dose Naltrexone: A Magic Bullet or a Long Shot to Aid Patients with Chronic Pain

By: Dr. Amy S Donnelly, PharmD, RPh

The current opioid epidemic in America has left the healthcare community searching for alternative therapies that are effective for chronic pain while minimizing the risk of harm. According to the CDC, more than 168 million opioid prescriptions were dispensed in 2018. (1) While this number has significantly decreased in recent years, there are still many patients using opioid medications that could benefit from other treatment options if available. Furthermore, because of the increased scrutiny surrounding the use of opioids, many patients struggle to obtain opioid medication access because of the potential misuse, abuse, and accidental overdose. Unfortunately, in some cases, patients who feel like they have no other options turn to illicit drugs and are at even higher risk of overdose; therefore, safer alternative therapies are needed. Low-dose naltrexone (LDN) is a potential therapy that is non-habit forming and has a low side-effect profile.

History and Mechanism of Action Naltrexone, synthesized in 1963, is an opioid receptor antagonist.

(2) The FDA approved it in 1984 to treat opioid addiction. (2) Available in many formulations, oral naltrexone is commercially available as 50 mg tablets. Compared to the traditional dosing of naltrexone, LDN, usually 4.5 mg, has been studied as a potential analgesic agent. When taken in doses this small, naltrexone displays paradoxical results to those seen in 50 mg or higher daily dosing, as indicated for opioid addiction. (2) The observed analgesic effects most likely result from increased endogenous opioid production.

(2) Similarly, the observed anti-inflammatory effects from naltrexone are likely due to antagonism on non-opioid Tolllike receptor 4 (TLR4), located on microglia immune cells of the central nervous system. (2) In Page 15

doing so, naltrexone acts as a glial modulator/inhibitor, resulting in neuroprotective effects by inhibiting cellular pathways that normally result in pro-inflammatory cytokines. (3) The Utility of LDN in Chronic Pain

The efficacy of LDN has been examined in chronic pain and inflammation-related diseases such as multiple sclerosis (MS), fibromyalgia, and Crohn’s disease. (4) Collectively, these disease states affect over 47 million Americans, all of whom struggle with pain, significantly impacting their quality of life. (4) A retrospective chart review of 215 patients with MS who received LDN showed 75% of participants reported an increase or stable quality of life and 60% of participants reported a reduction in fatigue; however, no disease-modification effects have been seen in patients with MS taking LDN. (4) In patients with fibromyalgia, a single-blind

trial that included eight weeks of LDN therapy showed reduced pro-inflammatory markers and fewer pain symptoms. (4) In another study, over 90 days, 50% of patients reported a 40% improvement in symptoms and functioning. (4) Similarly, in Crohn’s disease, one study showed an 88% decrease in the severity of symptoms. (4) Interestingly, this study completed an endoscopic examination, showing that 48% of those treated with LDN had improved disease from baseline. (4) This study highlights the need for continued examination of possible disease-modification potential of LDN in patients with Crohn’s disease.

LDN may also play an important role in patients requiring palliative care. For example, pain management is imperative in caring for patients dying from heart failure, lung disease, and diabetes. Although more studies are needed in palliative care, the potential exists to improve quality of life measurements in this patient population.

Safety

A low incidence of adverse side effects and drug-drug interactions were reported with the use of LDN. (2) Among those treated with LDN, the most common side effect reported was vivid dreams (37%). (2) Headaches were more common than placebo but are also notable in some disease states for which LDN is used.

(2) Anecdotal physician reports of anxiety and tachycardia have also been noted with the use of LDN. (2) No significant effects on hepatic enzymes have been ob-

served. (2) Importantly, no cases of misuse, abuse, dependence, or tolerance have been reported with LDN. (2) The favorable side-effect profile is reassuring as there are known health risks even when using non-opioids such as non-steroidal anti-inflammatory drugs. (2) Potential Impact on Clinical Practice

In clinical practice, we must pursue therapies that will provide effective pain relief and do so with as minimal harm as possible.

Presently, the choice to use LDN for the treatment of chronic pain should be made on a case-by-case basis in patients that desire an alternative to opioid therapy. LDN is not commercially available and must be compounded. However, compounded LDN is inexpensive and easily prepared, making it an affordable option regardless of insurance coverage. (5) Quality of life measurements, an important patient-centered outcome, have the potential to be enhanced using this emerging and novel approach with a low risk of patient harm.

Conclusion

LDN is a low-cost, minimal-side-effect alternative therapy for treating chronic pain. (2) While several studies across multiple high-burden disease states have shown clinical benefits, the positive benefits observed in some patients appear indistinguishable from placebo until at least one to two months after therapy is initiated. (2)

High-quality and rigorous studies are required to elucidate the role Page 16

of LDN in treating chronic pain. A call to action is needed to complete randomized, double-blind, placebo-controlled trials and determine the efficacy and safety of LDN in the care of patients with chronic pain. LDN has the potential to be a magic bullet amid America’s fight against the opioid epidemic.

Hopefully, time and high-quality trials will offer additional supportive evidence, and its use for this indication will increase while keeping patients safe from the known hazards associated with opioids.

Author: Amy S Donnelly, PharmD, RPh, is a Staff Pharmacist at UNC Healthcare’s Rex Outpatient Pharmacy of Raleigh; asdpharmd@hotmail.com.

References 1. Opioid Overdose: U.S. Prescribing Rate Maps. Accessed June 30, 2020. cdc.gov 2. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumato. 2014;33:451-9.

3. Trofimovitch D and Baumrucker SJ. Pharmacology update: Lowdose naltrexone as a possible nonopioid modality for some chronic, nonmalignant pain syndromes.

American Journal of Hospice & Palliative Medicine. 2019;36(10):90712.

4. Patten DK, Schultz BG, Berlau DJ. The safety and efficacy of low-dose naltrexone in the management of chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn’s disease, and other chronic pain disorders. Pharmacotherapy.

2018;38(3):382-9.

5. Bronfenbrener R. Inexpensive compounding of low-dose naltrexone (LDN) with orange juice. J Am Acad Dermatol, 2021 Sep;85(3):e139.

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Adolescent and Adult Chlamydial Infections and the Role of Pharmacists By: Briana Williams, PharmD Candidate

Chlamydia trachomatis, a Gram-negative bacterium, is the pathogen for the sexually transmitted infection (STI), commonly referred to as chlamydia. Chlamydia is transmitted through unprotected oral, anal, and vaginal sexual activities with an individual who has chlamydia, and infection can occur with or without the presence of ejaculate.

Individuals who engage in unprotected sex are at greater risk of infection than men who have sex with men. (1) Chlamydia is the most common STI reported in the United States. In 2019, according to a Centers for Disease Control and Prevention report, North Carolina ranked sixth in the nation for the number of positive chlamydia screenings.

(2) Patients infected with C. trachomatis are often asymptomatic, making the incidence of chlamydia much higher than reported due to the lack of proactive screening programs.

Untreated chlamydia can lead to complications such as cervicitis, urethritis, and proctitis. In gay, bisexual, and other identifying

men who have sex with men, chlamydia-induced proctitis has been shown to have a higher incidence of lymphogranuloma venereum, a chronic infection of the genital lymphatic system. (1) In women with chlamydia, lack of treatment can lead to irreversible damage to the reproductive system with issues ranging from pelvic inflammatory disease, ectopic pregnancy, chronic pelvic pain, and infertility. In pregnant women, chlamydia infection can lead to premature birth. The infection can be transmitted from mother to baby during vaginal delivery, leading to complications such as pneumonia and ophthalmia neonatorum, a form of conjunctivitis that, if left untreated, can result in corneal perforation and blindness. (1) Although chlamydia is often asymptomatic in both men and women, when symptoms are present, women typically experience vaginal discharge, painful intercourse, dysuria, pelvic pain, lower abdominal pain, and intermenstrual pain. Men can experience dysuria, urethral discharge, and scrotal pain and swelling.

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Symptoms in both men and women can appear several weeks after the initial exposure. (1)

Individuals aged 15-24 years also have a higher risk of chlamydia infection due to higher rates of risky sexual behaviors, such as multiple or frequent changes in sexual partners. (3) Health disparities also play a significant role in higher incidence rates of chlamydia. According to the CDC, in 2020, chlamydia rates were six times higher for African American/Black individuals than Whites. (2) Using condoms correctly each time an individual engages in sexual activity is the best way to dramatically reduce the risk of becoming infected or transmitting the infection to others. (1) Patients testing positive for chlamydia should also be tested for other STIs (e.g., HIV, gonorrhea, and syphilis) since the risk of other STIs is high. Table 1 shows the first-line and alternative treatment regimens for chlamydial infection. Main counseling points for patients include:

• Both the patient and their sexual partner(s) should be treated to cure and prevent reinfection.

• Patients should take the entire course of therapy to cure chlamydia.

• If treated with a single-dose regimen, the patient should abstain from sexual activities for seven days. (1) • If treated with a 7-day course, the patient should refrain from sexual activities until they have completed the entire duration of treatment and have no symptoms. (1) Doxycycline and azithromycin appear to be equally efficacious in managing urogenital chlamydial infections; however, doxycycline seems more effective in treating rectal and oropharyngeal chlamydial infections for both men and women. (4-7) However, doxycycline is contraindicated in pregnant women during the second and third trimesters.

Historically, C. trachomatis has responded well to antibiotic treatment. Globally, chlamydia has been sensitive to macrolides, tetracyclines, and fluoroquinolones; however, in recent decades, there have been a number of reports of in vitro antimicrobial resistance.

(8-11) In a 2000 case report

by Somani et al., chlamydia displayed unusual antibiotic-resistance characteristics, and the authors suggested that C. trachomatis displays heterotypic resistance, meaning the chlamydial population contains both susceptible and resistant organisms. (11) Once the an-

tibiotic is no longer present, resistant organisms continue to propagate. (11)

There is no clear treatment pathway for managing antibiotic-resistant chlamydia. In some cases, the pathogenic strain of C. trachomatis may be resistant to treatment or produce a relapse or latent symptom presentation. The patient may not have adhered to their treatment regimen or could be reinfected, presenting with a new infection. Therefore, if symptoms continue after treatment, the patient should be re-evaluated by their primary care provider.

(1) If treatment resistance is suspected after evaluation, an antibiotic from the recommended alternative list should be tried. If the second round of treatment is unsuccessful, culture and sensitivity tests may be necessary to determine the next course of action. (11) Access to care plays a major role in decreasing the rates of chlamydia in North Carolina. (12) As previously mentioned, disparities amongst certain populations leave patients vulnerable and unable to seek medical attention when needed. Affordability and accessibility of care are two key factors perpetuating the high incidence of chlamydia, making it a public health concern in the state. (3) Another attributable factor is acceptability, which refers to patient beliefs and how these translate to their comfort in seeking care and how welcome they feel when receiving care. Gender, sexual orientation, age, ethnicity, education, and socioeconomic characteristics Page 19

can all influence the perceived patient-provider relationship.

When coupled with a particularly sensitive healthcare need, such as an STI, patients may feel very uncomfortable seeking care in a timely manner. The limited availability and accommodation of medical appointments outside traditional medical practice hours further complicate access to care, particularly for disparate populations.

In the United States, there are an estimated 108 million people in which regular STI testing is appropriate. (13) Having efficient and highly accessible screening programs for STIs is essential for decreasing their spread. This is especially true for chlamydia due to the number of asymptomatic cases. In North Carolina, screening for chlamydia during pregnancy is required by law. (14) Sexually active females, 25 years of age or younger, and any individuals with STI risk factors should be screened for chlamydia at least annually. (1) Retesting three months after treatment for chlamydia infection is recommended for all infected individuals, even after successful treatment. (1) North Carolina currently funds local health departments and family planning facilities for chlamydia screening. (15) Yet, our state ranks well above the national average for chlamydia infections. (2)

Community pharmacists serve as a front-line approach for many health care issues, including a number of preventative care needs. What if pharmacists partnered with local health departments to help generate awareness

and assist with screening and treatment for STIs? Pharmacists would be ideal healthcare providers to offer point-of-care (POC) STI screening, risk-mitigation education, treatment, and referral due to their trusted role in their communities. If pharmacists were a more integral part of the screening and treatment initiation, they would have the information they need to help guide treatment adherence and encourage retesting when appropriate. (16-17)

In March 2021, the Food and Drug Administration granted Clinical Laboratory Improvement Amendments (CLIA) waiver for the first-ever molecular POC test and testing platform for chlamydia and gonorrhea. (18) This new technology, offered by Binx Health, provides a novel STI POC testing opportunity for innovative pharmacies that have applied for and received a CLIA waiver.

According to an article in Fortune, the company plans to provide free rentals for the Binx io POC equipment, with single-use cartridges (Figure 1) that can provide test results within 30 minutes. (19) Pharmacies not interested in purchasing, renting, or housing onsite testing equipment can still develop an STI service by partnering with a full-service lab company, such as Labcorp© or Mako Medical Laboratories.

Pharmacies may carry, promote, and sell STI home test kits like the Everlywell Chlamydia & Gonorrhea Test (Figure 2).

Everlywell, HealthLabs, Personalabs, QuestDirect, and LetsGet-

Checked are just a handful of the companies offering STI at-home testing kits run by CLIA-approved laboratories. (20) These at-home tests are easily administered by the patient. Depending on the kit, and the tests to be run, the patient collects finger-stick blood, urine, and/or vaginal swab sample. The collected sample(s) is mailed to the lab, and once the lab processes the test, the patient is contacted directly with their test results.

For pharmacists to be able to sustain a pharmacy-based STI service, major policy advancements are needed. Becoming and staying involved with the North Carolina Association of Pharmacists (NCAP) is an effective way to advocate for policy change in the profession. In North Carolina, pharmacists are allowed to perform CLIA-waived POC tests.

Gaining the authority for pharmacists to test and treat certain STIs could dramatically improve access to screening and treatment and should help produce a positive shift in managing this public health crisis. However, the challenge pharmacists and pharmacies face is that health plans typically do not recognize and pay pharmacists for screening and evaluation, nor do health plans reimburse for the test-related materials at an appropriate level.

In the next legislative session, NCAP will run a bill calling for fair reimbursement and test-andtreat authority for pharmacists. It would be advantageous to address chlamydia and other STIs if North Carolina pharmacies had access to state funding to help Page 20

cover the cost of STI screening and care for uninsured or underinsured individuals.

Author: Briana Williams is a 2023 PharmD Candidate at Campbell University College of Pharmacy and Health Sciences.

References 1. Detailed STD Facts - Chlamydia. https://www.cdc.gov/std/chlamydia/ stdfact-chlamydia-detailed.htm. Updated 2022. Accessed Jun 15, 2022.

2. Sexually Transmitted Disease Surveillance 2019. Table 2. Chlamydia — Reported Cases and Rates of Reported Cases by State, Ranked by Rates, United States, 2019. CDC Web site. https://www.cdc.gov/std/statistics/2019/tables/2.htm. Updated 2022. Accessed Jun 15, 2022.

3. Cooksey CMJL, Berggren EK, Lee J. Chlamydia trachomatis Infection in Minority Adolescent Women: A Public Health Challenge. Obstetrical & Gynecological Survey.

2010;65(11):729-735.

4. Kong FY, Tabrizi SN, Law M, et al.

Azithromycin versus doxycycline for the treatment of genital chlamydia infection: a meta-analysis of randomized controlled trials. Clin Infect Dis 2014;59:193–205.

5. Páez-Canro C, Alzate JP, González LM, Rubio-Romero JA, Lethaby A, Gaitán HG. Antibiotics for treating urogenital Chlamydia trachomatis infection in men and non-pregnant women.

Cochrane Database Syst Rev 2019.

6. Dukers-Muijrers NHTM, Wolffs PFG, De Vries H, et Treatment effectiveness of azithromycin and doxycycline in uncomplicated rectal and vaginal Chlamydia trachomatis infections in women: a multicentre observational study (FemCure). Clin Infect Dis 2019;69:1946–54.

7. Dombrowski JC, Wierzbicki MR, Newman LM, et al. Doxycycline versus azithromycin for the treatment of rectal chlamydia in men who have sex with men: a randomized controlled trial. Clin Infect Dis 2021.

8. Mourad A, Sweet RL, Sugg N, Schachter J. Relative resistance to erythromycin in Chlamydia trachomatis. Antimicrob Agents Chemother. 1980;18:696–8.

9. Jones RB, DerPol BV, Johnson RB. Susceptibility of Chlamydia trachomatis to trovafloxacin. J Antimicrob Chemother. 1997;39(Suppl B):63–5.

10. Lefevre JC, Lepargneur JP, Guion D, Bei S. Tetracycline-resistant Chlamydia trachomatis in Toulouse, France. Pathologie Biologie (Paris) 1997;45:376–8.

11. Somani J, Bhullar VB, Workowski KA, Farshy CE, Black CM. Multiple drug-resistant Chlamydia trachomatis associated with clinical treatment failure. J Infect Dis. 2000;181:1421– 7.

12. Wyszewianski L. Access to Care: Remembering Old Lessons. Health Serv Res. 2002;37(6):1441-1443. \ 13. U.S. Preventative Services Task Force. Chlamydia and Gonorrhea: Screening. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/chlamydia-and-gonorrhea-screening. Updated 2021.

Accessed July 18, 2022.

14. 10A NCAC 41A .0204. Control Measures - Sexually. http://reports.oah. state.nc.us/ncac/title%2010a%20 -%20health%20and%20human%20 services/chapter%2041%20-%20 epidemiology%20health/subchapter%20a/10a%20ncac%2041a%20 .0204.pdf. Accessed July 18, 2022.

15. North Carolina Department of Health and Human Services.

Chlamydia in North Carolina, 2020. https://epi.dph.ncdhhs.gov/cd/ stds/figures/2020-Chlamydia-Factsheet-Final.pdf. Updated 2021.

Accessed July 18, 2022.

16. Ross M. Three STDs Spreading: How Pharmacists Can Help. Pharmacy Times 2015. https://www.pharmacytimes.com/view/3-stds-spreadinghow-pharmacists-can-help. Accessed September 8, 2022.

17. Wood H, Gudka S. Pharmacist-led screening in sexually transmitted infections: current perspectives. IPRP. 2018;7:67-82.

18. U.S. Food and Drug Administration.

FDA Allows for First Point-of-Care Chlamydia and Gonorrhea Test to be Used in More Near-Patient Care Settings. https://www.fda.gov/ news-events/press-announcements/ fda-allows-first-point-care-chlamydia-and-gonorrhea-test-be-usedmore-near-patient-care-settings.

Updated 2021. Accessed July 18, 2022 19. Hay M. Binx aims to capture a milestone in STI testing technology. https://fortune.com/2020/04/21/ sti-testing-binx-io-clinics-pharmacy/.

Updated 2020. Accessed July 18, 2022.

20. Everlywell. Discreetly test for chlamydia and gonorrhea. https://www. everlywell.com/products/chlamyd-

ia-gonorrhea-test/. Updated 2022.

Accessed July 18, 2022.

21. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021.

MMWR Recomm Rep. 2021;70(4):1-

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187 22. Binx. CLIA-Waived, Point-of-Care Testing. That’s the binx io; https:// mybinxhealth.com/point-of-care. Updated 2020. Accessed July 18, 2022.

Table 1. Centers for Disease Control and Prevention (CDC) 2021 treatment guideline on urethral, cervical, or rectal C. trachomatis infection21 Treatment Regimens for Non-Pregnant Adolescents and Adults First-line Regimen

Alternative Regimens Treatment Regimens for Pregnant Women First-line Regimen

Alternative Regimen

Doxycycline 100 mg orally twice daily for 7 days Azithromycin 1 g orally in a single dose or Levofloxacin 500 mg orally once daily for 7 days Azithromycin 1 g orally in a single dose

Amoxicillin 500 mg orally 3 times/day for 7 days

Figure 1: Binx io Testing Platform for Chlamydia & Gonorrhea22

Figure 2: Everlywell Chlamydia & Gonorrhea Test Kit Components20

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Page 23

ANTI-NMDAR ENCEPHALITIS: A CASE SERIES

By: Dr. Stephanie Karvosky and Dr. Dawn MacElroy

ABSTRACT Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune illness caused by the production of antibodies against the N-methyl-D-aspartate (NMDA) receptor 1 (NR1) subunit of the NMDA receptor.

It presents most commonly in younger females, with a median age of 21 years, and is frequently associated with ovarian teratomas. Symptoms and clinical manifestations include viral-like prodromal syndrome, psychiatric manifestations, motor dysfunction, and autonomic instability.

Treatment consists of immunotherapy and resection of the underlying tumor if present. Psychiatric sequelae, such as agitation, mania, and catatonia, often require additional treatment.

PROBLEM/BACKGROUND

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neurological disease characterized by a complex range of symptoms, including prodromal syndrome, psychiatric manifestations, motor dysfunction, and autonomic instability.1-3 First described by Dalmau and colleagues in 2007, the condition is predominantly present in younger adults and children.4 In particular, those diagnosed are frequently females with an associated tumor.1 In up to 50% of females, the underlying tumor identified is an ovarian teratoma.5 Detection of anti-NMDAR immunoglobulin G (IgG) antibodies within the cerebrospinal fluid (CSF) is diagnostic for the disease.5-6 In the following case series, we describe anti-NMDAR encephalitis treatment management in two patients with related catatonic symptoms requiring electroconvulsive therapy (ECT) Page 24

at a community hospital.

ANALYSIS AND RESOLUTION CASE ONE

A 25-year-old Hispanic female (weight 68.1 kg) with no significant past medical history presented from an outside facility for disorganized thinking, pressured speech, catatonic-like behavior, and agitation. Treatment initiated at the facility included lithium, quetiapine, haloperidol, and clonazepam. She continued to decline, with subsequent worsening of manic behavior, posturing, and catatonic-like behavior.

Lorazepam was initiated with poor response. Per outside records, pertinent findings included a lithium level of 0.77 mEq/L, prolactin 51.52 ng/mL, TSH 4.19 mIU/mL, negative rapid plasma reagin, negative heavy metal screening, and MRI brain showed

no acute abnormalities. She was transferred for evaluation for ECT management.

At the time of transfer, medications included valproic acid 1000 mg daily orally, lorazepam 2 mg every 4 hours orally, and zolpidem 10 mg nightly orally. On admission, she was admitted to the intensive care unit for close monitoring and neurological workup. A repeat brain MRI and abdominal and chest CT did not reveal any abnormalities. Electroencephalography results revealed diffuse slowing without seizures.

Due to the rapidity of symptoms, a neurological workup for infectious and autoimmune etiologies ensued. HIV, HSV, and syphilis assays were unrevealing. A lumbar puncture was collected, and CSF autoimmune antibody panels were sent. Empiric treatment was then initiated with intravenous immune globulin (IVIG) 0.4 mg/kg/day and methylprednisolone 1000 mg/day intravenously for five days.

Ultrasound imaging of the pelvis revealed an ovarian mass consistent with a 1.6 cm dermoid cyst.

The patient underwent a successful oophorectomy with pathology consistent with a mature cystic teratoma. Plasmapheresis was considered post-IVIG but is unavailable at this institution and would have necessitated transfer to another facility. Thus, a rituximab 1000 mg infusion was initiated following the completion of IVIG and steroids, with a second dose two weeks after the initial and a third dose one month later. Premedication consisted of acetaminophen, diphenhydramine, and steroids. Following

treatment, anti-NMDA receptor antibodies were detected on the CSF paraneoplastic panel, and anti-NMDAR encephalitis was confirmed as the primary diagnosis.

Amid the patient’s anti-NMDAR encephalitis confirmation, her course was complicated by concomitant catatonia. Lorazepam was titrated to effect with dosing as high as 9 mg every three hours intravenously. However, her symptoms progressed to malignant catatonia, with worsening dysautonomia and fever. Medication trials included lorazepam, amantadine, memantine, bromocriptine, dantrolene, benztropine, and zolpidem. A zolpidem challenge was initiated for augmentation to lorazepam without clinical response. ECT was initiated throughout the hospital stay. The ECT schedule consisted of a range of frequencies, including twice daily, daily, and three times weekly, with the only complication being a bradycardic episode. Two sessions per ECT treatment day were administered for a period of one week of three times weekly treatments due to the severity of the patient’s dysautonomia. These sessions appeared not to cause significant complications; however, the patient began to demonstrate more autonomic instability and was then transitioned to daily ECT. Once medically stable during this stay, the patient was transferred to the rehabilitation unit to continue lorazepam, zolpidem, and ECT. At discharge, she had completed 34 ECT treatments and was transitioned to an outpatient regimen of every two-week treatment.

Page 25

The patient’s hospital course was also complicated by an Escherichia coli urinary tract infection and probable aspiration pneumonia, both of which were appropriately treated with antimicrobial agents. At the time of discharge, she was prescribed lorazepam 4 mg three times daily orally with a weekly taper and zolpidem 10 mg nightly orally. Upon follow-up, the patient’s every two-week ECT treatments were discontinued after 36 treatments. Per the documentation, she is continuing occupational and speech therapy with improving short-term memory and intact long-term memory.

Lorazepam and zolpidem have successfully been discontinued without recurrence of symptoms.

CASE TWO

A 37-year-old African American female (weight 75.8 kg) with no significant past medical history presented to an institution within our health system from an outside facility for seizure-like activity, agitation, and mania. The outside facility provided pertinent information, including MRI brain and CT brain with no acute abnormalities and detection of anti-NMDAR positive antibodies.

She had completed IVIG 0.4 mg/ kg/day intravenously and highdose methylprednisolone 1000 mg daily intravenously for five days.

Before admission to our facility, she was transferred to an intensive care unit within our health system. Electroencephalography results initially revealed diffuse slowing without seizures, and repeated results throughout her

stay revealed continuing diffuse slowing with delta slowing and delta brush. In the setting of confirmed anti-NMDAR encephalitis and lack of improvement after treatment, plasmapheresis and cyclophosphamide 750 mg/ m2 intravenously were initiated. She received a total of five plasmapheresis treatments. An ultrasound of the pelvis revealed an adnexal cystic lesion that was then resected with pathology, confirming a mature cystic teratoma. With no further response, she received a second course of IVIG 0.4 mg/kg/day intravenously for five days post-plasmapheresis and rituximab 1000 mg intravenously for two total doses.

Due to a continued lack of improvement, a repeat anti-NMDAR assay was sent and confirmed positive after treatment. Prolonged steroid therapy continued throughout her hospitalization and transfer to this facility.

The patient’s hospital course before admission to our facility also included concomitant dyskinesias, dysautonomia, and intermittent fevers related to her anti-NMDAR encephalitis diagnosis. In total, she was trialed on clonazepam, lorazepam, phenobarbital, trihexyphenidyl, diphenhydramine, benztropine, baclofen, gabapentin, and a botulinum injection. Lorazepam, with a maximum dose administered of 9 mg every three hours intravenously, was initiated. The patient showed slight improvement, and ECT three times weekly was begun for underlying catatonia.

The patient was then transferred to our facility on lorazepam 10 mg every 6 hours intravenously,

memantine 10 mg twice daily orally, and zolpidem 20 mg nightly orally to continue ECT treatment. Treatments with ECT were scheduled three times weekly, and once stable, she was transferred to our inpatient rehabilitation unit to continue ECT treatments. By admission to the rehabilitation unit, the patient was receiving prednisolone 21 mg daily orally along with Pneumocystis jirovecii pneumonia prophylaxis, lorazepam 2 mg every six hours orally, memantine 1 mg twice daily orally, and zolpidem 10 mg nightly orally. At discharge, she was prescribed a weekly taper of prednisolone and lorazepam orally, memantine, and zolpidem. She had received a total of 24 ECT treatments by hospital discharge.

Her hospital courses across institutions were complicated by bilateral upper extremity deep vein thrombosis, MRSA pneumonia, and thyroid hypertrophy requiring partial thyroidectomy for tracheostomy placement. She markedly improved throughout her multiple hospital admissions and has a third dose of rituximab scheduled. She initially continued ECT treatments in the outpatient setting and has since established neurology care outside of this health system.

DISCUSSION

Anti-NMDAR encephalitis is one of the most common types of autoimmune encephalitis, often detected in females with a median age of 21 years.1,5 It is caused

by IgG antibodies targeting the NRI subunit of the NMDAR. Laboratory testing is often nonPage 26

specific, apart from the detection of IgG antibodies within the CSF, and imaging of the brain frequently does not show an acute abnormality.5 Nonspecific findings on electroencephalography (EEG) are most often seen with anti-NMDAR encephalitis. However, the finding of delta brushes, which are identified by delta waves with overlaying bursts of beta activity, have been reported to result in a higher likelihood of poor outcomes.6,7,9 This finding is often found on neonatal EEGs and is present in approximately one-third of patients diagnosed with anti-NMDAR encephalitis.8 Due to the high rate of correlation between anti-NMDAR encephalitis and ovarian teratomas in females, imaging of the pelvic region should be completed in younger females presenting with symptoms indicative of encephalitis. Resection of the underlying tumor, if present, can rapidly improve symptoms.1

As the disease is caused by the targeting of NMDAR by IgG antibodies, immunotherapy is the first-line treatment. These therapies include high-dose corticosteroids, IVIG, and plasmapheresis.1,6 The peak effect of IVIG often takes weeks, whereas plasmapheresis effects are seen more rapidly. Available literature suggests that plasmapheresis may be more effective at improving clinical outcomes in those with refractory anti-NMDAR encephalitis, and it may be suggested as first-line over IVIG for these reasons.10 A limitation of this facility is that it does not perform plasmapheresis, and as such, IVIG is considered the available first-line treatment option for our patients.

Common first-line, second-line, and maintenance therapies, along with the most common dosing, are listed in Table 1.1,3,57 After second-line therapies, guidelines suggest utilizing more experimental therapies such as interleukin-6 inhibitors or bortezomib.3,6 Prompt treatment should be initiated empirically after a lumbar puncture, and CSF studies are obtained in suspected anti-NMDAR encephalitis.6

Early identification and the removal of an underlying tumor generally provide better outcomes, and treatment is more effective.1,6 Upwards of 50% of patients will recover, with approximately 46% having lasting deficits such as impaired memory or cognition. Relapse rates have been reported to be between 12% and 24%, with an estimated mortality rate of approximately 20%. In those without underlying tumors, the prognosis for recovery is often worse.3,6

Psychiatric manifestations of anti-NMDAR encephalitis often evolve into a catatonic state.

Evidence suggests that approximately 20% of catatonia has a non-psychiatric cause, with almost a third of this cohort caused by CNS inflammation and immunological conditions. Benzodiazepines and ECT treatment are generally considered the cornerstone of treatment. The severity of catatonia may warrant intensive care due to symptoms such as dyskinesia and dysautonomia. ECT has been shown to be activating in single sessions and down-regulate the immune system in multiple sessions.11 ECT has been found to be safe

as a treatment for catatonia in anti-NMDAR encephalitis.12 Interestingly, anti-NMDAR encephalitis is strongly associated with catatonia, particularly malignant catatonia. It is theorized that the cause of co-occurring catatonia may be due to adaptive immunity, which would coincide with anti-NMDAR encephalitis as an adaptive immune system disorder.11 To the authors’ knowledge, no other published literature describes the use of ECT twice-daily treatments for patients in general, let alone in anti-NMDAR encephalitis. It can be reported from the above case that this regimen was relatively safe, and no long-term deleterious effects were seen.

CONCLUSION

Anti-NMDAR encephalitis is a potentially fatal condition with a range of symptoms, including psychiatric manifestations. Empiric treatment should be initiated promptly, and immunotherapy should be recognized as the first line. Additional treatment for psychiatric manifestations, such as catatonia, is often warranted. This case series provides validation of the growing literature surrounding treatment in anti-NMDAR encephalitis.

To the authors’ knowledge, no published literature has reported twice-daily ECT regimens. As such, this case series adds to the literature surrounding the condition and various treatments, including treatment for concomitant catatonia.

Authors: Stephanie Karvosky, PharmD, BCPS, at the time this article was submitted, was a PGYPage 27

2 resident in internal medicine at Duke Regional Hospital. She is now a Heart Failure Clinical Pharmacy Specialist at Cape Fear Valley Hospital in Fayetteville, NC; skarvosky@capefearvalley. com. Dawn MacElroy PharmD, BCPS, is a Critical Care Clinical Pharmacist at Duke Regional Hospital in Durham, NC.

References 1. Ford B, McDonald A, Srinivasan S. Anti-NMDA receptor encephalitis: a case study and illness overview. Drugs Context.

2019;8:212589. Published 2019 Aug 30. doi:10.7573/dic.212589.

2. Bhat P, Ahmed A, Jolepalem P, Sittambalam C. A case report: anti-NMDA receptor encephalitis.

J Community Hosp Intern Med Perspect. 2018;8(3):158-160.

Published 2018 Jun 12. doi:10.10 80/20009666.2018.1481326.

3. Barry H, Byrne S, Barrett E, Murphy KC, Cotter DR. Anti-N-methyl-d-aspartate receptor encephalitis: review of clinical presentation, diagnosis and treatment. BJPsych Bull.

2015;39(1):19-23. doi:10.1192/ pb.bp.113.045518.

4. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.

Lancet Neurol. 2008;7(12):10911098. doi:10.1016/S14744422(08)70224-2.

5. Huang Q, Xie Y, Hu Z, Tang X. Anti-N-methyl-D-aspartate receptor encephalitis: A review of pathogenic mechanisms, treatment, prognosis.

Brain Res. 2020;1727:146549. doi:10.1016/j.brainres.2019.146549.

6. Samanta D, Lui F. Anti-NMDA Receptor Encephalitis. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.

7. Shin YW, Lee ST, Park KI, et al. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord.

2017;11:1756285617722347.

Published 2017 Aug 16.

Table 1. Treatment for anti-NDMAR encephalitis1,5-7

THERAPY

DOSING First-Line Therapies: Immunotherapy High-dose corticosteroids Methylprednisolone 1000 mg intravenously for 3-5 days Immune globulin (IVIG) 0.4 mg/kg/day (based on ideal body weight) for 5 days Plasmapheresis 5-10 cycles Second-Line Therapies: Immunosuppression Rituximab 1000 mg intravenously for two doses separated by two weeks or 375 mg/m2 weekly IV infusion for 4 weeks Cyclophosphamide 600-1000 mg/m2 intravenously for 3–6 months Maintenance Therapies: Immunosuppression Mycophenolate mofetil 500 mg twice daily, target 1000 mg twice daily Azathioprine 1–1.5 mg/kg once daily or divided twice daily, target 2–3 mg/kg/day

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c. Avoid alcohol (including overthe-counter drugs) while using codeine-containing cough preparations.

Case Report: Over-the-Counter Codeine Use in a Senior Adult By: Dr. Sara Meyer, BCPS An 84-year-old female patient with a cough unresponsive to dextromethorphan went to her local pharmacy to seek relief.

After describing her symptoms to the pharmacist, it was recommended she try a cough syrup containing guaifenesin and codeine. In North Carolina, pharmacists can dispense a small quantity of cough syrup containing codeine over the counter.

Because this medication does not require a prescription, this information is not logged into the prescription drug monitoring program (PDMP), which may contribute to providers being unaware of their patients’ use of codeine. About ten days later, a family member called the patient’s primary care provider concerned the patient was experiencing increased drowsiness and confusion, and communicated the cough syrup use. The patient was also taking cyclobenzaprine and taking both the dextromethorphan cough syrup and codeine/guaifenesin cough syrup. These medications taken in combination likely contributed to the patient’s adverse symptoms.

Codeine is a natural opioid with a long history of use in cough.

However, studies for this indica-

tion show it is no more effective than a placebo (1,2); moreover, it has been shown to cause dangerous adverse effects, including confusion, respiratory depression, and even death, especially in pediatric and elderly patients.

(3,4,5,6) Despite this, when dispensed in cough preparations containing less than 200 milligrams of codeine/100mL or per 100 gm, a prescription is not required, making it fairly accessible to the general public. (7) Recommendations for safe practice: 1. Always assess patients’ medications for concomitant central nervous system depressants (prescription or over-the-counter) or controlled substances, including a review of the PDMP. 2. Always provide important counseling points such as:

a. Possible side effects can include confusion, drowsiness, and even respiratory depression, especially in combination with certain other medications. b. Notify the physician of any medications they take over the counter.

Page 29

3. Consider dispensing naloxone if the patient is on concomitant CNS depressant(s) or has a history of medical conditions increasing the risk of overdose.

Author: Sara Meyer, PharmD, BCPS, is a Medication Safety Specialist and Opioid Stewardship Champion at Novant Health.

SRG024@novanthealth.org

References: 1. Morice A, Kardos P. Comprehensive evidence-based review on European antitussives. BMJ Open Respiratory Research 2016;3:e000137. doi: 10.1136/ bmjresp-2016-000137 2. Bolser DC, Davenport PW. Codeine and cough: an ineffective gold standard. Curr Opin Allergy Clin Immunol. 2007;7(1):32-36. doi:10.1097/ ACI.0b013e3280115145 3. Friedrichsdorf SJ, Nugent AP, Strobl AQ. Codeine-associated pediatric deaths despite using recommended dosing guidelines: three case reports. J Opioid Manag.

2013;9(2):151-155. doi:10.5055/ jom.2013.0156 4. Racoosin, JA, Roberson, DW, Pacanowski, MA, Nielsen, DR. New evidence about an old drug—risk with codeine after adenotonsillectomy. N Engl J Med. 2013;368(23):2155-2157.

5. Roxburgh A, Hall WD, Burns L, et al. Trends and characteristics of accidental and intentional codeine overdose deaths in Australia.

Med J Aust. 2015;203(7):299. doi:10.5694/mja15.00183 6. Tchoe, Ha jin MPharma; Jeong, Sohyun PhDa,b; Won, Dae Yeon PhDa; Nam, Jin Hyun PhDa; Joung, Kyung-In PhDa; Shin, Ju-Young PhDa,∗ Increased risk of death with codeine use in the elderly over 85 years old and patients with respiratory disease, Medicine: September 18, 2020 - Volume 99 Issue 38 - p e22155 doi: 10.1097/ MD.0000000000022155 7. Definition of Controlled Substance Schedules. Controlled substance schedules. https://www.deadiversion.usdoj.gov/schedules/.

Accessed April 29, 2022.

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Comparison of Glycemic Control in Adult Direct Primary Care Patients with Type 2 Diabetes Mellitus Before and After Implementation of Pharmacy-Based Services

By: Dr. Madison Treadway, Dr. Dustin Wilson, and Dr. Stephen Fuller

Introduction Many Americans struggle to afford healthcare costs and lack regular access to quality healthcare. These issues have been a major focus of legislation such as the Affordable Care Act. The Direct Primary Care (DPC) model sets out to overcome these obstacles while also improving patient and provider satisfaction.1-3 DPC, also known as “membership medicine,” is a practice model that charges patients a recurring fee for healthcare services which, in turn, eliminates the need for insurance billing.1 Instead of the traditional fee-for-service practice model, DPC memberships typically include evaluations, check-ups, basic medical services, and even laboratory work, depending on the contract.1,2 With the DPC model, patient interaction and the health needs of the patient become the focus instead of insurance coding and billing. While the removal of insurance billing frees up the provider to spend more time with the patient, the patient is also

able to benefit from the removal of potential financial barriers to routine healthcare.1 In a survey of more than 200 DPC physicians, 98% reported improved patient satisfaction, 81% reported lower out-of-pocket costs for primary care services, and 68% reported an increase in patient compliance with preventative care guidelines.3

The utilization of pharmacists in the primary care setting is well-established. In a systematic review and meta-analysis of 38 studies, pharmacist interventions varying from medication reviews, education, adherence assessment, lifestyle counseling, and/ or physical assessments had a positive impact on cardiovascular and diabetes-related outcomes.4 However, the utilization of pharmacists specifically within a DPC clinic has not been studied.

Access Healthcare, located in Apex, North Carolina, is one of the first DPC clinics which was established in 2002 and now serves over 300 patients under one physician. This clinic utilizes Page 31

the DPC model where patients pay a monthly membership fee to obtain urgent care and chronic care visits, basic primary care services, and laboratory services. Pharmacy services were integrated into the services available through the DPC membership in June 2021, and about 100 patients are currently being followed by pharmacy services.

Since the utilization of pharmacists within a DPC setting has not been specifically evaluated, this study sought to describe type 2 diabetes mellitus (T2DM) care indices following the integration of pharmacy services into this interdisciplinary DPC team.

Methods

This was a single-site, descriptive, pre-post, quality improvement study reviewed and exempted by the Campbell University Institutional Review Board. The primary objective of this study was to describe the change in hemoglobin A1c (HgbA1c) before and at least 3 months after the initial pharmacist intervention in adults with

T2DM at a DPC clinic. Secondary objectives were to describe the percentage of patients achieving a HgbA1c < 7%, the number of antidiabetic medications (see Appendix A) prescribed per patient, and the frequency of hypoglycemia episodes (defined as patient-reported blood glucose < 70mg/dL over the last 30 days) before pharmacist intervention and at least 3 months after the initial visit.

Patients at least 18 years of age receiving care at Access Healthcare with an active diagnosis of T2DM who were seen by pharmacy services from June 1, 2021, to February 22, 2022, were included in this study. Patients receiving diabetes mellitus management from an outside provider or endocrinologist were excluded. Patients were identified by data query through the electronic health record (EHR) at Access Healthcare (Practice Fusion©). Patient data were collected from the EHR and compiled and stored in a de-identified, password-protected Microsoft Excel Spreadsheet file by the primary investigator.

The pharmacy services included an initial face-to-face visit lasting 1-1.5 hours with the pharmacy team that consisted of the clinical pharmacist or pharmacy resident with or without student pharmacists. The initial visit included disease state education, diet and exercise education, medication reconciliation, self-monitoring blood glucose (SMBG) assessment, therapy adjustments, and medication counseling. Patients then received 30-minute faceto-face follow-up visits with the

pharmacy team at one-month intervals.

The primary endpoints included mean HgbA1c before pharmacist intervention and at least 3 months after pharmacist intervention. Secondary endpoints included the percentage of patients achieving a HgbA1c < 7%, the mean number of antidiabetic medications prescribed per patient, and the mean number of reported hypoglycemic episodes before pharmacist intervention and after at least 3 months.

Additionally, the mean number of down titrations of antidiabetic medications after pharmacist intervention was included as a secondary endpoint. A down titration was defined as medication discontinuation or dose reduction. The primary endpoint and secondary endpoints were analyzed using descriptive statistics. Each patient served as their own control.

Results

Seventy-seven subjects were screened, and twenty-five met the inclusion criteria. Of the twenty-five included in the study, the mean age was 67.6 ± 9.4 years, and 80% were male. Key characteristics of the patients at baseline are found in Table 1. The mean HgbA1c was 7.1% (95% CI, 6.5%-7.8%) and 6.6% (95% CI, 6.3%-7.0%) pre- and post-intervention, respectively (see Table 2). Figure 1 illustrates the HgbA1c for each individual patient pre-and post-intervention.

The percentage of patients with a HgbA1c < 7% were 56% and 76% in the pre-and post-interPage 32

vention periods, respectively.

The mean number of antidiabetic medications per person was 2.3 (95% CI, 1.8-2.8) vs. 2.2 (95% CI, 1.8-2.6), and the number of hypoglycemic episodes per person was 0.5 (95% CI, -0.4-1.5) vs. no hypoglycemic episodes, respectively. Additionally, 0.5 (95% CI, 0.2-0.8) down titrations of antidiabetic medications per person were observed.

Discussion

In this small quality improvement study, we observed trends towards a modest decrease in HgbA1c with no hypoglycemic episodes among adults with T2DM following initiation of pharmacy-based services into a DPC clinic. Large variations in the magnitude of HgbA1c changes were observed among the subjects. Compared to a systematic review and meta-analysis of 38 studies evaluating pharmacist integration into primary care practices, our study did not have as large of a decrease in HgbA1c.4 In this meta-analysis, HgbA1c reductions ranged from -0.70% to -1.30%, with a mean reduction of -0.88%.4 Pharmacist interventions provided, such as medication reviews, education, adherence assessment, lifestyle counseling, and/or physical assessments, were similar to the interventions provided by this DPC pharmacy team.4 However, many of the studies targeted uncontrolled populations. In contrast, our study included all patients at this DPC clinic with an active T2DM diagnosis regardless of the level of control.4 The proportion of individuals

with a HgbA1c < 7% increased from 56% pre-intervention to 76% post-intervention. Achieving a HgbA1c goal of < 7% can provide positive long-term benefits, as we saw in clinical trials such as the Diabetes Control and Complications Trial (DCCT).5,6 This study compared an intensive goal of 7% to the standard goal of 9%, which showed that better glycemic control was associated with 50-76% reductions in diabetes-related microvascular complications, including retinopathy, neuropathy, and diabetic kidney disease.5 Among the six individuals in our study with a HgbA1c > 7% post-intervention, two were nonadherent to their medications, one had frequent hypoglycemic events prior to pharmacist intervention, and two had large HgbA1c reductions of at least -1.5%. Given that this study only evaluated the first HgbA1c after pharmacist intervention, it is possible that this metric could improve after longer follow-up with pharmacy service.

Before pharmacist intervention, 44% of patients were on at least 3 antidiabetic medications. The mean number of antidiabetic medications per person was similar after pharmacist intervention with 2.3 (95% CI, 1.8-2.8) pre-intervention versus 2.2 (95% CI, 1.8-2.6) post-intervention. While reducing the number of unnecessary medications has the potential to reduce polypharmacy and the risk of adverse events in an overtreated population, we found this particular metric was not useful since our cohort was not characterized as an undertreated or overtreated population at baseline.

There are several limitations to this study worth noting. First, this study has limited external generalizability, given the findings are specific to a single site.

The small sample size prohibited meaningful hypothesis testing for differences. This study had a short duration of follow-up by only observing the first HgbA1c at least 3 months after pharmacist intervention. Lastly, there were several pre-intervention HgbA1c outliers (such as 12.1%, 11.1%, and 9.7%) that impacted both the degree of change possible and the likelihood of meeting the categorical cutoff of HgbA1c < 7%.

Conclusion

A trend toward a decrease in the HgbA1c without an increase in hypoglycemic events was observed after the initiation of pharmacy-based services among adult patients with T2DM at a DPC clinic. Though this was a small quality improvement study, the results of this study introduce the potential positive impact the integration of pharmacy-based services into this unique practice model can have on diabetes mellitus care indices among adults with T2DM. However, this needs to be confirmed in larger, controlled studies. In addition, future studies should assess the impact on other chronic disease states (i.e., hypertension, hyperlipidemia, and obesity).

Authors: Madison T. Treadway, PharmD, was a PGY2 Ambulatory Care Pharmacy Resident at Campbell University College Page 33

of Pharmacy & Health Sciences (CPHS) and Access Healthcare in Apex, NC. ma.treadway@wingate. edu. Dustin Wilson, PharmD, BCPS, is an Associate Professor at CPHS and a Clinical Pharmacist at Duke University Hospital.

Stephen Fuller, PharmD, BCACP, CPP, is a Vice-Chair and Professor at CPHS and a Clinical Pharmacist at Access Healthcare.

References: 1. Direct Primary Care [Internet].

American Academy of Family Physicians. AAFP; 2019 [cited 2021Aug16]. Available from: https://www.aafp.org/about/policies/all/direct-primary-care.html 2. Cole ES. Direct primary care: applying theory to potential changes in delivery and outcomes.

J Am Board Fam Med. 2018 JulAug;31(4):605-611. doi: 10.3122/ jabfm.2018.04.170214.

3. Grzeskowiak D, Huth E. Direct primary care: evaluating a new model of delivery and financing [Internet]. The Society of Actuaries. SOA; 2020 [cited 2021Aug16]. Available from: https://www.soa.org/globalassets/assets/files/resources/ research-report/2020/direct-primary-care-eval-model.pdf 4. Tan EC, Stewart K, Elliott RA, George J. Pharmacist services provided in general practice clinics: a systematic review and meta-analysis. Res Social Adm Pharm. 2014;10(4):608622. doi:10.1016/j.sapharm.2013.08.006 5. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.

N Engl J Med. 1993;329(14):977986. doi:10.1056/ NEJM199309303291401 6. American Diabetes Association Professional Practice Committee, Draznin B, Aroda VR, et al. 6. Glycemic targets: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S83-S96. doi:10.2337/dc22-S006

Appendix A. Antidiabetic Medications

• Sulfonylureas • Meglitinides • Biguanides • Alpha-glucosidase inhibitors • Thiazolidinediones • Dipeptidyl peptidase-4 inhibitors • Glucagon-Like Peptide-1 receptor agonists • Insulin • Amylin Table 1. Demographic Characteristics* Table 1. Demographic Characteristics* Characteristic

N = 25

Age – years

67.6 ± 9.4

Male – n (%)

20 (80%)

Race – n (%) White Black Hispanic Asian

16 (64%) 3 (12%) 3 (12%) 3 (12%)

Insurance status – n (%) Commercial insurance Medicare No insurance

5 (20%) 14 (56%) 6 (24%)

*Data are mean (± standard deviation) or n (%)

Table 2. Diabetes Mellitus Indices Before and After Pharmacist Intervention* Table 2. Diabetes Mellitus Indices Before and After Pharmacist Intervention* Pre-Intervention HgbA1c – % Change in HgbA1c – % No. of antidiabetic medications No. of down titrations No. of hypoglycemic events HgbA1c < 7% – n (%) *Data are 95% confidence intervals or n (%)

7.1 (6.5 to 7.8)

Post-Intervention 6.6 (6.3 to 7.0)

–

-0.5 (-1.1 to 0.8)

0.5 (-0.4 to 1.5)

0

2.3 (1.8 to 2.8)

2.2 (1.8 to 2.6)

–

0.5 (0.2 to 0.8)

19 (76%)

14 (56%)

Page 34

Figure 1. HgbA1c Before and After Pharmacist Intervention

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served following mavacamten’s administration with a high-fat meal.

New Drug

Distribution - Mavacamten is 9798% protein bound.

Metabolism - Mavacamten is primarily metabolized by CYP2C19 (74%) but is also metabolized by CYP3A4 and CYP2C9.

Camzyos (Mavacamten) By: Rana Oueijan, PharmD Candidate

Camzyos (Mavacamten) is manufactured by Bristol Myers Squibb, MyoKardia Inc., and was approved by the FDA on April 28th, 2022 TM

Classification1: Cardiac Myosin Inhibitor Indication1: Approved for the treatment of symptomatic New York Heart Association (NYHA) Class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.

potential to cause heart failure.

Contraindications1: Concomitant use with moderate to strong CYP2C19 and CYP3A4 inhibitors and inducers.

Pharmacology1: Mavacamten is a selective, reversible inhibitor of cardiac myosin. A hallmark of hypertrophic cardiomyopathy is a thickening of the heart muscles due to excess myosin-actin cross-bridging, making it difficult for the heart to function properly. Mavacamten modulates the number of myosin heads interacting with actin, reducing left ventricular outflow tract (LVOT) obstruction and improving cardiac function.

US Boxed Warning1: Mavacamten can reduce the left ventricular ejection fraction (LVEF), Pharmacokinetics1: leading to heart failure due to Absorption - Mavacamten is systolic dysfunction. Mavacamten orally absorbed and reaches peak should not be initiated in patients plasma concentrations within 1 with an LVEF <55% and requires hour. Mavacamten may be taken dispensing through the Risk without regard to food since no Evaluation and Mitigation Stratclinically significant differences egy (REMS) program due to its in pharmacokinetics were obPage 37

Elimination - Mavacamten has a half-life of approximately 6-9 days in normal CYP2C19 metabolizers. This agent is primarily excreted in the urine (85%).

Clinical Efficacy2-4: The MAVERICK-HCM trial was a phase 2 trial that assessed the safety and tolerability of mavacamten in patients with symptomatic non-obstructive HCM. In the study, 59 subjects were randomized into 3 separate groups: a placebo group (n=19), a group targeting drug serum levels of 200 ng/ mL (n=19), and a group targeting 500 ng/mL (n=21). Patients achieved a target of 200 ng/mL after 4 weeks of treatment with patient-specific mavacamten daily dosing and a target of 500 ng/ mL after 8 weeks of patient-specific mavacamten daily dosing with a dose titration occurring at week 6. More patients in the 500 ng/mL target group experienced adverse effects. Overall, serious adverse events occurred at a rate of 10.3% in the experimental group and 21% in placebo.

Patients receiving mavacamten had a 53% mean reduction of NT-proBNP (p=0.0005) and a 34% geometric mean of cardiac troponin I compared to placebo (p=0.009), marking the effectiveness of this drug.2

Mavacamten then proceeded to its phase 3 trial testing, beginning with EXPLORER-HCM. This trial covered 13 different countries and was conducted to assess efficacy and safety on a larger scale than the MAVERICK-HCM trial. In this double-blind, placebo-controlled trial, 251 participants were randomized 1:1 and received either mavacamten 5 mg by mouth once daily (the starting dose) or a placebo for 30 weeks.

Participants were included if they were at least 18 years of age with diagnosed obstructive HCM (maximal left ventricular wall thickness of greater than or equal to 15 mm), had a peak LVOT gradient of at least 50 mm Hg, had an LVEF of at least 55%, and NYHA Class II-III symptoms. Due to safety, patients were not included if they had a prior history of syncope or sustained ventricular tachyarrhythmia with exercise 6 months before screening, an extended QT interval (greater than 500 ms), paroxysmal or intermittent atrial fibrillation, or permanent atrial fibrillation that is uncontrolled and/or untreated.

Patients previously taking standard HCM medications (including beta-blockers or calcium channel blockers) were allowed to continue them during the trial, with the exception of disopyramide for safety reasons.

The primary endpoint was a composite clinical response from baseline to week 30 and was defined as a 1.5 mL/kg/min or greater increase in peak oxygen consumption plus at least one NYHA class reduction or a 3.0 mL/kg/min or greater increase in peak oxygen consumption without NYHA class worsening.

It was found that 37% (45 of 123 patients) of the experimental group met the primary composite endpoint (p=0.0005) compared to 17% (22 of 128 patients) of the placebo group (p=0.0005).

Based on these percentages, the NNT for the primary outcome is 5, meaning 5 patients would have to be treated with mavacamten for one patient to achieve the outcome. All secondary endpoints were significantly improved with the use of mavacamten: post-exercise LVOT gradient (p<0.0001), pVO change from baseline to week 30 (p=0.0006), NYHA class improvement from baseline (p<0.0001), and others.

In addition, a reduction in certain cardiac biomarkers, including serum NT-proBNP, added to the clinical benefit of mavacamten.

Assessments such as the KCCQ-CSS and the HCMSQ-SoB, which are specifically designed to evaluate symptomatic patients with HCM, were used to support the clinical benefit of mavacaIndividualized dose titrations for mten. These patient-reported mavacamten occurred at weeks 8 assessments showed more and 14 to achieve a target LVOT symptomatic improvement and gradient reduction of less than 30 more improvement in functional mm Hg. Of the 251 participants, 5 class with mavacamten than with patients discontinued treatment placebo. In addition to providing early due to either adverse effects symptomatic relief, patients also or simply choosing to withdraw reported that mavacamten was from the study. well-tolerated when taken either with a beta blocker, calcium Page 38

channel blocker or as monotherapy.

The most recent phase 3 trial, VALOR-HCM, is set to identify if the use of mavacamten could reduce the need for septal reduction therapy and focuses on patients with severely symptomatic, drug-refractory hypertrophic cardiomyopathy. This trial is currently active (no longer recruiting) and includes patients who are taking concurrent disopyramide therapy as well as patients with NYHA class IV symptoms, of which both populations were excluded from EXPLORER-HCM.

Drug Interactions1: Moderate or Strong CYP2C19 inhibitors - Concomitant use of mavacamten with a moderate to strong CYP2C19 inhibitor is contraindicated as concentrations of mavacamten may be increased, increasing the risk of developing heart failure. This information is also true for strong CYP3A4 inhibitors.

Moderate or Strong CYP2C19 inducers - Concomitant use of mavacamten with a moderate to strong CYP2C19 inducer is contraindicated as concentrations of mavacamten may be decreased, reducing the efficacy of this medication. This information is also true for strong CYP3A4 inducers.

Negative Inotropes - Mavacamten will produce additive negative inotropic effects if used in combination with other agents that reduce cardiac contractility, such as beta blockers or verapamil (both of which were studied as concomitant therapy with mavacamten in EXPLORER-HCM) Monitor

LVEF if concomitant therapy with a negative inotrope is initiated or the dose is increased. Monitoring should occur until clinical response has been achieved and dosing is stabilized.

Adverse Effects1-3: Dizziness (27%) and syncope (6%) were the most common adverse effects observed in clinical trials. Other reported adverse effects include reduced LVEF; however, these values normalized or returned to baseline in all patients after temporary treatment discontinuation or a washout period.

Dosing1: Proper dosing of mavacamten consists of a 12-week initiation phase followed by maintenance therapy. Dosing is individualized based upon clinical status and echocardiographic results. The recommended starting dose in most patients is 5 mg by mouth once daily without regard to food. Dosage may be titrated to a maximally tolerated dose providing the LVEF is greater than or equal to 55%.

A baseline echocardiogram must be done before starting mavacamten, and reassessment of ejection fraction and LVOT gradient should occur every 12 weeks before additional dosage modifications occur.

The need for dose adjustments based on severe renal impairment/kidney failure (eGFR less than 30 mL/min/1.73 m2) or severe liver failure (Child-Pugh C) is unknown.

Pregnancy and Lactation1: Mavacamten may be harmful to the fetus when administered to a

patient who is pregnant according to data from animal studies.

It is recommended that female patients have a negative pregnancy test before initiating mavacamten to prevent fetal harm Additionally, it is important for a woman of childbearing age to use effective contraception (meaning contraception not induced by CYP450 enzyme induction, such as an intrauterine system, and/ or non-hormonal contraception) during treatment and for four months after the last dose, as mavacamten can reduce the effectiveness of combined hormonal contraceptives.

For patients who are breastfeeding, there is not enough data to determine if mavacamten passes into the breastmilk. Prescribers should consider the benefit of mavacamten versus the potential risks that may occur.

Storage1: Store between 20°C and 25°C (68°F and 77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F).

Cost1,5: Mavacamten is supplied as 2.5 mg, 5 mg, 10 mg and 15 mg oral gelatin capsules. Capsules are priced at around $245.20, which places the annual cost at approximately $89,500.

Summary/Use in Clinical Practice1-6: Mavacamten is the first disease-specific agent that can be used to treat HCM and is FDA approved for treating patients with symptomatic NYHA Class II-III HCM. However, the most recent American Heart Association/ American College of Cardiology guidelines have not been updated to specify mavacamten’s place in Page 39

therapy for patients with HCM.

Currently, for patients with symptomatic obstructive HCM without heart failure, the guidelines recommend pharmacologic therapy with either beta-blockers or calcium channel blockers (specifically verapamil or diltiazem).

From there, if symptoms persist, therapy should progress to either disopyramide, procedural septal reduction therapy, or ablation.

Through phase III clinical trials, mavacamten has been shown to provide symptomatic relief and reductions in LVOT gradient in patients with HCM showing NYHA class II-III symptoms.

While mavacamten is not currently recommended as a firstline treatment option for this population, it may be considered in patients with HCM with preserved ejection fraction and an LVEF greater than 55% who are experiencing persistent symptoms after beta blocker or calcium channel blocker therapy or are intolerant to these therapies.

As for patients with HCM plus heart failure with reduced ejection fraction, guideline-directed medication therapy should be implemented, and mavacamten is not recommended in this population due to its boxed warning for inducing or worsening heart failure.

A baseline echocardiogram is recommended before initiating mavacamten to determine LVEF. If the patient’s LVEF is greater than 55%, the recommended starting dose for mavacamten is 5 mg by mouth daily. Up-titration is patient-specific and dependent upon the patient’s LVEF worsening and LVOT gradient.

Echocardiogram monitoring is recommended every 12 weeks throughout therapy with this medication, and treatment interruption is required if LVEF becomes less than 50%. An echocardiogram should be repeated every 4 weeks, and therapy may be restarted if the LVEF reaches above 50%; however, permanent discontinuation is recommended if the LVEF remains below 50% after frequent echocardiogram monitoring.

Patients should have a negative pregnancy test before initiating mavacamten, as fetal harm may be possible with this agent.

Patients of childbearing potential should also be on reliable and effective contraception during therapy with mavacamten. Lactating mothers should avoid mavacamten due to the lack of data regarding its presence in breast milk. Mavacamten has not been investigated in pediatric populations.

ijan1024@email.campbell.edu References:

1.

2.

3.

4.

Mavacamten. [package insert online]. Bristol Myers Squibb, Inc. Brisbane, CA. Issued April 2022. https://www.accessdata. fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf.

Accessed May 4, 2022.

Ho CY, Mealiffe ME, Bach RJ, et al. “Evaluation of Mavacamten in Symptomatic Patients with Nonobstructive Hypertrophic Cardiomyopathy.” Journal of the American College of Cardiology, vol. 75, no. 21, June 2020, pp. 2649–2660., https:// doi.org/10.1016/j.jacc.2020.03.064.

Olivotto I, Oreziac A, Barriales-Villa R, et al. “Mavacamten for Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy (EXPLORER-HCM): a Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial.” The Lancet, vol. 396, no. 10253, Sept. 2020, pp. 759–769., https://doi.org/ https://doi.org/10.1016/S01406736(20)31792-X. Desai MY, Wolski K, Owens A, et al. “Study Design and Rationale of Valor-HCM: Evaluation of Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomy-

The cost of treatment and continuous monitoring might also impact mavacamten’s place in therapy.

The most common adverse effects are dizziness and syncope.

The VALOR-HCM study is ongoing and will determine mavacamtem’s efficacy in patients with severely symptomatic (NYHA Class IV symptoms), treatment-refractory obstructive HCM to provide a non-invasive treatment option for this population.

Author: Rana Oueijan is a 2023 PharmD Candidate at the Campbell University College of Pharmacy and Health Sciences. rioue-

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5.

6.

opathy Who Are Eligible for Septal Reduction Therapy.” American Heart Journal, vol. 239, Sept. 2021, pp.

80–89., https://doi.org/10.1016/j. ahj.2021.05.007.

Satija B. “FDA Approves Bristol Myers’ Oral Heart Disease Drug.”

Reuters.com, Reuters, 29 Apr. 2022, https://www.reuters.com/business/healthcare-pharmaceuticals/ fda-approves-bristol-myers-heartdisease-drug-2022-04-29/.

Ommen SR, Mital S, Burke MA, et al. “2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy.” Circulation, vol. 142, no. 25, 20 Nov. 2020, https://doi.org/10.1161/ cir.0000000000000937.

www.medicationsafety.org

New Drug

Metabolism Tirzepatide is primarily metabolized by amide hydrolysis, beta-oxidation of the C20 fatty acid moiety, and proteolytic cleavage of its peptide backbone.

MounjaroTM (tirzepatide) By: Dr. Gloria Lo and Linda Nguyen, PharmD Candidate

MounjaroTM (tirzepatide) is manufactured by Lilly USA, LLC, and was FDA-approved on May 13, 2022.

Classification: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist.

Indication1: Approved as an adjunct to diet & exercise in adult patients with type 2 diabetes mellitus (T2DM) to improve blood glucose control.

Contraindications1: History or family history of medullary thyroid carcinoma or patients with Multiple Endocrine Neoplasia Syndrome (MENS) type 2.

Contraindicated in patients with known hypersensitivity to any of the components in tirzepatide.

Pharmacology1: Tirzepatide is a

GLP-1 and GIP receptor agonist.

The structure contains a modified peptide with a diacid moiety that allows albumin to bind and prolongs the half-life. Tirzepatide binds selectively to GIP and GLP1 receptors, which enhances both insulin secretion and sensitivity, lowers glucagon levels and slows gastric emptying.

Pharmacokinetics1: Absorption After subcutaneous administration, tirzepatide reaches peak plasma concentrations after 8-72 hours. Following subcutaneous administration, the bioavailability of tirzepatide is 80%, regardless of whether it was administered in the abdomen, thigh, or upper arm.

Distribution Tirzepatide is highly protein bound, with 99% of it found bound to albumin. The volume of distribution after subcutaneous administration was approximately 10.3 L. Page 41

Elimination Metabolites of tirzepatide are excreted mainly via urine and feces, while non-metabolized tirzepaptide is not. Clearance of tirzepatide is 0.061 L/h, and its elimination half-life is around 5 days.

Clinical Efficacy: In four SURPASS-trials, the safety, tolerability, and efficacy of tirzepatide versus several comparators were assessed for the management of type 2 diabetes in lowering A1c and weight lowering capabilities:

SURPASS-1: tirzepatide vs placebo3 SURPASS-1 was a multi-center (US, Mexico, Japan, India), randomized, double-blind, parallel, placebo-controlled study with 478 adult patients randomized to receive once-weekly subcutaneous tirzepatide 5 mg, 10 mg, 15 mg, or placebo in a 1:1:1:1 ratio. All study participants in the tirzepatide arm were initiated at a dose of 2.5 mg once weekly and then increased in a stepwise approach at 4 weeks. The primary endpoint was a change in A1c from baseline at 40 weeks.

Baseline characteristics of study participants had a mean A1c of 7.9%, type 2 diabetes for a duration of 4.7 years, and a mean weight of 85.9 kg. Participants were included if they were naïve to diabetes injectable therapies, had an A1c between ≥ 7.0% and

≤ 9.5%, and had a BMI ≥ 23kg/ m2. They were excluded if they had type 1 diabetes, a history of a previous heart attack or stroke, or were hospitalized for heart failure in the past 2 months, acute or chronic pancreatitis, eGFR <30 mL/min/1.73 m2, taking weight loss medications during the last 3 months, history or family history of thyroid carcinoma or have a personal history of multiple endocrine neoplasia syndrome type 2, and or required acute treatment for proliferative diabetic complications such as retinopathy or maculopathy.

Results from SURPASS-1 were statistically significant, all with a p-value < 0.0001 showing that patients in the tirzepatide arm achieved significantly lower A1c [-1.75% (5 mg), -1.71% (10 mg), -1.69% (15 mg)] compared to placebo (-0.09%) and an overall weight reduction of -6.3 kg (5 mg), -7.0 kg (10 mg), -7.8 kg (15 mg) compared to -1.0 kg in the placebo group.

SURPASS-2: tirzepatide vs semaglutide4 SURPASS-2 was a multicenter (US, Argentina, Australia, Brazil, Canada, Mexico, UK, Israel), randomized, parallel, open-label trial comparing the efficacy and safety of tirzepatide to semaglutide in 1879 adults with type 2 diabetes inadequately controlled with ≥1500 mg/day metformin alone. Subjects were randomized in a 1:1:1:1 ratio to receive either tirzepatide 5 mg, 10 mg, or 15 mg or semaglutide 1mg. The primary endpoint was a change in A1c from baseline at 40 weeks.

Inclusion and exclusion criteria are similar to SURPASS-1 with an additional exclusion to study

participants if they have acute or chronic liver disease. Baseline characteristics of study participants had a mean A1c 8.3% and type 2 diabetes duration of 8.6 years. Results from SURPASS-2 showed that patients in the tirzepatide arm achieved an A1c lowering of up to -2.01% (5 mg), -2.24% (10 mg), -2.30% (15 mg) compared to -1.86% in the semaglutide arm. Furthermore, the percent of participants achieving an A1c <7% with tirzepatide was 82% (5 mg), 86% (10 mg), 86% (15 mg) compared to 79% of participants treated with semaglutide. Each tirzepatide dose was found to be superior to semaglutide, with estimated treatment differences of -0.15% [95% CI (-0.28 to -0.03, p=0.02)] with tirzepatide 15 mg, −0.39 percentage points [95% CI (−0.51 to −0.26 p<0.001)] with tirzepatide 10 mg, and −0.45% [95% CI (−0.57 to −0.32, p<0.001)] with tirzepatide 5 mg. Weight reduction with tirzepatide compared to semaglutide had the following results: 7.6 kg (5 mg), -9.3 kg (10 mg), -11.2 kg (15 mg), -5.7 kg (semaglutide), with p<0.001 for all comparisons made.

SURPASS-3: tirzepatide vs insulin degludec5 SURPASS-3 was a randomized, phase 3, open-label, active-controlled trial that included 1444 adult patients with inadequately controlled type 2 diabetes despite being on metformin with or without SGLT-2 inhibitor. Patients were randomized in a 1:1:1:1 ratio to take tirzepatide subcutaneous once weekly (at doses of 5 mg, 10 mg, or 15 mg) or insulin degludec in a 1:1:1:1 ratio. Initial dose of insulin degludec was Page 42

10-units/day and was titrated to a fasting blood glucose goal of < 90 mg/dL. Primary and secondary efficacy points included changes in A1c lowering and weight changes from baseline at 52 weeks, respectively. Inclusion and exclusion criteria were the same as in the SURPASS trials.

Baseline characteristics of participants had a mean baseline A1c of 8.2%, type 2 diabetes duration of 8.4 years, and a mean weight of 94.3 kg. Results from SURPASS-3 demonstrated that tirzepatide was superior in reducing A1c and body weight across all 3 doses (5mg, 10mg, and 15mg) compared to insulin degludec (mean dose 48.8-units/day at 52 weeks). The mean A1c lowering seen with tirzepatide was -1.93% (5 mg), -2.20% (10 mg), -2.37% (15 mg) compared to -1.34% in the insulin degludec group, with p < 0.0001 for each group.

Weight change from baseline at 52-weeks with tirzepatide was: -7.5 kg (5 mg), -10.7kg (10 mg), -12.9kg (15 mg) versus a mean weight gain of +2.3 kg in patients treated with insulin degludec, with p < 0.0001 for each group.

SURPASS-5: tirzepatide vs insulin glargine vs placebo6 SURPASS-5 was a 40-week, randomized, double-blind, placebo-controlled, phase-3 trial that randomized 475 adult patients with uncontrolled type 2 diabetes who were on insulin glargine with or without metformin.

Participants were randomized to receive once-weekly subcutaneous tirzepatide 5 mg, 10 mg, 15 mg, or placebo in a 1:1:1:1 ratio.

Similar exclusion and inclusion criteria as previous SURPASS trials. Study participants had a

baseline mean of 8.31% A1c, type 2 diabetes duration of 13.3 years, a baseline weight of 95.2 kg, and a baseline dose of 37.6-units/day insulin glargine. The mean A1c lowering seen with tirzepatide was -2.11% (5 mg), -2.40% (10 mg), -2.34% (15 mg) compared to -0.86% with placebo. Mean weight reduction achieved with tirzepatide was -5.4 kg (5 mg), -7.5 kg (10 mg), -8.8 kg (15 mg) compared to a mean weight gain of +1.6 kg in the placebo arm.

The percentage of participants that were able to achieve an A1c <7% in the tirzepatide group was 87.3% (5 mg), 89.6% (10 mg), 84.7% (15 mg) compared to about 34.5% of participants in the placebo.

Overall, tirzepatide demonstrated superior A1c lowering and weight reductions from baseline compared to various comparators. In placebo-controlled trials, the most common adverse effects seen with tirzepatide in placebo-controlled trials were gastrointestinal effects (nausea, diarrhea, vomiting) which were noticeable during dose-escalation.

Dosing1,2: Tirzepatide titration in adult patients starts at 2.5 mg once weekly for 4 weeks.

Increase dose by 2.5 mg/week increments every 4 weeks to achieve glycemic goals. The maximum dose weekly is 15 mg/ week. No renal or hepatic adjustments are necessary. The safety and effectiveness of tirzepatide have not been established in the pediatric population <18 years of age.

GLP-1 Receptor Agonists and DP4-Inhibitors Increased risk of adverse/toxic effects of GLP-1 agonists. Avoid

Storage1,2: Store in the original carton and protect from light.

Keep refrigerated between 2°C and 8°C (36°F and 46°F). If

Drug Interactions 1,2: Hormonal Contraceptives: Tirzepatide may decrease serum concentrations of oral hormonal contraceptives. Patients on oral hormonal contraceptives should switch to non-oral contraceptive methods and use a barrier method for 4 weeks after initiating tirzepatide and for 4 weeks after each dose escalation.

combinations.

Sulfonylureas: Tirzepatide and other GLP-1 receptor agonists may enhance the hypoglycemic effects of sulfonylureas. Doses of sulfonylureas should be reduced when used in combination with GLP-1 receptor agonists.

Adverse Effects1,2: The most common adverse effects of tirzepatide observed in clinical trials were GI related (mild to moderate) and occurred mostly during the dose-escalation phase: nausea (12-18%), diarrhea (1217%), and vomiting (5-9%).

Pregnancy and Lactation1,2,4: The safety of tirzepatide in pregnant and/or lactating women have not been assessed in human patients; however, based on animal studies, in utero exposure of tirzepatide may lead to fetal harm. There is no data regarding the presence of tirzepatide in human milk or the effects it may have on an infant.

Page 43

necessary, each single-dose pen may be stored unrefrigerated at temperatures ≤ 30°C (≤ 86°F) for up to 21 days. Do not freeze or use if frozen.

Dosages and Cost2,4: Tirzepatide is available in 2.5 mg/0.5 mL, 5 mg/0.5 mL, 7.5 mg/0.5 mL, 10 mg/0.5 mL, 12.5 mg/0.5 mL, and 15 mg/0.5 mL solution pen-injector. Currently, each tirzepatide pen-injector costs around $300.00 for all strengths; however, manufacturer coupons may help patients pay as low as $25 a month for 4 pens.

Summary/Use in Clinical Practice1-7 When assessing which pharmacological agent should be used to treat Type 2 DM, a patient-centered approach should be used. Consideration should be given not only to patient preference but to which agent will best fit the patient’s comorbidities, the impact the medication may have on the patient’s weight, and medication cost. The American Diabetes Association (ADA) guidelines currently recommend metformin as the initial pharmacological agent (along with diet and exercise) for treating type 2 diabetes and should be continued as long as tolerated and no contraindications occur. The addition of other anti-diabetic agents should be added to metformin unless contraindicated. It is also recommended to consider the effects of any glucose-lowering medication in overweight or obese patients with type 2 diabetes. The 2022 ADA guidelines recommend considering GLP-1 receptor agonists in most patients with diabetes before initiating insulin. A GLP-1 receptor

agonist is preferred over insulin for the management of type 2 diabetes due to decreased weight gain as well as a lower risk of hypoglycemia.

Similar agents to tirzepatide are agents in the GLP-1 receptor agonist class, which have also demonstrated A1c lowering and weight reduction [semaglutide (Ozempic), dulaglutide (Trulicity), and exenatide (Byetta)] are also administered subcutaneously once weekly. Unlike some of the other GLP-1 receptor agonists, tirzepatide has not been studied for CV morbidity or mortality benefit, although it is expected to exhibit similar effects based on its mechanism of action.

For now, more studies are required to determine a CV benefit.

Patients should be counseled that the 2.5 mg dose is intended to reduce GI symptoms and does not provide effective glycemic control. Patients should be counseled to administer tirzepatide subcutaneously into the abdomen, thigh, or upper arm at any time of day on the same day of each week, with or without food. It is important not to mix tirzepatide with other injectable products such as insulin and rotate injection sites. The most common adverse effects of tirzepatide are nausea, diarrhea, and vomiting.

Authors: Gloria Lo, PharmD is currently a PGY-1 resident at UH Meds at Cleveland Medical Center. In Cleveland, OH. gplo1216@ email.campbell.edu. Linda Nguyen is a 2023 PharmD Candidate at the Campbell University College of Pharmacy in Buies Creek,

NC.

References 1.

2.

3.

4.

5.

Tirzepatide (MounjaroTM).

Package insert. Lilly USA, LLC; 2022.

Lexi-Drugs. Lexicomp [database online]. Hudson, OH: Lexicomp, Inc. http://online.lexi.com.

Updated 2022. Accessed May 19, 2022.

Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomized, phase 3 trial [published correction appears in Lancet. 2021 Jul 17;398(10296):212]. Lancet. 2021;398(10295):143155. doi:10.1016/S01406736(21)01324-6.

Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.

N Engl J Med. 2021;385(6):503515. doi:10.1056/NEJMoa2107519.

Ludvik B, Giorgino F, Jódar E,

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et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomized, open-label, parallel-group, phase 3 trial.

Lancet. 2021;398(10300):583598. doi:10.1016/S01406736(21)01443-4.

Dahl D, Onishi Y, Norwood P, et al. Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients with Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial. JAMA. 2022;327(6):534545. doi:10.1001/ jama.2022.0078 American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care 1 January 2022; 45 (Supplement_1): S125–S143. https://doi.org/10.2337/ dc22-S009

NCAP to Host 24th Annual Anti-Infective Conference If your area of practice is infectious diseases you won’t want to miss the 24th Annual Anti-Infective Conference on October 28th. Find out more here and register for the conference.

Time to Throw Your Hat in the Ring

The NCAP 2022 elections are almost here! Are you looking to become more involved in the success of our Association?

Now’s the time.

If you would like to run for a position on the Executive Board of Directors or one of the practice academies please make sure your NCAP membership is current, and submit your name, CV, and position you would like to be on the election ballot for to Angie Broughton, angie@ncpharmacists. org, no later than Friday, October 28, 2022. See below the available positions on each of the leadership teams. Service terms are 3 years.

NCAP’s Executive Board of Directors President-Elect Secretary 1 At-Large Seat

Ambulatory Care Practice Academy Leadership Team Chair-Elect 1 At-Large Seat Chronic Care Practice Academy Leadership Team Chair-Elect 2 At-Large Seats

Community Care Practice Academy Leadership Team Chair-Elect 1 At-Large Seat Health-Systems Practice Academy Leadership Team Chair-Elect 3 At-Large Seats

Student Conference and Residency Showcase Time to Register

The planning committee for the 2022 Student Conference and Residency Showcase is completing details for this event designed for all pharmacy students. The event will take place on Saturday, November 12th, at Campbell University, co-host for this event. There will be informative, engaging programming for P1 - P3 students and the ever popular, highly anticipated Residency Showcase for P4 students. Rounding out the day, Pharmacy Jeopardy! This exciting competition pits all four pharmacy schools against one another to see who comes out on top. Come cheer on your team! Residency programs, click here to register. Students wanting to attend, click here to register.

Webinar Sunday, October 16th From 6 PM - 7 PM

Join us for Making the Switch: Transitioning from Weight Promoting Medications. Our speaker will be Katie Trotta, PharmD. This session will discuss common medications that promote weight gain, identify weight favorable alternatives, and educate pharmacists and pharmacy technicians on how to help patients safely transition from weight-promoting medications to more favorable alternatives. Use this link for more information and to register. The webinar will be ACPE accredited for 1.0 hour of live CE.

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Did You Know NCAP Offers Three types of APPE Electives for Students!

Association Management & Practice Development Whether your interest lies in knowing more about the core operations and advocacy efforts of the association OR you want to help promote practice advancement around pharmacists delivered care at a state level, students can choose their area of focus for this elective experience.

Opioid Stewardship & Service Development This application based elective is designed specifically to utilize students in helping community pharmacies develop and implement harm reduction services to address opioid misuse and overdose.

To learn more in choosing the elective that best suits your interest visit the NCAP website at https://www.ncpharmacists.org/appe-elective-rotations Page 46

The North Carolina Association of Pharmacists

Co-Hosted By:

November 12th 8:00am-3:00pm At Campbell University This Year's Sessions: Residency Showcase Student Advocacy Session How to "Pitch" Yourself Diversity, Equity, and Inclusion Pharmacy Jeopardy!

Register Here

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