Pharmacology

In 2011, 5 VA medical centers (VAMCs) were selected by the Office of Academic Affiliations (OAA) to establish CoEPCE. Part of the VA New Models of Care initiative, the 5 Centers of Excellence (CoE) in Boise, Idaho; Cleveland, Ohio; San Francisco, California; Seattle, Washington; and West Haven, Connecticut, are utilizing VA primary care settings to develop and test innovative approaches to prepare physician residents and students, advanced practice nurse residents and undergraduate nursing students, and other professions of health trainees (eg, pharmacy, social work, psychology, physician assistants [PAs], physical therapists) for primary care practice in the 21st century. The CoEs are developing, implementing, and evaluating curricula designed to prepare learners from relevant professions to practice in patient-centered, interprofessional team-based primary care settings. The curricula at all CoEs must address 4 core domains (Table).

Health care professional education programs do not have many opportunities for workplace learning where trainees from different professions can learn and work together to provide care to patients in real time. 

The VA Connecticut Healthcare System CoEPCE developed and implemented an education and practice-based immersion learning model with physician residents, nurse practitioner (NP) residents and NP students, pharmacy residents, postdoctorate psychology learners, and PA and physical therapy learners and faculty. This interprofessional, collaborative team model breaks from the traditional independent model of siloed primary care providers (PCPs) caring for a panel of patients.

Methods

In 2015, OAA evaluators reviewed background documents and conducted open-ended interviews with 12 West Haven CoEPCE staff, participating trainees, VA faculty, VA facility leadership, and affiliate faculty. Informants described their involvement, challenges encountered, and benefits of the Initiative to Minimize Pharmaceutical Risk in Older Veterans (IMPROVE) program to trainees, veterans, and the VA.

Lack of Clinical Approaches to Interprofessional Education and Care

Polypharmacy is a common problem among older adults with multiple chronic conditions, which places patients at higher risk for multiple negative health outcomes.^2,3 The typical primary care visit rarely allows for a thorough review of a patient’s medications, much less the identification of strategies to reduce polypharmacy and improve medication management. Rather, the complexity inherent to polypharmacy makes it an ideal challenge for a team-based approach.

Team Approach to Medication Needs

A key CoEPCE program aim is to expand workplace learning instruction strategies and to create more clinical opportunities for CoEPCE trainees to work together as a team to anticipate and address the health care needs of veterans. To address this training need, the West Haven CoEPCE developed IMPROVE to focus on high-need patients and provides a venue in which trainees and supervisors from different professions can collaborate on a specific patient case, using a patient-centered framework. IMPROVE can be easily applied to a range of medication-related aims, such as reducing medications, managing medications and adherence, and addressing adverse effects (AEs). These goals are 2-fold: (1) implement a trainee-led performance improvement project that reduces polypharmacy in elderly veterans; and (2) develop a hands-on, experiential geriatrics training program that enhances trainee skills and knowledge related to safe prescribing.

Related: Pharmacist Interventions to Reduce Modifiable Bleeding Risk Factors Using HAS-BLED in Patients Taking Warfarin (FULL)

Planning and Implementation

IMPROVE has its origins in a scholarly project developed by a West Haven CoE physician resident trainee. Development of the IMPROVE program involved VA health psychology, internal medicine faculty, geriatric medicine faculty, NP faculty, and geriatric pharmacy residents and faculty. Planning started in 2013 with a series of pilot clinics and became an official project of the West Haven CoE in September 2014. The intervention required no change in West Haven VAMC policy. However, the initiative required buy-in from West Haven CoE leadership and the director of the West Haven primary care clinic.

Curriculum

IMPROVE is an educational, workplace learning, and clinical activity that combines a 1-hour trainee teaching session, a 45-minute group visit, and a 60-minute individual clinic visit to address the complex problem of polypharmacy. It emphasizes the sharing of trainee and faculty backgrounds by serving as a venue for interprofessional trainees and providers to discuss pharmacologic and nonpharmacologic treatment in the elderly and brainstorm strategies to optimize treatment regimens, minimize risk, and execute medication plans with patients.

All CoEPCE trainees in West Haven are required to participate in IMPROVE and on average, each trainee presents and sees one of their patients at least 3 times per year in the program. Up to 5 trainees participate in each IMPROVE session. Trainees are responsible for reviewing their panels to identify patients who might benefit from participation, followed by inviting the patient to participate. Patients are instructed to bring their pill bottles to the visit. To prepare for the polypharmacy clinic, the trainees, the geriatrician, and the geriatric pharmacist perform an extensive medication chart review, using the medication review worksheet developed by West Haven VAMC providers.⁴ They also work with a protocol for medication discontinuation, which was compiled by West Haven VAMC clinicians. The teams use a variety of tools that guide appropriate prescribing in older adult populations.^5,6 During a preclinic conference, trainees present their patients to the interprofessional team for discussion and participate in a short discussion led by a pharmacist, geriatrician, or health psychologist on a topic related to prescribing safety in older adults or nonpharmacologic treatments.

IMPROVE emphasizes a patient-centered approach to develop, execute, and monitor medication plans. Patients and their family members are invited by their trainee clinician to participate in a group visit. Typically, trainees invite patients aged ≥ 65 years who have ≥ 10 medications and are considered appropriate for a group visit. 

The group visit process is based on health psychology strategies, which often incorporate group-based engagement with patients. The health psychologist can give advice to facilitate the visit and optimize participant involvement. There is a discussion facilitator guide that lists the education points to be covered by a designated trainee facilitator and sample questions to guide the discussion.⁷ A health psychology resident and other rotating trainees cofacilitate the group visit with a goal to reach out to each group member, including family members, and have them discuss perceptions and share concerns and treatment goals. There is shared responsibility among the trainees to address the educational material as well as involve their respective patients during the sessions.

Immediately following the group visit, trainees conduct a 1-hour clinic session that includes medication reconciliation, a review of an IMPROVE questionnaire, orthostatic vital signs, and the St. Louis University Mental Status (SLUMS) exam to assess changes in cognition.^7,8 Discussion involved the patient’s medication list as well as possible changes that could be made to the list. Using shared decision-making techniques, this conversation considers the patients’ treatment goals, feelings about the medications, which medications they would like to stop, and AEs they may be experiencing. After the individual visit is completed, the trainee participates in a 10-minute interprofessional precepting session, which may include a geriatrician, a pharmacist, and a health psychologist. In the session they may discuss adjustments to medications and a safe follow-up plan, including appropriate referrals. Trainees discuss the plan with the patient and send a letter describing the plan shortly after the visit.

IMPROVE combines didactic teaching with experiential education. It embodies the 4 core domains that shape the CoEPCE curriculum. First, trainees learn interprofessional collaboration concepts, including highlighting the roles of each profession and working with an interprofessional team to solve problems. Second, CoEPCE trainees learn performance improvement under the supervision of faculty. Third, IMPROVE allows trainees to develop sustained relationships with other team members while improving the quality of the clinic experience as well as with patients through increased continuity of care. Trainees see patients on their panel and are responsible for outreach before and after the visit. Finally, with a focus on personalized patient goals, trainees have the opportunity to further develop skills in shared decision making (SDM).

Related: Reducing Benzodiazepine Prescribing in Older Veterans: A Direct-to-Consumer Educational Brochure

The IMPROVE model continues to evolve. The original curriculum involved an hour-long preclinic preparation session before the group visit in which trainees and faculty discussed the medication review for each patient scheduled that day. This preparation session was later shortened to 40 minutes, and a 20-minute didactic component was added to create the current preclinic session. The didactic component focused on a specific topic in appropriate prescribing for older patients. For example, one didactic lesson is on a particular class of medications, its common AEs, and practical prescribing and “deprescribing” strategies for that class. Initially, the oldest patients or patients who could be grouped thematically, such as those taking both narcotics and benzodiazepines, were invited to participate, but that limited the number of appropriate patients within the CoEPCE. Currently, trainees identify patients from their panels who might benefit, based on age, number of medications, or potential medication-related concerns, such as falls, cognitive impairment, or other concerns for adverse drug effects. These trainees have the unique opportunity to apply learned strategies to their patients to continue to optimize the medication regimen even after the IMPROVE visit. Another significant change was the inclusion of veterans who are comanaged with PCPs outside the VA, because we found that patients with multiple providers could benefit from improved coordination of care.

Faculty Role

CoE faculty and non-CoE VA faculty participate in supervisory, consulting, teaching and precepting roles. Some faculty members such as the health psychologists are already located in or near the VA primary care clinic, so they can assist in curriculum development and execution during their regular clinic duties. The geriatrician reviews the patients’ health records before the patients come into the clinic, participates in the group visit, and coprecepts during the 1:1 patient visits. Collaboration is inherent in IMPROVE. For example, the geriatrician works with the geriatric pharmacist to identify and teach an educational topic. IMPROVE is characterized by a strong faculty/trainee partnership, with trainees playing roles as both teacher and facilitator in addition to learning how to take a team approach to polypharmacy.

Resources

IMPROVE requires administrative and academic support, especially faculty and trainee preparation of education sessions. The CoEPCE internal medicine resident and the internal medicine chief resident work with the health technicians for each patient aligned care team (PACT) to enter the information into the VA medical scheduling system. Trainee clinic time is blocked for their group visits in advance. Patients are scheduled 1 to 3 weeks in advance. Trainees and faculty are expected to review the medication review worksheet and resources prior to the visit. One CoEPCE faculty member reviews patients prior to the preclinic session (about an hour of preparation per session). Sufficient space also is required: a room large enough to accommodate up to 10 people for both didactic lessons and preclinic sessions, a facility patient education conference room for the group visit, and up to 5 clinic exam rooms. CoEPCE staff developed a templated note in the VA Computerized Patient Record System (CPRS), the VA electronic health record system to guide trainees step-by-step through the clinic visit and allow them to directly enter information into the system.⁷

Monitoring and Assessment

CoEPCE staff are evaluating IMPROVE by building a database for patient-level and trainee-level outcomes, including changes in trainee knowledge and attitudes over time. The CoEPCE also validated the polypharmacy knowledge assessment tool for medicine and NP trainees.

Partnerships

IMPROVE has greatly benefited from partnerships with facility department leadership, particularly involvement of pharmacy staff. In addition, we have partnered with both the health psychology and pharmacy faculty and trainees to participate in the program. Geriatrics faculty and trainees also have contributed extensively to IMPROVE. Future goals include offering the program to non-COEPCE patients throughout primary care.

The Yale Primary Care Internal Medicine Residency program and the Yale Categorical Internal Medicine Residency Program are integral partners to the CoEPCE. IMPROVE supports their mandate to encourage interprofessional teamwork in primary care, meet the Accreditation Council for Graduate Medical Education interprofessional milestones, and promote individual trainee scholarship and performance improvement in areas of broad applicability. IMPROVE also is an opportunity to share ideas across institutions and stimulate new collaborations and dissemination of the model to other primary care settings outside the VA.

Challenges and Solutions

The demand for increased direct patient care pressures programs like IMPROVE, which is a time-intensive process with high impact on a few complex patients. The assumption is that managing medications will save money in the long run, but in the short-term, a strong case has to be made for securing resources, particularly blocking provider time and securing an education room for group visits and clinic exam rooms for individual visits. First, decision makers need to be convinced that polypharmacy is important and should be a training priority. The CoEPCE has tried different configurations to increase the number of patients being seen, such as having ≥ 1 IMPROVE session in an afternoon, but trainees found this to be labor intensive and stressful.

Second, patients with medications prescribed by providers outside the VA require additional communication and coordination to reduce medications. The CoEPCE initially excluded these patients, but after realizing that some of these patients needed the most help, it developed a process for reaching out to non-VA providers and coordinating care. Additionally, there is significant diversity in patient polypharmacy needs. These can range from adherence problems to the challenge of complex psychosocial needs that are more easily (but less effectively) addressed with medications. The issue of polypharmacy is further complicated by evolving understanding of medications’ relative risks and benefits in older adults with multiple chronic conditions. IMPROVE is an effective vehicle for synthesizing current science in medications and their management, especially in complex older patients with multiple chronic conditions.

Other challenges include developing a templated CPRS electronic note that interfaces with the VA information technology system. The process of creating a template, obtaining approval from the forms committee, and working with information technology personnel to implement the template was more time intensive than anticipated and required multiple iterations of proofreading and editing.

Related: Effect of High-Dose Ergocalciferol on Rate of Falls in a Community-Dwelling, Home-Based Primary Care Veteran Population: A Case-Crossover Study

Factors for Success

The commitment to support new models of trainee education by West Haven CoEPCE faculty and leadership, and West Haven VAMC and primary care clinic leadership facilitated the implementation of IMPROVE. Additionally, there is strong CoEPCE collaboration at all levels—codirectors, faculty, and trainees—for the program. High interprofessional trainee interest, organizational insight, and an academic orientation were critical for developing and launching IMPROVE.

Additionally, there is synergy with other team-based professions. Geriatrics has a tradition of working in multidisciplinary teams as well as working with SDM concepts as part of care discussions. High interest and collaboration by a geriatrician and an experienced geriatric pharmacist has been key. The 2 specialties complement each other and address the complex health needs of participating veterans. Health psychologists transition patients to nonpharmacologic treatments, such as sleep hygiene education and cognitive behavioral therapy, in addition to exploring barriers to behavior change.

Another factor for success has been the CoEPCE framework and expertise in interprofessional education. While refining the model, program planners tapped into existing expertise in polypharmacy within the VA from the geriatrics, pharmacy, and clinical health psychology departments. The success of the individual components—the preparation session, the group visit, and the 1:1 patient visit—is in large part the result of a collective effort by CoEPCE staff and the integration of CoEPCE staff through coordination, communications, logistics, quality improvement, and faculty involvement from multiple professions.

The IMPROVE model is flexible and can accommodate diverse patient interests and issues. Model components are based on sound practices that have demonstrated success in other arenas, such as diabetes mellitus group visits. The model can also accommodate diverse trainee levels. Senior trainees can be more independent in developing their care plans, teaching the didactic topic, or precepting during the 1:1 patient exam.

Accomplishments and Benefits

Trainees are using team skills to provide patient-centered care. They are strengthening their clinical skills through exposure to patients in a group visit and 1:1 clinic visit. There have been significant improvements in the trainees’ provision of individual patient care. Key IMPROVE outcomes are outlined below.

Interprofessional Education

Unlike a traditional didactic, IMPROVE is an opportunity for health care professionals to work together to provide care in a clinic setting. It also expands CoEPCE interprofessional education capacity through colocation of different trainee and faculty professions during the conference session. This combination trains participants to work as a team and reflect on patients together, which has strengthened communications among professions. The model provides sufficient time and expertise to discuss the medications in detail and as a team, something that would not normally happen during a regular primary care visit.

CoEPCE trainees learn about medication management, its importance in preventing complications and improving patient health outcomes. Trainees of all professions learn to translate the skills they learn in IMPROVE to other patients, such as how to perform a complete medication reconciliation or lead a discussion using SDM. IMPROVE also provides techniques useful in other contexts, such as group visits and consideration of different medication options for patients who have been cared for by other (VA and non-VA) providers.

Interprofessional Collaboration

Understanding and leveraging the expertise of trainees and faculty from different professions is a primary goal of IMPROVE. Education sessions, the group visit, and precepting model are intentionally designed to break down silos and foster a team approach to care, which supports the PACT team model. Trainees and faculty all have their unique strengths and look at the issue from a different perspective, which increases the likelihood that the patient will hear a cohesive solution or strategy. The result is that trainees are more well rounded and become better practitioners who seek advice from other professions and work well in teams.

Trainees are expected to learn about other professions and their skill sets. For example, trainees learn early about the roles and scopes of practice of pharmacists and health psychologists for more effective referrals. Discussions during the session before the group visit may bring conditions like depression or dementia to the trainees’ attention. This is significant because issues like patient motivation may be better handled from a behavioral perspective.

Expanded Clinical Performance

IMPROVE is an opportunity for CoEPCE trainees to expand their clinical expertise. It provides exposure to a variety of patients and patient care needs and is an opportunity to present a high-risk patient to colleagues of various professions. As of December 2015, about 30 internal medicine residents and 6 NP residents have seen patients in the polypharmacy clinic. Each year, 4 NP residents, 2 health psychology residents, 4 clinical pharmacy residents, and 1 geriatric pharmacy resident participate in the IMPROVE clinic during their yearlong training program. During their 3-year training program, 17 to 19 internal medicine residents participate in IMPROVE.

A structured forum for discussing patients and their care options supports professionals’ utilization of the full scope of their practice. Trainees learn and apply team skills, such as communication and the warm handoff, which can be used in other clinic settings. A warm handoff is often described as an intervention in which “a clinician directly introduces a patient to another clinician at the time of the patient’s visit and often a brief encounter between the patient and the health care professional occurs.”⁹ An interprofessional care plan supports trainee clinical performance, providing a more robust approach to patient care than individual providers might on their own.

Patient Outcomes

IMPROVE is an enriched care plan informed by multiple professions with the potential to improve medication use and provide better care. Veterans also are receiving better medication education as well as access to a health psychologist who can help them with goal setting and effective behavioral interventions. On average, 5 patients participate each month. As of December 2015, 68 patients have participated in IMPROVE.

The group visit and the 1:1 patient visits focus exclusively on medication issues and solutions, which would be less common in a typical primary care visit with a complex patient who brings a list of agenda items. In addition to taking a thorough look at their medications and related problems, it also educates patients on related issues such as sleep hygiene. Participating veterans also are encouraged to share their concerns, experiences, and solutions with the group, which may increase the saliency of the message beyond what is offered in counseling from a provider.

To date, preliminary data suggest that in some patients, cognition (as measured with SLUMS after 6 months) has modestly improved after decreasing their medications. Other outcomes being monitored in follow-up are utilization of care, reported history of falls, number of medications, and vital signs at initial and follow-up visits.

Patients experience increased continuity of care because the patient now has a team focusing on his or her care. Team members have a shared understanding of the patient’s situation and are better able to establish therapeutic rapport with patients during the group visit. Moreover, CoEPCE trainees and faculty try to ensure that everyone knows about and concurs with medication changes, including outside providers and family members.

Satisfaction Questionnaire

Patients that are presented at IMPROVE can be particularly challenging, and there may be a psychological benefit to working with a team to develop a new care plan. Providers are able to get input and look at the patient in a new light.

Results of postvisit patient satisfaction questionnaires are encouraging and result in a high level of patient satisfaction and perception of clinical benefit. Patients identify an improvement in the understanding of their medications, feel they are able to safely decrease their medications, and are interested in participating again.

CoEPCE Benefits

IMPROVE expands the prevention and treatment options for populations at risk of hospitalization and adverse outcomes from medication complications, such as AEs and drug-drug or drug-disease interactions. Embedding the polypharmacy clinic within the primary care setting rather than in a separate specialty clinic results in an increased likelihood of implementation of pharmacist and geriatrician recommendations for polypharmacy and allows for direct interprofessional education and collaboration.

IMPROVE also combines key components of interprofessional education—an enriched clinical training model and knowledge of medications in an elderly population—into a training activity that complements other CoEPCE activities. The model not only has strengthened CoEPCE partnerships with other VA departments and specialties, but also revealed opportunities for collaboration with academic affiliates as a means to break down traditional silos among medicine, nursing, pharmacy, geriatrics, and psychology.

IMPROVE combines key components of interprofessional education, including all 4 CoEPCE core domains, to provide hands-on experience with knowledge learned in other aspects of the CoEPCE training program (eg, shared decision-making strategies for eliciting patient goals, weighing risks and benefits in complex clinical situations). Physician and NP trainees work together with trainees in pharmacy and health psychology in the complex approach to polypharmacy. IMPROVE provides the framework for an interprofessional clinic that could be used in the treatment of other complex or high-risk chronic conditions.

The Future

An opportunity for improvement and expansion includes increased patient involvement (as patients continue to learn they have a team working on their behalf). Opportunities exist to connect with patients who have several clinicians prescribing medications outside the CoEPCE to provide comprehensive care and decrease medication complexity.

The CoEPCE has been proactive in increasing the visibility of IMPROVE through multiple presentations at local and national meetings, facilitating collaborations and greater adoption in primary care. Individual and collective IMPROVE components can be adapted to other contexts. For example, the 20-minute geriatrics education session and the forms completed prior and during the patient visit can be readily applied to other complex patients that trainees meet in clinic. Under stage 2 of the CoEPCE program, the CoEPCE is developing an implementation kit that describes the training process and includes the medication worksheet, assessment tools, and directions for conducting the group visit.

It is hoped that working collaboratively with the West Haven COEPCE polypharmacy faculty, a similar model of education and training will be implemented at other health professional training sites at Yale University in New Haven, Connecticut. Additionally, the West Haven CoEPCE is planning to partner with the other original CoEPCE program sites to implement similar interprofessional polypharmacy clinics.

In 2011, 5 VA medical centers (VAMCs) were selected by the Office of Academic Affiliations (OAA) to establish CoEPCE. Part of the VA New Models of Care initiative, the 5 Centers of Excellence (CoE) in Boise, Idaho; Cleveland, Ohio; San Francisco, California; Seattle, Washington; and West Haven, Connecticut, are utilizing VA primary care settings to develop and test innovative approaches to prepare physician residents and students, advanced practice nurse residents and undergraduate nursing students, and other professions of health trainees (eg, pharmacy, social work, psychology, physician assistants [PAs], physical therapists) for primary care practice in the 21st century. The CoEs are developing, implementing, and evaluating curricula designed to prepare learners from relevant professions to practice in patient-centered, interprofessional team-based primary care settings. The curricula at all CoEs must address 4 core domains (Table).

Health care professional education programs do not have many opportunities for workplace learning where trainees from different professions can learn and work together to provide care to patients in real time. 

The VA Connecticut Healthcare System CoEPCE developed and implemented an education and practice-based immersion learning model with physician residents, nurse practitioner (NP) residents and NP students, pharmacy residents, postdoctorate psychology learners, and PA and physical therapy learners and faculty. This interprofessional, collaborative team model breaks from the traditional independent model of siloed primary care providers (PCPs) caring for a panel of patients.

Methods

In 2015, OAA evaluators reviewed background documents and conducted open-ended interviews with 12 West Haven CoEPCE staff, participating trainees, VA faculty, VA facility leadership, and affiliate faculty. Informants described their involvement, challenges encountered, and benefits of the Initiative to Minimize Pharmaceutical Risk in Older Veterans (IMPROVE) program to trainees, veterans, and the VA.

Lack of Clinical Approaches to Interprofessional Education and Care

Polypharmacy is a common problem among older adults with multiple chronic conditions, which places patients at higher risk for multiple negative health outcomes.^2,3 The typical primary care visit rarely allows for a thorough review of a patient’s medications, much less the identification of strategies to reduce polypharmacy and improve medication management. Rather, the complexity inherent to polypharmacy makes it an ideal challenge for a team-based approach.

Team Approach to Medication Needs

A key CoEPCE program aim is to expand workplace learning instruction strategies and to create more clinical opportunities for CoEPCE trainees to work together as a team to anticipate and address the health care needs of veterans. To address this training need, the West Haven CoEPCE developed IMPROVE to focus on high-need patients and provides a venue in which trainees and supervisors from different professions can collaborate on a specific patient case, using a patient-centered framework. IMPROVE can be easily applied to a range of medication-related aims, such as reducing medications, managing medications and adherence, and addressing adverse effects (AEs). These goals are 2-fold: (1) implement a trainee-led performance improvement project that reduces polypharmacy in elderly veterans; and (2) develop a hands-on, experiential geriatrics training program that enhances trainee skills and knowledge related to safe prescribing.

Related: Pharmacist Interventions to Reduce Modifiable Bleeding Risk Factors Using HAS-BLED in Patients Taking Warfarin (FULL)

Planning and Implementation

IMPROVE has its origins in a scholarly project developed by a West Haven CoE physician resident trainee. Development of the IMPROVE program involved VA health psychology, internal medicine faculty, geriatric medicine faculty, NP faculty, and geriatric pharmacy residents and faculty. Planning started in 2013 with a series of pilot clinics and became an official project of the West Haven CoE in September 2014. The intervention required no change in West Haven VAMC policy. However, the initiative required buy-in from West Haven CoE leadership and the director of the West Haven primary care clinic.

Curriculum

IMPROVE is an educational, workplace learning, and clinical activity that combines a 1-hour trainee teaching session, a 45-minute group visit, and a 60-minute individual clinic visit to address the complex problem of polypharmacy. It emphasizes the sharing of trainee and faculty backgrounds by serving as a venue for interprofessional trainees and providers to discuss pharmacologic and nonpharmacologic treatment in the elderly and brainstorm strategies to optimize treatment regimens, minimize risk, and execute medication plans with patients.

All CoEPCE trainees in West Haven are required to participate in IMPROVE and on average, each trainee presents and sees one of their patients at least 3 times per year in the program. Up to 5 trainees participate in each IMPROVE session. Trainees are responsible for reviewing their panels to identify patients who might benefit from participation, followed by inviting the patient to participate. Patients are instructed to bring their pill bottles to the visit. To prepare for the polypharmacy clinic, the trainees, the geriatrician, and the geriatric pharmacist perform an extensive medication chart review, using the medication review worksheet developed by West Haven VAMC providers.⁴ They also work with a protocol for medication discontinuation, which was compiled by West Haven VAMC clinicians. The teams use a variety of tools that guide appropriate prescribing in older adult populations.^5,6 During a preclinic conference, trainees present their patients to the interprofessional team for discussion and participate in a short discussion led by a pharmacist, geriatrician, or health psychologist on a topic related to prescribing safety in older adults or nonpharmacologic treatments.

IMPROVE emphasizes a patient-centered approach to develop, execute, and monitor medication plans. Patients and their family members are invited by their trainee clinician to participate in a group visit. Typically, trainees invite patients aged ≥ 65 years who have ≥ 10 medications and are considered appropriate for a group visit. 

The group visit process is based on health psychology strategies, which often incorporate group-based engagement with patients. The health psychologist can give advice to facilitate the visit and optimize participant involvement. There is a discussion facilitator guide that lists the education points to be covered by a designated trainee facilitator and sample questions to guide the discussion.⁷ A health psychology resident and other rotating trainees cofacilitate the group visit with a goal to reach out to each group member, including family members, and have them discuss perceptions and share concerns and treatment goals. There is shared responsibility among the trainees to address the educational material as well as involve their respective patients during the sessions.

Immediately following the group visit, trainees conduct a 1-hour clinic session that includes medication reconciliation, a review of an IMPROVE questionnaire, orthostatic vital signs, and the St. Louis University Mental Status (SLUMS) exam to assess changes in cognition.^7,8 Discussion involved the patient’s medication list as well as possible changes that could be made to the list. Using shared decision-making techniques, this conversation considers the patients’ treatment goals, feelings about the medications, which medications they would like to stop, and AEs they may be experiencing. After the individual visit is completed, the trainee participates in a 10-minute interprofessional precepting session, which may include a geriatrician, a pharmacist, and a health psychologist. In the session they may discuss adjustments to medications and a safe follow-up plan, including appropriate referrals. Trainees discuss the plan with the patient and send a letter describing the plan shortly after the visit.

IMPROVE combines didactic teaching with experiential education. It embodies the 4 core domains that shape the CoEPCE curriculum. First, trainees learn interprofessional collaboration concepts, including highlighting the roles of each profession and working with an interprofessional team to solve problems. Second, CoEPCE trainees learn performance improvement under the supervision of faculty. Third, IMPROVE allows trainees to develop sustained relationships with other team members while improving the quality of the clinic experience as well as with patients through increased continuity of care. Trainees see patients on their panel and are responsible for outreach before and after the visit. Finally, with a focus on personalized patient goals, trainees have the opportunity to further develop skills in shared decision making (SDM).

Related: Reducing Benzodiazepine Prescribing in Older Veterans: A Direct-to-Consumer Educational Brochure

The IMPROVE model continues to evolve. The original curriculum involved an hour-long preclinic preparation session before the group visit in which trainees and faculty discussed the medication review for each patient scheduled that day. This preparation session was later shortened to 40 minutes, and a 20-minute didactic component was added to create the current preclinic session. The didactic component focused on a specific topic in appropriate prescribing for older patients. For example, one didactic lesson is on a particular class of medications, its common AEs, and practical prescribing and “deprescribing” strategies for that class. Initially, the oldest patients or patients who could be grouped thematically, such as those taking both narcotics and benzodiazepines, were invited to participate, but that limited the number of appropriate patients within the CoEPCE. Currently, trainees identify patients from their panels who might benefit, based on age, number of medications, or potential medication-related concerns, such as falls, cognitive impairment, or other concerns for adverse drug effects. These trainees have the unique opportunity to apply learned strategies to their patients to continue to optimize the medication regimen even after the IMPROVE visit. Another significant change was the inclusion of veterans who are comanaged with PCPs outside the VA, because we found that patients with multiple providers could benefit from improved coordination of care.

Faculty Role

CoE faculty and non-CoE VA faculty participate in supervisory, consulting, teaching and precepting roles. Some faculty members such as the health psychologists are already located in or near the VA primary care clinic, so they can assist in curriculum development and execution during their regular clinic duties. The geriatrician reviews the patients’ health records before the patients come into the clinic, participates in the group visit, and coprecepts during the 1:1 patient visits. Collaboration is inherent in IMPROVE. For example, the geriatrician works with the geriatric pharmacist to identify and teach an educational topic. IMPROVE is characterized by a strong faculty/trainee partnership, with trainees playing roles as both teacher and facilitator in addition to learning how to take a team approach to polypharmacy.

Resources

IMPROVE requires administrative and academic support, especially faculty and trainee preparation of education sessions. The CoEPCE internal medicine resident and the internal medicine chief resident work with the health technicians for each patient aligned care team (PACT) to enter the information into the VA medical scheduling system. Trainee clinic time is blocked for their group visits in advance. Patients are scheduled 1 to 3 weeks in advance. Trainees and faculty are expected to review the medication review worksheet and resources prior to the visit. One CoEPCE faculty member reviews patients prior to the preclinic session (about an hour of preparation per session). Sufficient space also is required: a room large enough to accommodate up to 10 people for both didactic lessons and preclinic sessions, a facility patient education conference room for the group visit, and up to 5 clinic exam rooms. CoEPCE staff developed a templated note in the VA Computerized Patient Record System (CPRS), the VA electronic health record system to guide trainees step-by-step through the clinic visit and allow them to directly enter information into the system.⁷

Monitoring and Assessment

CoEPCE staff are evaluating IMPROVE by building a database for patient-level and trainee-level outcomes, including changes in trainee knowledge and attitudes over time. The CoEPCE also validated the polypharmacy knowledge assessment tool for medicine and NP trainees.

Partnerships

IMPROVE has greatly benefited from partnerships with facility department leadership, particularly involvement of pharmacy staff. In addition, we have partnered with both the health psychology and pharmacy faculty and trainees to participate in the program. Geriatrics faculty and trainees also have contributed extensively to IMPROVE. Future goals include offering the program to non-COEPCE patients throughout primary care.

The Yale Primary Care Internal Medicine Residency program and the Yale Categorical Internal Medicine Residency Program are integral partners to the CoEPCE. IMPROVE supports their mandate to encourage interprofessional teamwork in primary care, meet the Accreditation Council for Graduate Medical Education interprofessional milestones, and promote individual trainee scholarship and performance improvement in areas of broad applicability. IMPROVE also is an opportunity to share ideas across institutions and stimulate new collaborations and dissemination of the model to other primary care settings outside the VA.

Challenges and Solutions

The demand for increased direct patient care pressures programs like IMPROVE, which is a time-intensive process with high impact on a few complex patients. The assumption is that managing medications will save money in the long run, but in the short-term, a strong case has to be made for securing resources, particularly blocking provider time and securing an education room for group visits and clinic exam rooms for individual visits. First, decision makers need to be convinced that polypharmacy is important and should be a training priority. The CoEPCE has tried different configurations to increase the number of patients being seen, such as having ≥ 1 IMPROVE session in an afternoon, but trainees found this to be labor intensive and stressful.

Second, patients with medications prescribed by providers outside the VA require additional communication and coordination to reduce medications. The CoEPCE initially excluded these patients, but after realizing that some of these patients needed the most help, it developed a process for reaching out to non-VA providers and coordinating care. Additionally, there is significant diversity in patient polypharmacy needs. These can range from adherence problems to the challenge of complex psychosocial needs that are more easily (but less effectively) addressed with medications. The issue of polypharmacy is further complicated by evolving understanding of medications’ relative risks and benefits in older adults with multiple chronic conditions. IMPROVE is an effective vehicle for synthesizing current science in medications and their management, especially in complex older patients with multiple chronic conditions.

Other challenges include developing a templated CPRS electronic note that interfaces with the VA information technology system. The process of creating a template, obtaining approval from the forms committee, and working with information technology personnel to implement the template was more time intensive than anticipated and required multiple iterations of proofreading and editing.

Related: Effect of High-Dose Ergocalciferol on Rate of Falls in a Community-Dwelling, Home-Based Primary Care Veteran Population: A Case-Crossover Study

Factors for Success

The commitment to support new models of trainee education by West Haven CoEPCE faculty and leadership, and West Haven VAMC and primary care clinic leadership facilitated the implementation of IMPROVE. Additionally, there is strong CoEPCE collaboration at all levels—codirectors, faculty, and trainees—for the program. High interprofessional trainee interest, organizational insight, and an academic orientation were critical for developing and launching IMPROVE.

Additionally, there is synergy with other team-based professions. Geriatrics has a tradition of working in multidisciplinary teams as well as working with SDM concepts as part of care discussions. High interest and collaboration by a geriatrician and an experienced geriatric pharmacist has been key. The 2 specialties complement each other and address the complex health needs of participating veterans. Health psychologists transition patients to nonpharmacologic treatments, such as sleep hygiene education and cognitive behavioral therapy, in addition to exploring barriers to behavior change.

Another factor for success has been the CoEPCE framework and expertise in interprofessional education. While refining the model, program planners tapped into existing expertise in polypharmacy within the VA from the geriatrics, pharmacy, and clinical health psychology departments. The success of the individual components—the preparation session, the group visit, and the 1:1 patient visit—is in large part the result of a collective effort by CoEPCE staff and the integration of CoEPCE staff through coordination, communications, logistics, quality improvement, and faculty involvement from multiple professions.

The IMPROVE model is flexible and can accommodate diverse patient interests and issues. Model components are based on sound practices that have demonstrated success in other arenas, such as diabetes mellitus group visits. The model can also accommodate diverse trainee levels. Senior trainees can be more independent in developing their care plans, teaching the didactic topic, or precepting during the 1:1 patient exam.

Accomplishments and Benefits

Trainees are using team skills to provide patient-centered care. They are strengthening their clinical skills through exposure to patients in a group visit and 1:1 clinic visit. There have been significant improvements in the trainees’ provision of individual patient care. Key IMPROVE outcomes are outlined below.

Interprofessional Education

Unlike a traditional didactic, IMPROVE is an opportunity for health care professionals to work together to provide care in a clinic setting. It also expands CoEPCE interprofessional education capacity through colocation of different trainee and faculty professions during the conference session. This combination trains participants to work as a team and reflect on patients together, which has strengthened communications among professions. The model provides sufficient time and expertise to discuss the medications in detail and as a team, something that would not normally happen during a regular primary care visit.

CoEPCE trainees learn about medication management, its importance in preventing complications and improving patient health outcomes. Trainees of all professions learn to translate the skills they learn in IMPROVE to other patients, such as how to perform a complete medication reconciliation or lead a discussion using SDM. IMPROVE also provides techniques useful in other contexts, such as group visits and consideration of different medication options for patients who have been cared for by other (VA and non-VA) providers.

Interprofessional Collaboration

Understanding and leveraging the expertise of trainees and faculty from different professions is a primary goal of IMPROVE. Education sessions, the group visit, and precepting model are intentionally designed to break down silos and foster a team approach to care, which supports the PACT team model. Trainees and faculty all have their unique strengths and look at the issue from a different perspective, which increases the likelihood that the patient will hear a cohesive solution or strategy. The result is that trainees are more well rounded and become better practitioners who seek advice from other professions and work well in teams.

Trainees are expected to learn about other professions and their skill sets. For example, trainees learn early about the roles and scopes of practice of pharmacists and health psychologists for more effective referrals. Discussions during the session before the group visit may bring conditions like depression or dementia to the trainees’ attention. This is significant because issues like patient motivation may be better handled from a behavioral perspective.

Expanded Clinical Performance

IMPROVE is an opportunity for CoEPCE trainees to expand their clinical expertise. It provides exposure to a variety of patients and patient care needs and is an opportunity to present a high-risk patient to colleagues of various professions. As of December 2015, about 30 internal medicine residents and 6 NP residents have seen patients in the polypharmacy clinic. Each year, 4 NP residents, 2 health psychology residents, 4 clinical pharmacy residents, and 1 geriatric pharmacy resident participate in the IMPROVE clinic during their yearlong training program. During their 3-year training program, 17 to 19 internal medicine residents participate in IMPROVE.

A structured forum for discussing patients and their care options supports professionals’ utilization of the full scope of their practice. Trainees learn and apply team skills, such as communication and the warm handoff, which can be used in other clinic settings. A warm handoff is often described as an intervention in which “a clinician directly introduces a patient to another clinician at the time of the patient’s visit and often a brief encounter between the patient and the health care professional occurs.”⁹ An interprofessional care plan supports trainee clinical performance, providing a more robust approach to patient care than individual providers might on their own.

Patient Outcomes

IMPROVE is an enriched care plan informed by multiple professions with the potential to improve medication use and provide better care. Veterans also are receiving better medication education as well as access to a health psychologist who can help them with goal setting and effective behavioral interventions. On average, 5 patients participate each month. As of December 2015, 68 patients have participated in IMPROVE.

The group visit and the 1:1 patient visits focus exclusively on medication issues and solutions, which would be less common in a typical primary care visit with a complex patient who brings a list of agenda items. In addition to taking a thorough look at their medications and related problems, it also educates patients on related issues such as sleep hygiene. Participating veterans also are encouraged to share their concerns, experiences, and solutions with the group, which may increase the saliency of the message beyond what is offered in counseling from a provider.

To date, preliminary data suggest that in some patients, cognition (as measured with SLUMS after 6 months) has modestly improved after decreasing their medications. Other outcomes being monitored in follow-up are utilization of care, reported history of falls, number of medications, and vital signs at initial and follow-up visits.

Patients experience increased continuity of care because the patient now has a team focusing on his or her care. Team members have a shared understanding of the patient’s situation and are better able to establish therapeutic rapport with patients during the group visit. Moreover, CoEPCE trainees and faculty try to ensure that everyone knows about and concurs with medication changes, including outside providers and family members.

Satisfaction Questionnaire

Patients that are presented at IMPROVE can be particularly challenging, and there may be a psychological benefit to working with a team to develop a new care plan. Providers are able to get input and look at the patient in a new light.

Results of postvisit patient satisfaction questionnaires are encouraging and result in a high level of patient satisfaction and perception of clinical benefit. Patients identify an improvement in the understanding of their medications, feel they are able to safely decrease their medications, and are interested in participating again.

CoEPCE Benefits

IMPROVE expands the prevention and treatment options for populations at risk of hospitalization and adverse outcomes from medication complications, such as AEs and drug-drug or drug-disease interactions. Embedding the polypharmacy clinic within the primary care setting rather than in a separate specialty clinic results in an increased likelihood of implementation of pharmacist and geriatrician recommendations for polypharmacy and allows for direct interprofessional education and collaboration.

IMPROVE also combines key components of interprofessional education—an enriched clinical training model and knowledge of medications in an elderly population—into a training activity that complements other CoEPCE activities. The model not only has strengthened CoEPCE partnerships with other VA departments and specialties, but also revealed opportunities for collaboration with academic affiliates as a means to break down traditional silos among medicine, nursing, pharmacy, geriatrics, and psychology.

IMPROVE combines key components of interprofessional education, including all 4 CoEPCE core domains, to provide hands-on experience with knowledge learned in other aspects of the CoEPCE training program (eg, shared decision-making strategies for eliciting patient goals, weighing risks and benefits in complex clinical situations). Physician and NP trainees work together with trainees in pharmacy and health psychology in the complex approach to polypharmacy. IMPROVE provides the framework for an interprofessional clinic that could be used in the treatment of other complex or high-risk chronic conditions.

The Future

An opportunity for improvement and expansion includes increased patient involvement (as patients continue to learn they have a team working on their behalf). Opportunities exist to connect with patients who have several clinicians prescribing medications outside the CoEPCE to provide comprehensive care and decrease medication complexity.

The CoEPCE has been proactive in increasing the visibility of IMPROVE through multiple presentations at local and national meetings, facilitating collaborations and greater adoption in primary care. Individual and collective IMPROVE components can be adapted to other contexts. For example, the 20-minute geriatrics education session and the forms completed prior and during the patient visit can be readily applied to other complex patients that trainees meet in clinic. Under stage 2 of the CoEPCE program, the CoEPCE is developing an implementation kit that describes the training process and includes the medication worksheet, assessment tools, and directions for conducting the group visit.

It is hoped that working collaboratively with the West Haven COEPCE polypharmacy faculty, a similar model of education and training will be implemented at other health professional training sites at Yale University in New Haven, Connecticut. Additionally, the West Haven CoEPCE is planning to partner with the other original CoEPCE program sites to implement similar interprofessional polypharmacy clinics.

In 2011, 5 VA medical centers (VAMCs) were selected by the Office of Academic Affiliations (OAA) to establish CoEPCE. Part of the VA New Models of Care initiative, the 5 Centers of Excellence (CoE) in Boise, Idaho; Cleveland, Ohio; San Francisco, California; Seattle, Washington; and West Haven, Connecticut, are utilizing VA primary care settings to develop and test innovative approaches to prepare physician residents and students, advanced practice nurse residents and undergraduate nursing students, and other professions of health trainees (eg, pharmacy, social work, psychology, physician assistants [PAs], physical therapists) for primary care practice in the 21st century. The CoEs are developing, implementing, and evaluating curricula designed to prepare learners from relevant professions to practice in patient-centered, interprofessional team-based primary care settings. The curricula at all CoEs must address 4 core domains (Table).

Health care professional education programs do not have many opportunities for workplace learning where trainees from different professions can learn and work together to provide care to patients in real time. 

The VA Connecticut Healthcare System CoEPCE developed and implemented an education and practice-based immersion learning model with physician residents, nurse practitioner (NP) residents and NP students, pharmacy residents, postdoctorate psychology learners, and PA and physical therapy learners and faculty. This interprofessional, collaborative team model breaks from the traditional independent model of siloed primary care providers (PCPs) caring for a panel of patients.

Methods

In 2015, OAA evaluators reviewed background documents and conducted open-ended interviews with 12 West Haven CoEPCE staff, participating trainees, VA faculty, VA facility leadership, and affiliate faculty. Informants described their involvement, challenges encountered, and benefits of the Initiative to Minimize Pharmaceutical Risk in Older Veterans (IMPROVE) program to trainees, veterans, and the VA.

Lack of Clinical Approaches to Interprofessional Education and Care

Polypharmacy is a common problem among older adults with multiple chronic conditions, which places patients at higher risk for multiple negative health outcomes.^2,3 The typical primary care visit rarely allows for a thorough review of a patient’s medications, much less the identification of strategies to reduce polypharmacy and improve medication management. Rather, the complexity inherent to polypharmacy makes it an ideal challenge for a team-based approach.

Team Approach to Medication Needs

A key CoEPCE program aim is to expand workplace learning instruction strategies and to create more clinical opportunities for CoEPCE trainees to work together as a team to anticipate and address the health care needs of veterans. To address this training need, the West Haven CoEPCE developed IMPROVE to focus on high-need patients and provides a venue in which trainees and supervisors from different professions can collaborate on a specific patient case, using a patient-centered framework. IMPROVE can be easily applied to a range of medication-related aims, such as reducing medications, managing medications and adherence, and addressing adverse effects (AEs). These goals are 2-fold: (1) implement a trainee-led performance improvement project that reduces polypharmacy in elderly veterans; and (2) develop a hands-on, experiential geriatrics training program that enhances trainee skills and knowledge related to safe prescribing.

Related: Pharmacist Interventions to Reduce Modifiable Bleeding Risk Factors Using HAS-BLED in Patients Taking Warfarin (FULL)

Planning and Implementation

IMPROVE has its origins in a scholarly project developed by a West Haven CoE physician resident trainee. Development of the IMPROVE program involved VA health psychology, internal medicine faculty, geriatric medicine faculty, NP faculty, and geriatric pharmacy residents and faculty. Planning started in 2013 with a series of pilot clinics and became an official project of the West Haven CoE in September 2014. The intervention required no change in West Haven VAMC policy. However, the initiative required buy-in from West Haven CoE leadership and the director of the West Haven primary care clinic.

Curriculum

IMPROVE is an educational, workplace learning, and clinical activity that combines a 1-hour trainee teaching session, a 45-minute group visit, and a 60-minute individual clinic visit to address the complex problem of polypharmacy. It emphasizes the sharing of trainee and faculty backgrounds by serving as a venue for interprofessional trainees and providers to discuss pharmacologic and nonpharmacologic treatment in the elderly and brainstorm strategies to optimize treatment regimens, minimize risk, and execute medication plans with patients.

All CoEPCE trainees in West Haven are required to participate in IMPROVE and on average, each trainee presents and sees one of their patients at least 3 times per year in the program. Up to 5 trainees participate in each IMPROVE session. Trainees are responsible for reviewing their panels to identify patients who might benefit from participation, followed by inviting the patient to participate. Patients are instructed to bring their pill bottles to the visit. To prepare for the polypharmacy clinic, the trainees, the geriatrician, and the geriatric pharmacist perform an extensive medication chart review, using the medication review worksheet developed by West Haven VAMC providers.⁴ They also work with a protocol for medication discontinuation, which was compiled by West Haven VAMC clinicians. The teams use a variety of tools that guide appropriate prescribing in older adult populations.^5,6 During a preclinic conference, trainees present their patients to the interprofessional team for discussion and participate in a short discussion led by a pharmacist, geriatrician, or health psychologist on a topic related to prescribing safety in older adults or nonpharmacologic treatments.

IMPROVE emphasizes a patient-centered approach to develop, execute, and monitor medication plans. Patients and their family members are invited by their trainee clinician to participate in a group visit. Typically, trainees invite patients aged ≥ 65 years who have ≥ 10 medications and are considered appropriate for a group visit. 

The group visit process is based on health psychology strategies, which often incorporate group-based engagement with patients. The health psychologist can give advice to facilitate the visit and optimize participant involvement. There is a discussion facilitator guide that lists the education points to be covered by a designated trainee facilitator and sample questions to guide the discussion.⁷ A health psychology resident and other rotating trainees cofacilitate the group visit with a goal to reach out to each group member, including family members, and have them discuss perceptions and share concerns and treatment goals. There is shared responsibility among the trainees to address the educational material as well as involve their respective patients during the sessions.

Immediately following the group visit, trainees conduct a 1-hour clinic session that includes medication reconciliation, a review of an IMPROVE questionnaire, orthostatic vital signs, and the St. Louis University Mental Status (SLUMS) exam to assess changes in cognition.^7,8 Discussion involved the patient’s medication list as well as possible changes that could be made to the list. Using shared decision-making techniques, this conversation considers the patients’ treatment goals, feelings about the medications, which medications they would like to stop, and AEs they may be experiencing. After the individual visit is completed, the trainee participates in a 10-minute interprofessional precepting session, which may include a geriatrician, a pharmacist, and a health psychologist. In the session they may discuss adjustments to medications and a safe follow-up plan, including appropriate referrals. Trainees discuss the plan with the patient and send a letter describing the plan shortly after the visit.

IMPROVE combines didactic teaching with experiential education. It embodies the 4 core domains that shape the CoEPCE curriculum. First, trainees learn interprofessional collaboration concepts, including highlighting the roles of each profession and working with an interprofessional team to solve problems. Second, CoEPCE trainees learn performance improvement under the supervision of faculty. Third, IMPROVE allows trainees to develop sustained relationships with other team members while improving the quality of the clinic experience as well as with patients through increased continuity of care. Trainees see patients on their panel and are responsible for outreach before and after the visit. Finally, with a focus on personalized patient goals, trainees have the opportunity to further develop skills in shared decision making (SDM).

Related: Reducing Benzodiazepine Prescribing in Older Veterans: A Direct-to-Consumer Educational Brochure

The IMPROVE model continues to evolve. The original curriculum involved an hour-long preclinic preparation session before the group visit in which trainees and faculty discussed the medication review for each patient scheduled that day. This preparation session was later shortened to 40 minutes, and a 20-minute didactic component was added to create the current preclinic session. The didactic component focused on a specific topic in appropriate prescribing for older patients. For example, one didactic lesson is on a particular class of medications, its common AEs, and practical prescribing and “deprescribing” strategies for that class. Initially, the oldest patients or patients who could be grouped thematically, such as those taking both narcotics and benzodiazepines, were invited to participate, but that limited the number of appropriate patients within the CoEPCE. Currently, trainees identify patients from their panels who might benefit, based on age, number of medications, or potential medication-related concerns, such as falls, cognitive impairment, or other concerns for adverse drug effects. These trainees have the unique opportunity to apply learned strategies to their patients to continue to optimize the medication regimen even after the IMPROVE visit. Another significant change was the inclusion of veterans who are comanaged with PCPs outside the VA, because we found that patients with multiple providers could benefit from improved coordination of care.

Faculty Role

CoE faculty and non-CoE VA faculty participate in supervisory, consulting, teaching and precepting roles. Some faculty members such as the health psychologists are already located in or near the VA primary care clinic, so they can assist in curriculum development and execution during their regular clinic duties. The geriatrician reviews the patients’ health records before the patients come into the clinic, participates in the group visit, and coprecepts during the 1:1 patient visits. Collaboration is inherent in IMPROVE. For example, the geriatrician works with the geriatric pharmacist to identify and teach an educational topic. IMPROVE is characterized by a strong faculty/trainee partnership, with trainees playing roles as both teacher and facilitator in addition to learning how to take a team approach to polypharmacy.

Resources

IMPROVE requires administrative and academic support, especially faculty and trainee preparation of education sessions. The CoEPCE internal medicine resident and the internal medicine chief resident work with the health technicians for each patient aligned care team (PACT) to enter the information into the VA medical scheduling system. Trainee clinic time is blocked for their group visits in advance. Patients are scheduled 1 to 3 weeks in advance. Trainees and faculty are expected to review the medication review worksheet and resources prior to the visit. One CoEPCE faculty member reviews patients prior to the preclinic session (about an hour of preparation per session). Sufficient space also is required: a room large enough to accommodate up to 10 people for both didactic lessons and preclinic sessions, a facility patient education conference room for the group visit, and up to 5 clinic exam rooms. CoEPCE staff developed a templated note in the VA Computerized Patient Record System (CPRS), the VA electronic health record system to guide trainees step-by-step through the clinic visit and allow them to directly enter information into the system.⁷

Monitoring and Assessment

CoEPCE staff are evaluating IMPROVE by building a database for patient-level and trainee-level outcomes, including changes in trainee knowledge and attitudes over time. The CoEPCE also validated the polypharmacy knowledge assessment tool for medicine and NP trainees.

Partnerships

IMPROVE has greatly benefited from partnerships with facility department leadership, particularly involvement of pharmacy staff. In addition, we have partnered with both the health psychology and pharmacy faculty and trainees to participate in the program. Geriatrics faculty and trainees also have contributed extensively to IMPROVE. Future goals include offering the program to non-COEPCE patients throughout primary care.

The Yale Primary Care Internal Medicine Residency program and the Yale Categorical Internal Medicine Residency Program are integral partners to the CoEPCE. IMPROVE supports their mandate to encourage interprofessional teamwork in primary care, meet the Accreditation Council for Graduate Medical Education interprofessional milestones, and promote individual trainee scholarship and performance improvement in areas of broad applicability. IMPROVE also is an opportunity to share ideas across institutions and stimulate new collaborations and dissemination of the model to other primary care settings outside the VA.

Challenges and Solutions

The demand for increased direct patient care pressures programs like IMPROVE, which is a time-intensive process with high impact on a few complex patients. The assumption is that managing medications will save money in the long run, but in the short-term, a strong case has to be made for securing resources, particularly blocking provider time and securing an education room for group visits and clinic exam rooms for individual visits. First, decision makers need to be convinced that polypharmacy is important and should be a training priority. The CoEPCE has tried different configurations to increase the number of patients being seen, such as having ≥ 1 IMPROVE session in an afternoon, but trainees found this to be labor intensive and stressful.

Second, patients with medications prescribed by providers outside the VA require additional communication and coordination to reduce medications. The CoEPCE initially excluded these patients, but after realizing that some of these patients needed the most help, it developed a process for reaching out to non-VA providers and coordinating care. Additionally, there is significant diversity in patient polypharmacy needs. These can range from adherence problems to the challenge of complex psychosocial needs that are more easily (but less effectively) addressed with medications. The issue of polypharmacy is further complicated by evolving understanding of medications’ relative risks and benefits in older adults with multiple chronic conditions. IMPROVE is an effective vehicle for synthesizing current science in medications and their management, especially in complex older patients with multiple chronic conditions.

Other challenges include developing a templated CPRS electronic note that interfaces with the VA information technology system. The process of creating a template, obtaining approval from the forms committee, and working with information technology personnel to implement the template was more time intensive than anticipated and required multiple iterations of proofreading and editing.

Related: Effect of High-Dose Ergocalciferol on Rate of Falls in a Community-Dwelling, Home-Based Primary Care Veteran Population: A Case-Crossover Study

Factors for Success

The commitment to support new models of trainee education by West Haven CoEPCE faculty and leadership, and West Haven VAMC and primary care clinic leadership facilitated the implementation of IMPROVE. Additionally, there is strong CoEPCE collaboration at all levels—codirectors, faculty, and trainees—for the program. High interprofessional trainee interest, organizational insight, and an academic orientation were critical for developing and launching IMPROVE.

Additionally, there is synergy with other team-based professions. Geriatrics has a tradition of working in multidisciplinary teams as well as working with SDM concepts as part of care discussions. High interest and collaboration by a geriatrician and an experienced geriatric pharmacist has been key. The 2 specialties complement each other and address the complex health needs of participating veterans. Health psychologists transition patients to nonpharmacologic treatments, such as sleep hygiene education and cognitive behavioral therapy, in addition to exploring barriers to behavior change.

Another factor for success has been the CoEPCE framework and expertise in interprofessional education. While refining the model, program planners tapped into existing expertise in polypharmacy within the VA from the geriatrics, pharmacy, and clinical health psychology departments. The success of the individual components—the preparation session, the group visit, and the 1:1 patient visit—is in large part the result of a collective effort by CoEPCE staff and the integration of CoEPCE staff through coordination, communications, logistics, quality improvement, and faculty involvement from multiple professions.

The IMPROVE model is flexible and can accommodate diverse patient interests and issues. Model components are based on sound practices that have demonstrated success in other arenas, such as diabetes mellitus group visits. The model can also accommodate diverse trainee levels. Senior trainees can be more independent in developing their care plans, teaching the didactic topic, or precepting during the 1:1 patient exam.

Accomplishments and Benefits

Trainees are using team skills to provide patient-centered care. They are strengthening their clinical skills through exposure to patients in a group visit and 1:1 clinic visit. There have been significant improvements in the trainees’ provision of individual patient care. Key IMPROVE outcomes are outlined below.

Interprofessional Education

Unlike a traditional didactic, IMPROVE is an opportunity for health care professionals to work together to provide care in a clinic setting. It also expands CoEPCE interprofessional education capacity through colocation of different trainee and faculty professions during the conference session. This combination trains participants to work as a team and reflect on patients together, which has strengthened communications among professions. The model provides sufficient time and expertise to discuss the medications in detail and as a team, something that would not normally happen during a regular primary care visit.

CoEPCE trainees learn about medication management, its importance in preventing complications and improving patient health outcomes. Trainees of all professions learn to translate the skills they learn in IMPROVE to other patients, such as how to perform a complete medication reconciliation or lead a discussion using SDM. IMPROVE also provides techniques useful in other contexts, such as group visits and consideration of different medication options for patients who have been cared for by other (VA and non-VA) providers.

Interprofessional Collaboration

Understanding and leveraging the expertise of trainees and faculty from different professions is a primary goal of IMPROVE. Education sessions, the group visit, and precepting model are intentionally designed to break down silos and foster a team approach to care, which supports the PACT team model. Trainees and faculty all have their unique strengths and look at the issue from a different perspective, which increases the likelihood that the patient will hear a cohesive solution or strategy. The result is that trainees are more well rounded and become better practitioners who seek advice from other professions and work well in teams.

Trainees are expected to learn about other professions and their skill sets. For example, trainees learn early about the roles and scopes of practice of pharmacists and health psychologists for more effective referrals. Discussions during the session before the group visit may bring conditions like depression or dementia to the trainees’ attention. This is significant because issues like patient motivation may be better handled from a behavioral perspective.

Expanded Clinical Performance

IMPROVE is an opportunity for CoEPCE trainees to expand their clinical expertise. It provides exposure to a variety of patients and patient care needs and is an opportunity to present a high-risk patient to colleagues of various professions. As of December 2015, about 30 internal medicine residents and 6 NP residents have seen patients in the polypharmacy clinic. Each year, 4 NP residents, 2 health psychology residents, 4 clinical pharmacy residents, and 1 geriatric pharmacy resident participate in the IMPROVE clinic during their yearlong training program. During their 3-year training program, 17 to 19 internal medicine residents participate in IMPROVE.

A structured forum for discussing patients and their care options supports professionals’ utilization of the full scope of their practice. Trainees learn and apply team skills, such as communication and the warm handoff, which can be used in other clinic settings. A warm handoff is often described as an intervention in which “a clinician directly introduces a patient to another clinician at the time of the patient’s visit and often a brief encounter between the patient and the health care professional occurs.”⁹ An interprofessional care plan supports trainee clinical performance, providing a more robust approach to patient care than individual providers might on their own.

Patient Outcomes

IMPROVE is an enriched care plan informed by multiple professions with the potential to improve medication use and provide better care. Veterans also are receiving better medication education as well as access to a health psychologist who can help them with goal setting and effective behavioral interventions. On average, 5 patients participate each month. As of December 2015, 68 patients have participated in IMPROVE.

The group visit and the 1:1 patient visits focus exclusively on medication issues and solutions, which would be less common in a typical primary care visit with a complex patient who brings a list of agenda items. In addition to taking a thorough look at their medications and related problems, it also educates patients on related issues such as sleep hygiene. Participating veterans also are encouraged to share their concerns, experiences, and solutions with the group, which may increase the saliency of the message beyond what is offered in counseling from a provider.

To date, preliminary data suggest that in some patients, cognition (as measured with SLUMS after 6 months) has modestly improved after decreasing their medications. Other outcomes being monitored in follow-up are utilization of care, reported history of falls, number of medications, and vital signs at initial and follow-up visits.

Patients experience increased continuity of care because the patient now has a team focusing on his or her care. Team members have a shared understanding of the patient’s situation and are better able to establish therapeutic rapport with patients during the group visit. Moreover, CoEPCE trainees and faculty try to ensure that everyone knows about and concurs with medication changes, including outside providers and family members.

Satisfaction Questionnaire

Patients that are presented at IMPROVE can be particularly challenging, and there may be a psychological benefit to working with a team to develop a new care plan. Providers are able to get input and look at the patient in a new light.

Results of postvisit patient satisfaction questionnaires are encouraging and result in a high level of patient satisfaction and perception of clinical benefit. Patients identify an improvement in the understanding of their medications, feel they are able to safely decrease their medications, and are interested in participating again.

CoEPCE Benefits

IMPROVE expands the prevention and treatment options for populations at risk of hospitalization and adverse outcomes from medication complications, such as AEs and drug-drug or drug-disease interactions. Embedding the polypharmacy clinic within the primary care setting rather than in a separate specialty clinic results in an increased likelihood of implementation of pharmacist and geriatrician recommendations for polypharmacy and allows for direct interprofessional education and collaboration.

IMPROVE also combines key components of interprofessional education—an enriched clinical training model and knowledge of medications in an elderly population—into a training activity that complements other CoEPCE activities. The model not only has strengthened CoEPCE partnerships with other VA departments and specialties, but also revealed opportunities for collaboration with academic affiliates as a means to break down traditional silos among medicine, nursing, pharmacy, geriatrics, and psychology.

IMPROVE combines key components of interprofessional education, including all 4 CoEPCE core domains, to provide hands-on experience with knowledge learned in other aspects of the CoEPCE training program (eg, shared decision-making strategies for eliciting patient goals, weighing risks and benefits in complex clinical situations). Physician and NP trainees work together with trainees in pharmacy and health psychology in the complex approach to polypharmacy. IMPROVE provides the framework for an interprofessional clinic that could be used in the treatment of other complex or high-risk chronic conditions.

The Future

An opportunity for improvement and expansion includes increased patient involvement (as patients continue to learn they have a team working on their behalf). Opportunities exist to connect with patients who have several clinicians prescribing medications outside the CoEPCE to provide comprehensive care and decrease medication complexity.

The CoEPCE has been proactive in increasing the visibility of IMPROVE through multiple presentations at local and national meetings, facilitating collaborations and greater adoption in primary care. Individual and collective IMPROVE components can be adapted to other contexts. For example, the 20-minute geriatrics education session and the forms completed prior and during the patient visit can be readily applied to other complex patients that trainees meet in clinic. Under stage 2 of the CoEPCE program, the CoEPCE is developing an implementation kit that describes the training process and includes the medication worksheet, assessment tools, and directions for conducting the group visit.

It is hoped that working collaboratively with the West Haven COEPCE polypharmacy faculty, a similar model of education and training will be implemented at other health professional training sites at Yale University in New Haven, Connecticut. Additionally, the West Haven CoEPCE is planning to partner with the other original CoEPCE program sites to implement similar interprofessional polypharmacy clinics.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

DESOGEN (DESOGESTREL AND ETHINYL ESTRADIOL TABLETS

• Edited boxed warning, June 2018

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age, and smoke.

TRIZIVIR (ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE TABLETS)

• Edited boxed warning, April 2018

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].

ERBITUX (CETUXIMAB)

• Edited boxed warning, June 2018

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration (2.4)].

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions (5.2, 5.6)].

AUSTEDO (DEUTETRABENAZINE)

• Edited boxed warning, June 2018

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression …

EXJADE (DEFERASIROX)

• Edited boxed warning, May 2018

Renal Failure: EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with pre-existing renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE)

• Edited boxed warning, June 2018

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME.

Addiction, Abuse, and Misuse: TUXARIN ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression
are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each
patient’s risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient
treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of TUXARIN ER.
Monitor for respiratory depression, especially during initiation of TUXARIN ER therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion: Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life threatening
respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. [see Warnings and Precautions (5.3)]. TUXARIN ER is contraindicated in children younger than 12 years of age and
in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUXARIN ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. [see Warnings and Precautions (5.1)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.8), Drug Interactions (7.1,7.2, 7.4)]

Risks from Concomitant Use with Benzodiazepines, CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of TUXARIN ER in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.9) Drug Interactions (7.5)].

Neonatal Opioid Withdrawal Syndrome: TUXARIN ER is not recommended for use in pregnant women [see Use in Specific Populations
(8.1)]. Prolonged use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUXARIN ER is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.15)].

PROGRAF (TACROLIMUS)

• Edited boxed warning, May 2018

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death [(see Warnings and Precautions 5.1,5.2)].

SAMSCA (TOLVAPTAN)

• Edited boxed warning, April 2018

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

GLUCOPHAGE/GLUCOPHAGE XR (METFORMIN HYDROCHLORIDE)

• Edited boxed warning, May 2018

PLR conversion; Lactic Acidosis warning is highlighted as boxed warning.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

DESOGEN (DESOGESTREL AND ETHINYL ESTRADIOL TABLETS

• Edited boxed warning, June 2018

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age, and smoke.

TRIZIVIR (ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE TABLETS)

• Edited boxed warning, April 2018

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].

ERBITUX (CETUXIMAB)

• Edited boxed warning, June 2018

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration (2.4)].

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions (5.2, 5.6)].

AUSTEDO (DEUTETRABENAZINE)

• Edited boxed warning, June 2018

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression …

EXJADE (DEFERASIROX)

• Edited boxed warning, May 2018

Renal Failure: EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with pre-existing renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE)

• Edited boxed warning, June 2018

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME.

Addiction, Abuse, and Misuse: TUXARIN ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression
are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each
patient’s risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient
treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of TUXARIN ER.
Monitor for respiratory depression, especially during initiation of TUXARIN ER therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion: Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life threatening
respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. [see Warnings and Precautions (5.3)]. TUXARIN ER is contraindicated in children younger than 12 years of age and
in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUXARIN ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. [see Warnings and Precautions (5.1)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.8), Drug Interactions (7.1,7.2, 7.4)]

Risks from Concomitant Use with Benzodiazepines, CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of TUXARIN ER in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.9) Drug Interactions (7.5)].

Neonatal Opioid Withdrawal Syndrome: TUXARIN ER is not recommended for use in pregnant women [see Use in Specific Populations
(8.1)]. Prolonged use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUXARIN ER is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.15)].

PROGRAF (TACROLIMUS)

• Edited boxed warning, May 2018

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death [(see Warnings and Precautions 5.1,5.2)].

SAMSCA (TOLVAPTAN)

• Edited boxed warning, April 2018

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

GLUCOPHAGE/GLUCOPHAGE XR (METFORMIN HYDROCHLORIDE)

• Edited boxed warning, May 2018

PLR conversion; Lactic Acidosis warning is highlighted as boxed warning.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

DESOGEN (DESOGESTREL AND ETHINYL ESTRADIOL TABLETS

• Edited boxed warning, June 2018

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age, and smoke.

TRIZIVIR (ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE TABLETS)

• Edited boxed warning, April 2018

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].

ERBITUX (CETUXIMAB)

• Edited boxed warning, June 2018

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration (2.4)].

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions (5.2, 5.6)].

AUSTEDO (DEUTETRABENAZINE)

• Edited boxed warning, June 2018

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression …

EXJADE (DEFERASIROX)

• Edited boxed warning, May 2018

Renal Failure: EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with pre-existing renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE)

• Edited boxed warning, June 2018

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME.

Addiction, Abuse, and Misuse: TUXARIN ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression
are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each
patient’s risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient
treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of TUXARIN ER.
Monitor for respiratory depression, especially during initiation of TUXARIN ER therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion: Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life threatening
respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. [see Warnings and Precautions (5.3)]. TUXARIN ER is contraindicated in children younger than 12 years of age and
in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUXARIN ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. [see Warnings and Precautions (5.1)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.8), Drug Interactions (7.1,7.2, 7.4)]

Risks from Concomitant Use with Benzodiazepines, CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of TUXARIN ER in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.9) Drug Interactions (7.5)].

Neonatal Opioid Withdrawal Syndrome: TUXARIN ER is not recommended for use in pregnant women [see Use in Specific Populations
(8.1)]. Prolonged use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUXARIN ER is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.15)].

PROGRAF (TACROLIMUS)

• Edited boxed warning, May 2018

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death [(see Warnings and Precautions 5.1,5.2)].

SAMSCA (TOLVAPTAN)

• Edited boxed warning, April 2018

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

GLUCOPHAGE/GLUCOPHAGE XR (METFORMIN HYDROCHLORIDE)

• Edited boxed warning, May 2018

PLR conversion; Lactic Acidosis warning is highlighted as boxed warning.

Immunocompromised patients are often susceptible to opportunistic infections, including those caused by multidrug-resistant organisms (MDROs). Transplant recipients are at high risk for developing infections due to lifelong immunosuppressive therapy.^1,2 Additionally, patients receiving chemotherapy and those with HIV and AIDS are in an immunocompromised state.^3-8

Regardless of the etiology for immunosuppression, decreased absolute neutrophil and platelet counts are seen in this condition. Although immunosuppressed individuals may be at increased risk of Gram-negative or Gram-positive infections, this review focuses on the treatment of Gram-positive bacterial infections. Of particular concern are opportunistic infections caused by Gram-positive MDROs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus species (VRE), penicillin-resistant Streptococcus pneumoniae, and Nocardia species. Treatment of infections in the immunocompromised patient population warrants careful antimicrobial selection to ensure that a patient’s immune system is not further compromised due to adverse effects (AEs) secondary to therapy. As such, clinicians are exploring alternative antimicrobials, such as tedizolid, to treat various opportunistic infections.

Recently, requests at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin, for off-label use of tedizolid have increased despite having other cheaper alternatives with comparable Gram-positive coverage. This review examines available literature regarding off-label use of tedizolid with a focus on use in immunocompromised patients.

Tedizolid phosphate (Sivextro) is an oxazolidinone antibiotic prodrug that joined linezolid as the second in its class in 2014. Oxazolidinones inhibit bacterial protein synthesis by binding to the 50S subunit of bacterial ribosomes in Gram-positive bacteria and are often used to treat MRSA and VRE infections.⁹ In vitro, oxazolidinones have shown bacteriostatic activity against Enterococcus and Staphylococcus species while exhibiting bactericidal activity against most Streptococcus species.¹⁰ Tedizolid has a US Food and Drug Administration (FDA) -approved, simplified dosing profile of 200 mg daily for 6 days compared with linezolid 400 to 600 mg twice daily for 10 to 14 days. Both medications are highly bioavailable with direct IV to oral conversion.^11,12 Potential, expanded use of tedizolid against Gram-positive MDROs rests on a more favorable AE profile than does its linezolid predecessor. Tedizolid has been associated with less antibiotic-induced myelosuppression, which could prove valuable for immunocompromised patients.¹³

Tedizolid is approved for the sole indication of acute bacterial skin and skin structure infections (ABSSSI), whereas its predecessor has many approved indications and has been used extensively for off-label indications (Table). 

Adverse reactions, as determined by 2 phase 2 and 2 phase 3 clinical trials evaluating 1,050 patients treated with tedizolid and 662 patients treated with linezolid, were similar between the oxazolidinones. Nausea was the most common AE and was reported in 8% and 12% of patients taking tedizolid and linezolid, respectively. Other common AEs (1%-6%) reported for both agents included vomiting, diarrhea, headache, and dizziness.¹¹ Myelosuppression, peripheral neuropathy, and optic nerve disorders were the most common severe AEs reported with oxazolidinones. Tedizolid demonstrated a significantly decreased incidence of neutropenia (3%), defined by absolute neutrophil count 9/L compared with that of linezolid (7%) (P = .024).¹³ Evaluation of peripheral neuropathy and optic nerve disorders within the tedizolid and linezolid groups revealed similar incidences (peripheral neuropathy 1.2% vs 0.6%; optic nerve disorders 0.3% vs 0.2%, respectively).¹¹

There is one preclinical trial that described the use of tedizolid in a murine model. A murine model study compared the antistaphylococcal killing effect of doses of tedizolid equivalent to human exposures ranging from 200 to 3,200 mg/d in both granulocytopenic and normal mice. The mice were evaluated at 24, 48, and 72 hours after therapy initiation. The presence of granulocytes had a dramatic effect on the antimicrobial effect of tedizolid. Dose response, demonstrated by the ratio of the area under the curve over the minimum inhibitory concentration, was on average > 25-fold for nonneutropenic vs neutropenic models. Near maximal effect of the nonneutropenic group, irrespective of duration of therapy, was achieved at the lowest dose tested (an exposure of about 200-mg tedizolid phosphate per day in humans).This study suggests that immunocompromised patients may warrant higher doses of tedizolid than the currently FDA-approved dose due to a decreased number of granulocytes available for modulating bacterial infections.¹⁵

Use of tedizolid doses higher than that which is FDA-approved may negate the favorable AE profile. A phase 1 clinical study was conducted to evaluate the safety, tolerability, and pharmacokinetics of tedizolid compared with those of linezolid in 40 healthy volunteers in a 21-day multiple ascending dose study.¹⁶ Subjects were stratified into 5 treatment cohorts: 200-, 300-, or 400-mg tedizolid orally once a day, 600-mg linezolid orally twice a day, and placebo. Tedizolid given at 200 mg had a hematologic safety profile similar to that of placebo. However, mean platelet counts decreased over time in a dose-dependent manner for tedizolid, with the 400-mg tedizolid and linezolid groups reporting similar reductions in platelet counts.¹⁶

Some evidence is available examining linezolid in neutropenic patients. Rafailidis and colleagues reviewed available literature regarding linezolid in neutropenic patients with Gram-positive infections. Evaluation of linezolid administration at usual doses to 438 neutropenic patients from 2 prospective comparative studies, a prospective cohort study, 2 retrospective studies, and 8 case reports was performed. Results of the evaluation revealed a clinical cure rate between 57% and 87% in the intention-to-treat population of the prospective studies.¹⁷ Given the similarities in bacterial spectrum of activity between linezolid and tedizolid, it may be reasonable to infer that tedizolid’s decreased myelosuppression profile would make it useful in the setting of neutropenia in immunocompromised patients.

There is little evidence regarding the use of tedizolid in immunocompromised patients, as only 2 case reports were found. The first described a 60-year-old male postrenal transplant complicated with VRE bacteremia, rhabdomyolysis, and thrombocytopenia. This patient was treated with prolonged tedizolid 200 mg daily due to multiple contraindications for treatment with other antibiotics. The patient was cured with a 14-day course of tedizolid without any noted AEs.¹⁸

The second identified case report described the use of tedizolid for the treatment of central nervous system (CNS) manifestations secondary to nocardiosis. Effective treatment of CNS nocardiosis requires high concentrations and prolonged duration of antimicrobial exposure. This case report described a 68-year-old, chronically immunocompromised female patient with multiple myeloma who was hospitalized for 3 months for the treatment of a CNS nocardiosis infection. After discharge, the patient was treated with an oral regimen of 200-mg tedizolid daily in combination with sulfamethoxazole/trimethoprim (800 mg/160 mg) 3 times daily. After 6 months of combination therapy, magnetic resonance imaging revealed complete resolution of nocardiosis-related central lesions. Although the patient’s malignancy advanced during combination antibiotic therapy, the patient’s absolute neutrophil count remained stable and showed an increase in absolute CD4+ cell counts with no other documented AEs.¹⁹

Tedizolid is the latest FDA-approved oxazolidinone antibiotic for susceptible Gram-positive acute bacterial skin and skin structure infections. It has a simplified and shorter duration of treatment and imparts similar AEs at improved rates compared with that of linezolid, most notably in relation to hematologic AEs. Due to the lack of established literature and an agreed-upon dosing strategy for the use of tedizolid in immunocompromised patients, tedizolid therapy for Gram-positive infections in immunocompromised patients should be reserved for salvage therapy when more established Gram-positive antibiotic agents lack efficacy or when patient contraindications to their use exist.

Immunocompromised patients are often susceptible to opportunistic infections, including those caused by multidrug-resistant organisms (MDROs). Transplant recipients are at high risk for developing infections due to lifelong immunosuppressive therapy.^1,2 Additionally, patients receiving chemotherapy and those with HIV and AIDS are in an immunocompromised state.^3-8

Regardless of the etiology for immunosuppression, decreased absolute neutrophil and platelet counts are seen in this condition. Although immunosuppressed individuals may be at increased risk of Gram-negative or Gram-positive infections, this review focuses on the treatment of Gram-positive bacterial infections. Of particular concern are opportunistic infections caused by Gram-positive MDROs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus species (VRE), penicillin-resistant Streptococcus pneumoniae, and Nocardia species. Treatment of infections in the immunocompromised patient population warrants careful antimicrobial selection to ensure that a patient’s immune system is not further compromised due to adverse effects (AEs) secondary to therapy. As such, clinicians are exploring alternative antimicrobials, such as tedizolid, to treat various opportunistic infections.

Recently, requests at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin, for off-label use of tedizolid have increased despite having other cheaper alternatives with comparable Gram-positive coverage. This review examines available literature regarding off-label use of tedizolid with a focus on use in immunocompromised patients.

Tedizolid phosphate (Sivextro) is an oxazolidinone antibiotic prodrug that joined linezolid as the second in its class in 2014. Oxazolidinones inhibit bacterial protein synthesis by binding to the 50S subunit of bacterial ribosomes in Gram-positive bacteria and are often used to treat MRSA and VRE infections.⁹ In vitro, oxazolidinones have shown bacteriostatic activity against Enterococcus and Staphylococcus species while exhibiting bactericidal activity against most Streptococcus species.¹⁰ Tedizolid has a US Food and Drug Administration (FDA) -approved, simplified dosing profile of 200 mg daily for 6 days compared with linezolid 400 to 600 mg twice daily for 10 to 14 days. Both medications are highly bioavailable with direct IV to oral conversion.^11,12 Potential, expanded use of tedizolid against Gram-positive MDROs rests on a more favorable AE profile than does its linezolid predecessor. Tedizolid has been associated with less antibiotic-induced myelosuppression, which could prove valuable for immunocompromised patients.¹³

Tedizolid is approved for the sole indication of acute bacterial skin and skin structure infections (ABSSSI), whereas its predecessor has many approved indications and has been used extensively for off-label indications (Table). 

Adverse reactions, as determined by 2 phase 2 and 2 phase 3 clinical trials evaluating 1,050 patients treated with tedizolid and 662 patients treated with linezolid, were similar between the oxazolidinones. Nausea was the most common AE and was reported in 8% and 12% of patients taking tedizolid and linezolid, respectively. Other common AEs (1%-6%) reported for both agents included vomiting, diarrhea, headache, and dizziness.¹¹ Myelosuppression, peripheral neuropathy, and optic nerve disorders were the most common severe AEs reported with oxazolidinones. Tedizolid demonstrated a significantly decreased incidence of neutropenia (3%), defined by absolute neutrophil count 9/L compared with that of linezolid (7%) (P = .024).¹³ Evaluation of peripheral neuropathy and optic nerve disorders within the tedizolid and linezolid groups revealed similar incidences (peripheral neuropathy 1.2% vs 0.6%; optic nerve disorders 0.3% vs 0.2%, respectively).¹¹

There is one preclinical trial that described the use of tedizolid in a murine model. A murine model study compared the antistaphylococcal killing effect of doses of tedizolid equivalent to human exposures ranging from 200 to 3,200 mg/d in both granulocytopenic and normal mice. The mice were evaluated at 24, 48, and 72 hours after therapy initiation. The presence of granulocytes had a dramatic effect on the antimicrobial effect of tedizolid. Dose response, demonstrated by the ratio of the area under the curve over the minimum inhibitory concentration, was on average > 25-fold for nonneutropenic vs neutropenic models. Near maximal effect of the nonneutropenic group, irrespective of duration of therapy, was achieved at the lowest dose tested (an exposure of about 200-mg tedizolid phosphate per day in humans).This study suggests that immunocompromised patients may warrant higher doses of tedizolid than the currently FDA-approved dose due to a decreased number of granulocytes available for modulating bacterial infections.¹⁵

Use of tedizolid doses higher than that which is FDA-approved may negate the favorable AE profile. A phase 1 clinical study was conducted to evaluate the safety, tolerability, and pharmacokinetics of tedizolid compared with those of linezolid in 40 healthy volunteers in a 21-day multiple ascending dose study.¹⁶ Subjects were stratified into 5 treatment cohorts: 200-, 300-, or 400-mg tedizolid orally once a day, 600-mg linezolid orally twice a day, and placebo. Tedizolid given at 200 mg had a hematologic safety profile similar to that of placebo. However, mean platelet counts decreased over time in a dose-dependent manner for tedizolid, with the 400-mg tedizolid and linezolid groups reporting similar reductions in platelet counts.¹⁶

Some evidence is available examining linezolid in neutropenic patients. Rafailidis and colleagues reviewed available literature regarding linezolid in neutropenic patients with Gram-positive infections. Evaluation of linezolid administration at usual doses to 438 neutropenic patients from 2 prospective comparative studies, a prospective cohort study, 2 retrospective studies, and 8 case reports was performed. Results of the evaluation revealed a clinical cure rate between 57% and 87% in the intention-to-treat population of the prospective studies.¹⁷ Given the similarities in bacterial spectrum of activity between linezolid and tedizolid, it may be reasonable to infer that tedizolid’s decreased myelosuppression profile would make it useful in the setting of neutropenia in immunocompromised patients.

There is little evidence regarding the use of tedizolid in immunocompromised patients, as only 2 case reports were found. The first described a 60-year-old male postrenal transplant complicated with VRE bacteremia, rhabdomyolysis, and thrombocytopenia. This patient was treated with prolonged tedizolid 200 mg daily due to multiple contraindications for treatment with other antibiotics. The patient was cured with a 14-day course of tedizolid without any noted AEs.¹⁸

The second identified case report described the use of tedizolid for the treatment of central nervous system (CNS) manifestations secondary to nocardiosis. Effective treatment of CNS nocardiosis requires high concentrations and prolonged duration of antimicrobial exposure. This case report described a 68-year-old, chronically immunocompromised female patient with multiple myeloma who was hospitalized for 3 months for the treatment of a CNS nocardiosis infection. After discharge, the patient was treated with an oral regimen of 200-mg tedizolid daily in combination with sulfamethoxazole/trimethoprim (800 mg/160 mg) 3 times daily. After 6 months of combination therapy, magnetic resonance imaging revealed complete resolution of nocardiosis-related central lesions. Although the patient’s malignancy advanced during combination antibiotic therapy, the patient’s absolute neutrophil count remained stable and showed an increase in absolute CD4+ cell counts with no other documented AEs.¹⁹

Tedizolid is the latest FDA-approved oxazolidinone antibiotic for susceptible Gram-positive acute bacterial skin and skin structure infections. It has a simplified and shorter duration of treatment and imparts similar AEs at improved rates compared with that of linezolid, most notably in relation to hematologic AEs. Due to the lack of established literature and an agreed-upon dosing strategy for the use of tedizolid in immunocompromised patients, tedizolid therapy for Gram-positive infections in immunocompromised patients should be reserved for salvage therapy when more established Gram-positive antibiotic agents lack efficacy or when patient contraindications to their use exist.

Immunocompromised patients are often susceptible to opportunistic infections, including those caused by multidrug-resistant organisms (MDROs). Transplant recipients are at high risk for developing infections due to lifelong immunosuppressive therapy.^1,2 Additionally, patients receiving chemotherapy and those with HIV and AIDS are in an immunocompromised state.^3-8

Regardless of the etiology for immunosuppression, decreased absolute neutrophil and platelet counts are seen in this condition. Although immunosuppressed individuals may be at increased risk of Gram-negative or Gram-positive infections, this review focuses on the treatment of Gram-positive bacterial infections. Of particular concern are opportunistic infections caused by Gram-positive MDROs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus species (VRE), penicillin-resistant Streptococcus pneumoniae, and Nocardia species. Treatment of infections in the immunocompromised patient population warrants careful antimicrobial selection to ensure that a patient’s immune system is not further compromised due to adverse effects (AEs) secondary to therapy. As such, clinicians are exploring alternative antimicrobials, such as tedizolid, to treat various opportunistic infections.

Recently, requests at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin, for off-label use of tedizolid have increased despite having other cheaper alternatives with comparable Gram-positive coverage. This review examines available literature regarding off-label use of tedizolid with a focus on use in immunocompromised patients.

Tedizolid phosphate (Sivextro) is an oxazolidinone antibiotic prodrug that joined linezolid as the second in its class in 2014. Oxazolidinones inhibit bacterial protein synthesis by binding to the 50S subunit of bacterial ribosomes in Gram-positive bacteria and are often used to treat MRSA and VRE infections.⁹ In vitro, oxazolidinones have shown bacteriostatic activity against Enterococcus and Staphylococcus species while exhibiting bactericidal activity against most Streptococcus species.¹⁰ Tedizolid has a US Food and Drug Administration (FDA) -approved, simplified dosing profile of 200 mg daily for 6 days compared with linezolid 400 to 600 mg twice daily for 10 to 14 days. Both medications are highly bioavailable with direct IV to oral conversion.^11,12 Potential, expanded use of tedizolid against Gram-positive MDROs rests on a more favorable AE profile than does its linezolid predecessor. Tedizolid has been associated with less antibiotic-induced myelosuppression, which could prove valuable for immunocompromised patients.¹³

Tedizolid is approved for the sole indication of acute bacterial skin and skin structure infections (ABSSSI), whereas its predecessor has many approved indications and has been used extensively for off-label indications (Table). 

Adverse reactions, as determined by 2 phase 2 and 2 phase 3 clinical trials evaluating 1,050 patients treated with tedizolid and 662 patients treated with linezolid, were similar between the oxazolidinones. Nausea was the most common AE and was reported in 8% and 12% of patients taking tedizolid and linezolid, respectively. Other common AEs (1%-6%) reported for both agents included vomiting, diarrhea, headache, and dizziness.¹¹ Myelosuppression, peripheral neuropathy, and optic nerve disorders were the most common severe AEs reported with oxazolidinones. Tedizolid demonstrated a significantly decreased incidence of neutropenia (3%), defined by absolute neutrophil count 9/L compared with that of linezolid (7%) (P = .024).¹³ Evaluation of peripheral neuropathy and optic nerve disorders within the tedizolid and linezolid groups revealed similar incidences (peripheral neuropathy 1.2% vs 0.6%; optic nerve disorders 0.3% vs 0.2%, respectively).¹¹

There is one preclinical trial that described the use of tedizolid in a murine model. A murine model study compared the antistaphylococcal killing effect of doses of tedizolid equivalent to human exposures ranging from 200 to 3,200 mg/d in both granulocytopenic and normal mice. The mice were evaluated at 24, 48, and 72 hours after therapy initiation. The presence of granulocytes had a dramatic effect on the antimicrobial effect of tedizolid. Dose response, demonstrated by the ratio of the area under the curve over the minimum inhibitory concentration, was on average > 25-fold for nonneutropenic vs neutropenic models. Near maximal effect of the nonneutropenic group, irrespective of duration of therapy, was achieved at the lowest dose tested (an exposure of about 200-mg tedizolid phosphate per day in humans).This study suggests that immunocompromised patients may warrant higher doses of tedizolid than the currently FDA-approved dose due to a decreased number of granulocytes available for modulating bacterial infections.¹⁵

Use of tedizolid doses higher than that which is FDA-approved may negate the favorable AE profile. A phase 1 clinical study was conducted to evaluate the safety, tolerability, and pharmacokinetics of tedizolid compared with those of linezolid in 40 healthy volunteers in a 21-day multiple ascending dose study.¹⁶ Subjects were stratified into 5 treatment cohorts: 200-, 300-, or 400-mg tedizolid orally once a day, 600-mg linezolid orally twice a day, and placebo. Tedizolid given at 200 mg had a hematologic safety profile similar to that of placebo. However, mean platelet counts decreased over time in a dose-dependent manner for tedizolid, with the 400-mg tedizolid and linezolid groups reporting similar reductions in platelet counts.¹⁶

Some evidence is available examining linezolid in neutropenic patients. Rafailidis and colleagues reviewed available literature regarding linezolid in neutropenic patients with Gram-positive infections. Evaluation of linezolid administration at usual doses to 438 neutropenic patients from 2 prospective comparative studies, a prospective cohort study, 2 retrospective studies, and 8 case reports was performed. Results of the evaluation revealed a clinical cure rate between 57% and 87% in the intention-to-treat population of the prospective studies.¹⁷ Given the similarities in bacterial spectrum of activity between linezolid and tedizolid, it may be reasonable to infer that tedizolid’s decreased myelosuppression profile would make it useful in the setting of neutropenia in immunocompromised patients.

There is little evidence regarding the use of tedizolid in immunocompromised patients, as only 2 case reports were found. The first described a 60-year-old male postrenal transplant complicated with VRE bacteremia, rhabdomyolysis, and thrombocytopenia. This patient was treated with prolonged tedizolid 200 mg daily due to multiple contraindications for treatment with other antibiotics. The patient was cured with a 14-day course of tedizolid without any noted AEs.¹⁸

The second identified case report described the use of tedizolid for the treatment of central nervous system (CNS) manifestations secondary to nocardiosis. Effective treatment of CNS nocardiosis requires high concentrations and prolonged duration of antimicrobial exposure. This case report described a 68-year-old, chronically immunocompromised female patient with multiple myeloma who was hospitalized for 3 months for the treatment of a CNS nocardiosis infection. After discharge, the patient was treated with an oral regimen of 200-mg tedizolid daily in combination with sulfamethoxazole/trimethoprim (800 mg/160 mg) 3 times daily. After 6 months of combination therapy, magnetic resonance imaging revealed complete resolution of nocardiosis-related central lesions. Although the patient’s malignancy advanced during combination antibiotic therapy, the patient’s absolute neutrophil count remained stable and showed an increase in absolute CD4+ cell counts with no other documented AEs.¹⁹

Tedizolid is the latest FDA-approved oxazolidinone antibiotic for susceptible Gram-positive acute bacterial skin and skin structure infections. It has a simplified and shorter duration of treatment and imparts similar AEs at improved rates compared with that of linezolid, most notably in relation to hematologic AEs. Due to the lack of established literature and an agreed-upon dosing strategy for the use of tedizolid in immunocompromised patients, tedizolid therapy for Gram-positive infections in immunocompromised patients should be reserved for salvage therapy when more established Gram-positive antibiotic agents lack efficacy or when patient contraindications to their use exist.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

VIDEX AND VIDEX EC (DIDANOSINE):

• Edited boxed warning, January 2018

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

Coadministration of VIDEX or VIDEX EC and stavudine is contraindicated because of increased risk of serious and/or life-threatening events. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occurs.

ZYDELIG (IDELALISIB):

• Edited boxed warning, January 2018

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients…

Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients…

Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients…

AQUAMEPHYTON (PHYTONADIONE):

• Edited boxed warning, March 2018

WARNING: HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE

Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after INTRAVENOUS and INTRAMUSCULAR injection of Aqua-MEPHYTON. Reactions have occurred despite dilution to avoid rapid infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified.

FERAHEME (FERUMOXYTOL):

• Edited boxed warning, February 2018

WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS

Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients receiving feraheme. Initial symptoms may
include hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest.

Only administer feraheme as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

METHADONE HYDROCHLORIDE, METHADOSE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death.

Reserve concomitant prescribing of benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting daily methadone dosing.

DOLOPHINE HYDROCHLORIDE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of DOLOPHINE Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Limit dosages and durations to the minimum required for patients being treated for pain.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting the daily methadone dose.

PARNATE (TRANYLCYPROMINE SULFATE):

• Edited boxed warning, January 2018

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS AND HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE

SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. PARNATE is not approved for use in pediatric patients.

HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE
Excessive consumption of foods or beverages with significant tyramine content or the use of certain drugs with PARNATE or after PARNATE discontinuation can precipitate hypertensive crisis. Monitor blood pressure and allow for medication-free intervals between administration of PARNATE and interacting drugs. Instruct patients to avoid ingestion of foods and beverages with high tyramine content.

OCALIVA (OBETICHOLIC ACID):

• New boxed warning/Newly added section, February 2018

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.

The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

VIDEX AND VIDEX EC (DIDANOSINE):

• Edited boxed warning, January 2018

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

Coadministration of VIDEX or VIDEX EC and stavudine is contraindicated because of increased risk of serious and/or life-threatening events. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occurs.

ZYDELIG (IDELALISIB):

• Edited boxed warning, January 2018

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients…

Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients…

Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients…

AQUAMEPHYTON (PHYTONADIONE):

• Edited boxed warning, March 2018

WARNING: HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE

Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after INTRAVENOUS and INTRAMUSCULAR injection of Aqua-MEPHYTON. Reactions have occurred despite dilution to avoid rapid infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified.

FERAHEME (FERUMOXYTOL):

• Edited boxed warning, February 2018

WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS

Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients receiving feraheme. Initial symptoms may
include hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest.

Only administer feraheme as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

METHADONE HYDROCHLORIDE, METHADOSE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death.

Reserve concomitant prescribing of benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting daily methadone dosing.

DOLOPHINE HYDROCHLORIDE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of DOLOPHINE Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Limit dosages and durations to the minimum required for patients being treated for pain.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting the daily methadone dose.

PARNATE (TRANYLCYPROMINE SULFATE):

• Edited boxed warning, January 2018

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS AND HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE

SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. PARNATE is not approved for use in pediatric patients.

HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE
Excessive consumption of foods or beverages with significant tyramine content or the use of certain drugs with PARNATE or after PARNATE discontinuation can precipitate hypertensive crisis. Monitor blood pressure and allow for medication-free intervals between administration of PARNATE and interacting drugs. Instruct patients to avoid ingestion of foods and beverages with high tyramine content.

OCALIVA (OBETICHOLIC ACID):

• New boxed warning/Newly added section, February 2018

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.

The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

VIDEX AND VIDEX EC (DIDANOSINE):

• Edited boxed warning, January 2018

WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

Coadministration of VIDEX or VIDEX EC and stavudine is contraindicated because of increased risk of serious and/or life-threatening events. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occurs.

ZYDELIG (IDELALISIB):

• Edited boxed warning, January 2018

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients…

Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients…

Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients…

AQUAMEPHYTON (PHYTONADIONE):

• Edited boxed warning, March 2018

WARNING: HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE

Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after INTRAVENOUS and INTRAMUSCULAR injection of Aqua-MEPHYTON. Reactions have occurred despite dilution to avoid rapid infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified.

FERAHEME (FERUMOXYTOL):

• Edited boxed warning, February 2018

WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS

Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients receiving feraheme. Initial symptoms may
include hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest.

Only administer feraheme as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

METHADONE HYDROCHLORIDE, METHADOSE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death.

Reserve concomitant prescribing of benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting daily methadone dosing.

DOLOPHINE HYDROCHLORIDE (METHADONE HYDROCHLORIDE):

• Edited boxed warning, February 2018

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of DOLOPHINE Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

Limit dosages and durations to the minimum required for patients being treated for pain.

Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting the daily methadone dose.

PARNATE (TRANYLCYPROMINE SULFATE):

• Edited boxed warning, January 2018

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS AND HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE

SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. PARNATE is not approved for use in pediatric patients.

HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE
Excessive consumption of foods or beverages with significant tyramine content or the use of certain drugs with PARNATE or after PARNATE discontinuation can precipitate hypertensive crisis. Monitor blood pressure and allow for medication-free intervals between administration of PARNATE and interacting drugs. Instruct patients to avoid ingestion of foods and beverages with high tyramine content.

OCALIVA (OBETICHOLIC ACID):

• New boxed warning/Newly added section, February 2018

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended.

The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event.

According to the US Department of Veterans Affairs (VA) Pharmacy Benefits Management Service, about 80% of all outpatient prescriptions filled by the VA are sent to veterans by mail order, using the Centralized Mail Order Pharmacy (CMOP) network of highly automated pharmacies around the country.¹ During fiscal year (FY) 2016, the 7 VA CMOP facilities throughout the US processed 119.7 million outpatient prescriptions. Each day, these CMOPs process nearly 470,000 prescriptions, an evidence of the efficiency provided through this mail-order service.¹ The use of CMOP results in lower processing costs and increased convenience for veterans compared with filling prescriptions at pharmacies at individual VA facilities. Notably, VA CMOP has been rated “among the best” mail-order pharmacies in customer satisfaction according to the 2017 J.D. Power US Pharmacy Study.²

Background

Within the Fayetteville VA Medical Center (FVAMC) system in North Carolina, on-site patients receive a new prescription where an on-site pharmacy is available (at health care centers [HCC] and the medical center). For veterans seen at community-based outpatient clinics (CBOCs), emergent new prescriptions are filled through vouchers at contract community pharmacies, and nonemergent new prescriptions are filled by the CMOP (Figure 1). 

The appropriate use of the VA CMOP for refills is intended to allow on-site pharmacy staff to focus on providing customer service for veterans requesting medication counseling from a clinical pharmacist, as well as those with new, changing, or urgent prescription needs. Filling prescriptions through the CMOP also can help control the VA facility pharmacy budget.

Despite the established mail-order process, FVAMC staff noted a high volume of medication refill and partial-fill prescriptions being requested at the on-site pharmacy. When a veteran presented to a pharmacy requesting a medication refill, pharmacy staff members ordered a refill to be filled by the CMOP and provided a limited quantity, otherwise known as a partial fill, to serve as an emergency supply to supplement the veteran until the full quantity of the prescription arrived by mail. Partial fills also were completed for new prescriptions that veterans requested to pick up at the on-site pharmacy. For new 90-day supply prescriptions, pharmacy staff often filled a 30-day supply in addition to submitting the entire 90-day prescription through the CMOP, which led to an unnecessary increase in material expenditures and workload.Preliminary data noted the most frequently used partial-fill days’ supply to be 10 days. Due to the lack of partial-fill criteria, prescriptions of all classes, quantities, and days’ supplies were provided as partial fills. Prior to the implementation of this quality improvement (QI) project, there was no standard approach for how to handle these requests.

Partial fills do not provide copay reimbursement to the facility filling the prescription. In an effort to steward the funds provided to the FVAMC pharmacy department wisely, an evaluation was performed with reference to partial fills. During FY 2016, about $350,000 was spent on medications, materials, and workload associated with the partial filling of FVAMC prescriptions. With respect to unique individuals who were provided care over the course of FY 2015 and 2016, the number of unique patients served by local comparator hospitals increased by only 2%, while the number of unique patients served by FVAMC increased by 12%. This substantial growth in the number of veterans served places further emphasis on the necessity of stewarding the allotted pharmacy budget. Moreover, the excessive number of medication refill and partial-fill prescriptions filled at on-site VA pharmacies can contribute to increased wait times for veterans with urgent prescription needs.

In November 2016, FVAMC implemented an updated partial-fill guidance. Partial-fill process and refill education was provided for VA staff and veterans in an effort to allow all parties involved to use pharmacy services efficiently. This analysis reviewed the reduction in partial-fill expenditures with a secondary focus on workload expenditures following the execution of this education.

Methods

This project was deemed to be a QI project and did not require institutional review board approval. Implementation for this QI project began in November 2016. Baseline raw drug cost, number, and class of prescriptions partialed were retrospectively collected for a 90-day period prior to implementation using all available data. Postintervention data were collected for 90 days following the implementation phase to compare partial-fill expenditures and workload expenditures with baseline data.

Calculations

Materials included in the partial-fill expenditure calculation were prescription vials, prescription vial caps, and prescription labeling. Material cost per partial fill was determined by using the facility’s wholesaler acquisition unit costs to estimate a summed cost for an individual prescription vial and prescription vial cap. The estimated acquisition price of 7 prescription-labeling pages was used in the material calculation, as this was the average number of pages used when performing test partial fills.

The following equation was used to calculate total partial-fill expenditures for any specified time frame:

Total partial-fill expenditure = total raw drug cost + (material cost × number of partial fills)

In addition, the average personnel cost per partial-fill prescription was determined. Average workload expenditure per partial fill was calculated by filling a subset of 10 test prescriptions and multiplying the average time spent by an average of the general station (GS) rate for pharmacists and technicians. The average hourly rate of a GS-12 pharmacist was calculated based on an average of the 10 available pay grades within the GS-12 ranking. The average hourly rate of a GS-6 pharmacy technician was calculated based on an average of the 10 available pay grades within the GS-6 ranking.³ The average workload expenditures were calculated using the following equations:

Average pharmacist workload expenditure per partial fill = time (in hours) × average hourly rate.

Average technician workload expenditure per partial fill = time (in hours) × average hourly rate.

Partial-Fill Guidance

Updated partial-fill guidance was drafted designating acceptable prescriptions to be limited to those responsible for preventing hospitalization and treatment of acute illness. This guidance provided generalized examples of medication classes that could be acceptable for partial filling, though it was not intended to be an all-inclusive list. The guidance also noted examples of classes or groups that should not be partial filled for nonemergent reasons (vitamins, nonprescription items, antilipemics), as well as controlled substances. The refill-process education was reiterated throughout the entirety of the guidance. Specifically, if a pharmacy staff member was to perform a partial fill, a review explaining the appropriate refill process to the veteran also must be provided. If the medication was determined to be of emergent need and not yet transmitted for filling via the CMOP, the directive recommended to fill the entire quantity locally as a onetime fill.

If a onetime on-site fill was determined infeasible, partial-fill quantities were recommended to be limited to only a 7-day supply, and the full quantity filled through the CMOP. Anticipated mail wait time for CMOP prescription delivery was estimated to be less than 7 days based on experience, local pending queues, and guidance from the regional CMOP; however, time could vary among VA and CMOP facilities. Original prescriptions were to be filled for the entire quantity for the first fill at the on-site pharmacy if requested by the veteran. If the pharmacy had an insufficient quantity for an entire initial supply, it could then be partial filled for a 7-day supply and then filled through the CMOP.

The final portion of the partial-fill guidance pertained to the use of partial-fill justification codes. Prior to the execution of the partial-fill guidance, free text was entered into the comments field when processing a partial-fill prescription, as the prescription-processing system used requires a comment to proceed with the partial fill. The use of these codes served to streamline data collection in the postintervention phase and helped identify areas for further education following the close of this project.

Education

Education to the pharmacy staff was disseminated by various modalities, including in-person sessions and written and electronic correspondences. This written guidance was distributed to pharmacy staff by e-mail, the pharmacy newsletter (R_x-tra), signage posted throughout the outpatient pharmacies, and on the facility’s pharmacy Microsoft SharePoint (Redmond, WA) site. In-services provided during pharmacy staff meetings detailed information on the updated partial-fill guidance. A FVAMC Talent Management System (TMS) training module was developed and assigned to all pharmacy service staff to reiterate key points regarding this QI initiative (eAppendix).

Nonpharmacy staff were educated through staff and in-service meetings and e-mail correspondences. These in-services emphasized how nurses, medical support assistants, and health care providers (HCPs) could assist veterans by knowing the correct refill process, ensuring sufficient refills remained until the next appointment, and providing continual refill-process education.

Following implementation, all veterans receiving prescriptions through the on-site pharmacies in the FVAMC were provided a copy of the refill-process handout with each trip to the pharmacy. Nonpharmacy staff and HCPs also were provided this handout to distribute to patients. The intent of this handout was to clearly detail the various ways in which refills could be ordered and the time frame in which they should be ordered. The pharmacy became involved in new patient orientation classes for all veterans new to FVAMC. Digital signage and messaging was created and circulated throughout several of the FVAMC facilities.

Results

The results of calculations for material cost, personnel time spent, hourly employee rates, and average workload expenditure per partial fill are summarized in Table 1.

Following the implementation of partial-fill and refill-process education, there was a 54.3% decrease in the total number of partial fills from 5,596 in the 90 days prior to implementation, to 2,555 partials completed over the 90 days postimplementation. Regarding the primary objective, total partial-fill expenditures decreased from $52,015.44 to $44,063.01 (-15.3%). When dissecting the individual components of partial-fill expenditures, material expenditures decreased from $1,454.96 to $664.28 (-54.3%), and raw drug cost expenditures decreased from $50,596.48 to $43,398.73 (-14.3%). Workload expenditures also decreased from $27,140.60 to $12,391.75 (-54.3%).

Several points of descriptive information also were collected. The average days’ supply trended down from a mode of 10 days to 7 days. This reduction in days’ supply likely was seen because staff became more aware of the customary amount required to bridge the veteran until the CMOP supply arrived by mail. Postintervention data showed a 70% utilization of partial-fill reasoning codes. The reasons for partial filling of prescriptions are summarized in Table 2. 

Discussion

Following the implementation of the updated partial-fill guidance and provision of education to the FVAMC veterans and staff, a noteworthy cost savings was observed with respect to both material and workload expenditures. This large reduction in expenditure likely was not related to a reduction in the total prescription volume, as the number of total prescriptions filled by the CMOP and at FVAMC were similar in both the preliminary and postintervention periods. When the results of this 3-month QI project were extrapolated, the annual projected cost avoidance was $91,949.12.

Of note, there was no established process for adjudicating appeals to the partial-fill guidance. Any extenuating circumstances that fell outside the guidance were addressed by the outpatient pharmacy supervisor. There was no formal documentation for these disputed cases. Since there was no prespecified supervisory override code, the most appropriate partial-fill code was entered into the comments field for these scenarios. As such, there is no way to distinguish precisely how many of these partial fills were escalated to a supervisory level for a decision.

The positive fiscal impact noted from the implementation of this project should not be viewed as the only utility for such guidance. Though not directly measured within the confines of this project, a reduction in pharmacy staff time spent on partial-fill prescriptions will likely result in shorter pharmacy wait times, line lengths, and streamlining of pharmacy workflow. When the pharmacy staff is free to work on pressing issues rather than on continually educating veterans on the partial-fill or refill process, many will benefit. Veteran satisfaction was not directly measured during this project but could be an interesting topic to review as a future study.

Each VA facility is unique, with its own challenges for implementation of a project such as this. Nevertheless, the incorporation of a formal guidance and education process, perhaps adapted to the indi vidual facility’s needs may be considered for overall pharmacy operations QI.

Limitations

During the preliminary data collection period, FVAMC and its catchment area were impacted by a natural disaster, Hurricane Matthew. Based on a review of the text entered into the comments field for all partial fills, about 4% of the partial fills completed in the preliminary phase can be attributed to the hurricane. The effects of this hurricane may have potentially increased the number of partial fills completed in the preliminary phase compared with that in the postintervention phase, due to the number of veterans who were temporarily or permanently displaced from their homes. This increase in partial fills and associated expenses preintervention likely caused a slightly higher cost savings to be reflected in the postimplementation phase than what would have traditionally been observed without extenuating factors.

Several other limitations must be considered for this QI project. The implementation phase, during which all education and training was completed, was only 1 month. A longer implementation period and more opportunities to educate veterans and staff might have created a greater impact on the results. Additionally, because there were no data collected on New Patient Orientation attendance for this project, it is unclear exactly how many veterans received refill-process education through this outlet.

Though all staff members were trained on the appropriate process, it was discovered during interim analysis that several pharmacists were not following the partial-fill guidance, potentially negatively impacting the results. It is likely that staff would have benefited from continual reeducation of the process throughout the entirety of the project, as the restriction of partial filling was a novel concept to many. In addition to continual reeducation of current employees, any new hires would likely need this information as part of initial training.

Cost variance in the type of partial fills completed between the preliminary and postintervention phases also may have negatively impacted the results. The postintervention phase contained 2 high-cost classes of drugs (antivirals and immunoglobulins) that received multiple partial fills but were not partialed in the preliminary phase, which increased the raw drug cost in the postintervention phase.

Conclusion

The implementation of partial-fill and process education to FVAMC staff and veterans proved beneficial in reducing the expenditures and workload associated with partial-fill prescription processing. The continued use of the updated partial-fill guidance will provide a standardized approach for pharmacy staff when completing partial-fill prescriptions.

Facilities may consider annual reeducation on their guidance through a local TMS module, as well as occasional process reminders during staff meetings to improve staff adherence to the guidance. Moreover, the sustained incorporation of improved refill process education to new patients and with every prescription pickup could help guide the FVAMC veteran population to use pharmacy services more effectively. The adoption of such procedures may be useful for VA facilities’ health care system looking to maximize the use of funding provided for prescription services as well as improve veterans’ understanding of how to appropriately order prescription refills.

According to the US Department of Veterans Affairs (VA) Pharmacy Benefits Management Service, about 80% of all outpatient prescriptions filled by the VA are sent to veterans by mail order, using the Centralized Mail Order Pharmacy (CMOP) network of highly automated pharmacies around the country.¹ During fiscal year (FY) 2016, the 7 VA CMOP facilities throughout the US processed 119.7 million outpatient prescriptions. Each day, these CMOPs process nearly 470,000 prescriptions, an evidence of the efficiency provided through this mail-order service.¹ The use of CMOP results in lower processing costs and increased convenience for veterans compared with filling prescriptions at pharmacies at individual VA facilities. Notably, VA CMOP has been rated “among the best” mail-order pharmacies in customer satisfaction according to the 2017 J.D. Power US Pharmacy Study.²

Background

Within the Fayetteville VA Medical Center (FVAMC) system in North Carolina, on-site patients receive a new prescription where an on-site pharmacy is available (at health care centers [HCC] and the medical center). For veterans seen at community-based outpatient clinics (CBOCs), emergent new prescriptions are filled through vouchers at contract community pharmacies, and nonemergent new prescriptions are filled by the CMOP (Figure 1). 

The appropriate use of the VA CMOP for refills is intended to allow on-site pharmacy staff to focus on providing customer service for veterans requesting medication counseling from a clinical pharmacist, as well as those with new, changing, or urgent prescription needs. Filling prescriptions through the CMOP also can help control the VA facility pharmacy budget.

Despite the established mail-order process, FVAMC staff noted a high volume of medication refill and partial-fill prescriptions being requested at the on-site pharmacy. When a veteran presented to a pharmacy requesting a medication refill, pharmacy staff members ordered a refill to be filled by the CMOP and provided a limited quantity, otherwise known as a partial fill, to serve as an emergency supply to supplement the veteran until the full quantity of the prescription arrived by mail. Partial fills also were completed for new prescriptions that veterans requested to pick up at the on-site pharmacy. For new 90-day supply prescriptions, pharmacy staff often filled a 30-day supply in addition to submitting the entire 90-day prescription through the CMOP, which led to an unnecessary increase in material expenditures and workload.Preliminary data noted the most frequently used partial-fill days’ supply to be 10 days. Due to the lack of partial-fill criteria, prescriptions of all classes, quantities, and days’ supplies were provided as partial fills. Prior to the implementation of this quality improvement (QI) project, there was no standard approach for how to handle these requests.

Partial fills do not provide copay reimbursement to the facility filling the prescription. In an effort to steward the funds provided to the FVAMC pharmacy department wisely, an evaluation was performed with reference to partial fills. During FY 2016, about $350,000 was spent on medications, materials, and workload associated with the partial filling of FVAMC prescriptions. With respect to unique individuals who were provided care over the course of FY 2015 and 2016, the number of unique patients served by local comparator hospitals increased by only 2%, while the number of unique patients served by FVAMC increased by 12%. This substantial growth in the number of veterans served places further emphasis on the necessity of stewarding the allotted pharmacy budget. Moreover, the excessive number of medication refill and partial-fill prescriptions filled at on-site VA pharmacies can contribute to increased wait times for veterans with urgent prescription needs.

In November 2016, FVAMC implemented an updated partial-fill guidance. Partial-fill process and refill education was provided for VA staff and veterans in an effort to allow all parties involved to use pharmacy services efficiently. This analysis reviewed the reduction in partial-fill expenditures with a secondary focus on workload expenditures following the execution of this education.

Methods

This project was deemed to be a QI project and did not require institutional review board approval. Implementation for this QI project began in November 2016. Baseline raw drug cost, number, and class of prescriptions partialed were retrospectively collected for a 90-day period prior to implementation using all available data. Postintervention data were collected for 90 days following the implementation phase to compare partial-fill expenditures and workload expenditures with baseline data.

Calculations

Materials included in the partial-fill expenditure calculation were prescription vials, prescription vial caps, and prescription labeling. Material cost per partial fill was determined by using the facility’s wholesaler acquisition unit costs to estimate a summed cost for an individual prescription vial and prescription vial cap. The estimated acquisition price of 7 prescription-labeling pages was used in the material calculation, as this was the average number of pages used when performing test partial fills.

The following equation was used to calculate total partial-fill expenditures for any specified time frame:

Total partial-fill expenditure = total raw drug cost + (material cost × number of partial fills)

In addition, the average personnel cost per partial-fill prescription was determined. Average workload expenditure per partial fill was calculated by filling a subset of 10 test prescriptions and multiplying the average time spent by an average of the general station (GS) rate for pharmacists and technicians. The average hourly rate of a GS-12 pharmacist was calculated based on an average of the 10 available pay grades within the GS-12 ranking. The average hourly rate of a GS-6 pharmacy technician was calculated based on an average of the 10 available pay grades within the GS-6 ranking.³ The average workload expenditures were calculated using the following equations:

Average pharmacist workload expenditure per partial fill = time (in hours) × average hourly rate.

Average technician workload expenditure per partial fill = time (in hours) × average hourly rate.

Partial-Fill Guidance

Updated partial-fill guidance was drafted designating acceptable prescriptions to be limited to those responsible for preventing hospitalization and treatment of acute illness. This guidance provided generalized examples of medication classes that could be acceptable for partial filling, though it was not intended to be an all-inclusive list. The guidance also noted examples of classes or groups that should not be partial filled for nonemergent reasons (vitamins, nonprescription items, antilipemics), as well as controlled substances. The refill-process education was reiterated throughout the entirety of the guidance. Specifically, if a pharmacy staff member was to perform a partial fill, a review explaining the appropriate refill process to the veteran also must be provided. If the medication was determined to be of emergent need and not yet transmitted for filling via the CMOP, the directive recommended to fill the entire quantity locally as a onetime fill.

If a onetime on-site fill was determined infeasible, partial-fill quantities were recommended to be limited to only a 7-day supply, and the full quantity filled through the CMOP. Anticipated mail wait time for CMOP prescription delivery was estimated to be less than 7 days based on experience, local pending queues, and guidance from the regional CMOP; however, time could vary among VA and CMOP facilities. Original prescriptions were to be filled for the entire quantity for the first fill at the on-site pharmacy if requested by the veteran. If the pharmacy had an insufficient quantity for an entire initial supply, it could then be partial filled for a 7-day supply and then filled through the CMOP.

The final portion of the partial-fill guidance pertained to the use of partial-fill justification codes. Prior to the execution of the partial-fill guidance, free text was entered into the comments field when processing a partial-fill prescription, as the prescription-processing system used requires a comment to proceed with the partial fill. The use of these codes served to streamline data collection in the postintervention phase and helped identify areas for further education following the close of this project.

Education

Education to the pharmacy staff was disseminated by various modalities, including in-person sessions and written and electronic correspondences. This written guidance was distributed to pharmacy staff by e-mail, the pharmacy newsletter (R_x-tra), signage posted throughout the outpatient pharmacies, and on the facility’s pharmacy Microsoft SharePoint (Redmond, WA) site. In-services provided during pharmacy staff meetings detailed information on the updated partial-fill guidance. A FVAMC Talent Management System (TMS) training module was developed and assigned to all pharmacy service staff to reiterate key points regarding this QI initiative (eAppendix).

Nonpharmacy staff were educated through staff and in-service meetings and e-mail correspondences. These in-services emphasized how nurses, medical support assistants, and health care providers (HCPs) could assist veterans by knowing the correct refill process, ensuring sufficient refills remained until the next appointment, and providing continual refill-process education.

Following implementation, all veterans receiving prescriptions through the on-site pharmacies in the FVAMC were provided a copy of the refill-process handout with each trip to the pharmacy. Nonpharmacy staff and HCPs also were provided this handout to distribute to patients. The intent of this handout was to clearly detail the various ways in which refills could be ordered and the time frame in which they should be ordered. The pharmacy became involved in new patient orientation classes for all veterans new to FVAMC. Digital signage and messaging was created and circulated throughout several of the FVAMC facilities.

Results

The results of calculations for material cost, personnel time spent, hourly employee rates, and average workload expenditure per partial fill are summarized in Table 1.

Following the implementation of partial-fill and refill-process education, there was a 54.3% decrease in the total number of partial fills from 5,596 in the 90 days prior to implementation, to 2,555 partials completed over the 90 days postimplementation. Regarding the primary objective, total partial-fill expenditures decreased from $52,015.44 to $44,063.01 (-15.3%). When dissecting the individual components of partial-fill expenditures, material expenditures decreased from $1,454.96 to $664.28 (-54.3%), and raw drug cost expenditures decreased from $50,596.48 to $43,398.73 (-14.3%). Workload expenditures also decreased from $27,140.60 to $12,391.75 (-54.3%).

Several points of descriptive information also were collected. The average days’ supply trended down from a mode of 10 days to 7 days. This reduction in days’ supply likely was seen because staff became more aware of the customary amount required to bridge the veteran until the CMOP supply arrived by mail. Postintervention data showed a 70% utilization of partial-fill reasoning codes. The reasons for partial filling of prescriptions are summarized in Table 2. 

Discussion

Following the implementation of the updated partial-fill guidance and provision of education to the FVAMC veterans and staff, a noteworthy cost savings was observed with respect to both material and workload expenditures. This large reduction in expenditure likely was not related to a reduction in the total prescription volume, as the number of total prescriptions filled by the CMOP and at FVAMC were similar in both the preliminary and postintervention periods. When the results of this 3-month QI project were extrapolated, the annual projected cost avoidance was $91,949.12.

Of note, there was no established process for adjudicating appeals to the partial-fill guidance. Any extenuating circumstances that fell outside the guidance were addressed by the outpatient pharmacy supervisor. There was no formal documentation for these disputed cases. Since there was no prespecified supervisory override code, the most appropriate partial-fill code was entered into the comments field for these scenarios. As such, there is no way to distinguish precisely how many of these partial fills were escalated to a supervisory level for a decision.

The positive fiscal impact noted from the implementation of this project should not be viewed as the only utility for such guidance. Though not directly measured within the confines of this project, a reduction in pharmacy staff time spent on partial-fill prescriptions will likely result in shorter pharmacy wait times, line lengths, and streamlining of pharmacy workflow. When the pharmacy staff is free to work on pressing issues rather than on continually educating veterans on the partial-fill or refill process, many will benefit. Veteran satisfaction was not directly measured during this project but could be an interesting topic to review as a future study.

Each VA facility is unique, with its own challenges for implementation of a project such as this. Nevertheless, the incorporation of a formal guidance and education process, perhaps adapted to the indi vidual facility’s needs may be considered for overall pharmacy operations QI.

Limitations

During the preliminary data collection period, FVAMC and its catchment area were impacted by a natural disaster, Hurricane Matthew. Based on a review of the text entered into the comments field for all partial fills, about 4% of the partial fills completed in the preliminary phase can be attributed to the hurricane. The effects of this hurricane may have potentially increased the number of partial fills completed in the preliminary phase compared with that in the postintervention phase, due to the number of veterans who were temporarily or permanently displaced from their homes. This increase in partial fills and associated expenses preintervention likely caused a slightly higher cost savings to be reflected in the postimplementation phase than what would have traditionally been observed without extenuating factors.

Several other limitations must be considered for this QI project. The implementation phase, during which all education and training was completed, was only 1 month. A longer implementation period and more opportunities to educate veterans and staff might have created a greater impact on the results. Additionally, because there were no data collected on New Patient Orientation attendance for this project, it is unclear exactly how many veterans received refill-process education through this outlet.

Though all staff members were trained on the appropriate process, it was discovered during interim analysis that several pharmacists were not following the partial-fill guidance, potentially negatively impacting the results. It is likely that staff would have benefited from continual reeducation of the process throughout the entirety of the project, as the restriction of partial filling was a novel concept to many. In addition to continual reeducation of current employees, any new hires would likely need this information as part of initial training.

Cost variance in the type of partial fills completed between the preliminary and postintervention phases also may have negatively impacted the results. The postintervention phase contained 2 high-cost classes of drugs (antivirals and immunoglobulins) that received multiple partial fills but were not partialed in the preliminary phase, which increased the raw drug cost in the postintervention phase.

Conclusion

The implementation of partial-fill and process education to FVAMC staff and veterans proved beneficial in reducing the expenditures and workload associated with partial-fill prescription processing. The continued use of the updated partial-fill guidance will provide a standardized approach for pharmacy staff when completing partial-fill prescriptions.

Facilities may consider annual reeducation on their guidance through a local TMS module, as well as occasional process reminders during staff meetings to improve staff adherence to the guidance. Moreover, the sustained incorporation of improved refill process education to new patients and with every prescription pickup could help guide the FVAMC veteran population to use pharmacy services more effectively. The adoption of such procedures may be useful for VA facilities’ health care system looking to maximize the use of funding provided for prescription services as well as improve veterans’ understanding of how to appropriately order prescription refills.

According to the US Department of Veterans Affairs (VA) Pharmacy Benefits Management Service, about 80% of all outpatient prescriptions filled by the VA are sent to veterans by mail order, using the Centralized Mail Order Pharmacy (CMOP) network of highly automated pharmacies around the country.¹ During fiscal year (FY) 2016, the 7 VA CMOP facilities throughout the US processed 119.7 million outpatient prescriptions. Each day, these CMOPs process nearly 470,000 prescriptions, an evidence of the efficiency provided through this mail-order service.¹ The use of CMOP results in lower processing costs and increased convenience for veterans compared with filling prescriptions at pharmacies at individual VA facilities. Notably, VA CMOP has been rated “among the best” mail-order pharmacies in customer satisfaction according to the 2017 J.D. Power US Pharmacy Study.²

Background

Within the Fayetteville VA Medical Center (FVAMC) system in North Carolina, on-site patients receive a new prescription where an on-site pharmacy is available (at health care centers [HCC] and the medical center). For veterans seen at community-based outpatient clinics (CBOCs), emergent new prescriptions are filled through vouchers at contract community pharmacies, and nonemergent new prescriptions are filled by the CMOP (Figure 1). 

The appropriate use of the VA CMOP for refills is intended to allow on-site pharmacy staff to focus on providing customer service for veterans requesting medication counseling from a clinical pharmacist, as well as those with new, changing, or urgent prescription needs. Filling prescriptions through the CMOP also can help control the VA facility pharmacy budget.

Despite the established mail-order process, FVAMC staff noted a high volume of medication refill and partial-fill prescriptions being requested at the on-site pharmacy. When a veteran presented to a pharmacy requesting a medication refill, pharmacy staff members ordered a refill to be filled by the CMOP and provided a limited quantity, otherwise known as a partial fill, to serve as an emergency supply to supplement the veteran until the full quantity of the prescription arrived by mail. Partial fills also were completed for new prescriptions that veterans requested to pick up at the on-site pharmacy. For new 90-day supply prescriptions, pharmacy staff often filled a 30-day supply in addition to submitting the entire 90-day prescription through the CMOP, which led to an unnecessary increase in material expenditures and workload.Preliminary data noted the most frequently used partial-fill days’ supply to be 10 days. Due to the lack of partial-fill criteria, prescriptions of all classes, quantities, and days’ supplies were provided as partial fills. Prior to the implementation of this quality improvement (QI) project, there was no standard approach for how to handle these requests.

Partial fills do not provide copay reimbursement to the facility filling the prescription. In an effort to steward the funds provided to the FVAMC pharmacy department wisely, an evaluation was performed with reference to partial fills. During FY 2016, about $350,000 was spent on medications, materials, and workload associated with the partial filling of FVAMC prescriptions. With respect to unique individuals who were provided care over the course of FY 2015 and 2016, the number of unique patients served by local comparator hospitals increased by only 2%, while the number of unique patients served by FVAMC increased by 12%. This substantial growth in the number of veterans served places further emphasis on the necessity of stewarding the allotted pharmacy budget. Moreover, the excessive number of medication refill and partial-fill prescriptions filled at on-site VA pharmacies can contribute to increased wait times for veterans with urgent prescription needs.

In November 2016, FVAMC implemented an updated partial-fill guidance. Partial-fill process and refill education was provided for VA staff and veterans in an effort to allow all parties involved to use pharmacy services efficiently. This analysis reviewed the reduction in partial-fill expenditures with a secondary focus on workload expenditures following the execution of this education.

Methods

This project was deemed to be a QI project and did not require institutional review board approval. Implementation for this QI project began in November 2016. Baseline raw drug cost, number, and class of prescriptions partialed were retrospectively collected for a 90-day period prior to implementation using all available data. Postintervention data were collected for 90 days following the implementation phase to compare partial-fill expenditures and workload expenditures with baseline data.

Calculations

Materials included in the partial-fill expenditure calculation were prescription vials, prescription vial caps, and prescription labeling. Material cost per partial fill was determined by using the facility’s wholesaler acquisition unit costs to estimate a summed cost for an individual prescription vial and prescription vial cap. The estimated acquisition price of 7 prescription-labeling pages was used in the material calculation, as this was the average number of pages used when performing test partial fills.

The following equation was used to calculate total partial-fill expenditures for any specified time frame:

Total partial-fill expenditure = total raw drug cost + (material cost × number of partial fills)

In addition, the average personnel cost per partial-fill prescription was determined. Average workload expenditure per partial fill was calculated by filling a subset of 10 test prescriptions and multiplying the average time spent by an average of the general station (GS) rate for pharmacists and technicians. The average hourly rate of a GS-12 pharmacist was calculated based on an average of the 10 available pay grades within the GS-12 ranking. The average hourly rate of a GS-6 pharmacy technician was calculated based on an average of the 10 available pay grades within the GS-6 ranking.³ The average workload expenditures were calculated using the following equations:

Average pharmacist workload expenditure per partial fill = time (in hours) × average hourly rate.

Average technician workload expenditure per partial fill = time (in hours) × average hourly rate.

Partial-Fill Guidance

Updated partial-fill guidance was drafted designating acceptable prescriptions to be limited to those responsible for preventing hospitalization and treatment of acute illness. This guidance provided generalized examples of medication classes that could be acceptable for partial filling, though it was not intended to be an all-inclusive list. The guidance also noted examples of classes or groups that should not be partial filled for nonemergent reasons (vitamins, nonprescription items, antilipemics), as well as controlled substances. The refill-process education was reiterated throughout the entirety of the guidance. Specifically, if a pharmacy staff member was to perform a partial fill, a review explaining the appropriate refill process to the veteran also must be provided. If the medication was determined to be of emergent need and not yet transmitted for filling via the CMOP, the directive recommended to fill the entire quantity locally as a onetime fill.

If a onetime on-site fill was determined infeasible, partial-fill quantities were recommended to be limited to only a 7-day supply, and the full quantity filled through the CMOP. Anticipated mail wait time for CMOP prescription delivery was estimated to be less than 7 days based on experience, local pending queues, and guidance from the regional CMOP; however, time could vary among VA and CMOP facilities. Original prescriptions were to be filled for the entire quantity for the first fill at the on-site pharmacy if requested by the veteran. If the pharmacy had an insufficient quantity for an entire initial supply, it could then be partial filled for a 7-day supply and then filled through the CMOP.

The final portion of the partial-fill guidance pertained to the use of partial-fill justification codes. Prior to the execution of the partial-fill guidance, free text was entered into the comments field when processing a partial-fill prescription, as the prescription-processing system used requires a comment to proceed with the partial fill. The use of these codes served to streamline data collection in the postintervention phase and helped identify areas for further education following the close of this project.

Education

Education to the pharmacy staff was disseminated by various modalities, including in-person sessions and written and electronic correspondences. This written guidance was distributed to pharmacy staff by e-mail, the pharmacy newsletter (R_x-tra), signage posted throughout the outpatient pharmacies, and on the facility’s pharmacy Microsoft SharePoint (Redmond, WA) site. In-services provided during pharmacy staff meetings detailed information on the updated partial-fill guidance. A FVAMC Talent Management System (TMS) training module was developed and assigned to all pharmacy service staff to reiterate key points regarding this QI initiative (eAppendix).

Nonpharmacy staff were educated through staff and in-service meetings and e-mail correspondences. These in-services emphasized how nurses, medical support assistants, and health care providers (HCPs) could assist veterans by knowing the correct refill process, ensuring sufficient refills remained until the next appointment, and providing continual refill-process education.

Following implementation, all veterans receiving prescriptions through the on-site pharmacies in the FVAMC were provided a copy of the refill-process handout with each trip to the pharmacy. Nonpharmacy staff and HCPs also were provided this handout to distribute to patients. The intent of this handout was to clearly detail the various ways in which refills could be ordered and the time frame in which they should be ordered. The pharmacy became involved in new patient orientation classes for all veterans new to FVAMC. Digital signage and messaging was created and circulated throughout several of the FVAMC facilities.

Results

The results of calculations for material cost, personnel time spent, hourly employee rates, and average workload expenditure per partial fill are summarized in Table 1.

Following the implementation of partial-fill and refill-process education, there was a 54.3% decrease in the total number of partial fills from 5,596 in the 90 days prior to implementation, to 2,555 partials completed over the 90 days postimplementation. Regarding the primary objective, total partial-fill expenditures decreased from $52,015.44 to $44,063.01 (-15.3%). When dissecting the individual components of partial-fill expenditures, material expenditures decreased from $1,454.96 to $664.28 (-54.3%), and raw drug cost expenditures decreased from $50,596.48 to $43,398.73 (-14.3%). Workload expenditures also decreased from $27,140.60 to $12,391.75 (-54.3%).

Several points of descriptive information also were collected. The average days’ supply trended down from a mode of 10 days to 7 days. This reduction in days’ supply likely was seen because staff became more aware of the customary amount required to bridge the veteran until the CMOP supply arrived by mail. Postintervention data showed a 70% utilization of partial-fill reasoning codes. The reasons for partial filling of prescriptions are summarized in Table 2. 

Discussion

Following the implementation of the updated partial-fill guidance and provision of education to the FVAMC veterans and staff, a noteworthy cost savings was observed with respect to both material and workload expenditures. This large reduction in expenditure likely was not related to a reduction in the total prescription volume, as the number of total prescriptions filled by the CMOP and at FVAMC were similar in both the preliminary and postintervention periods. When the results of this 3-month QI project were extrapolated, the annual projected cost avoidance was $91,949.12.

Of note, there was no established process for adjudicating appeals to the partial-fill guidance. Any extenuating circumstances that fell outside the guidance were addressed by the outpatient pharmacy supervisor. There was no formal documentation for these disputed cases. Since there was no prespecified supervisory override code, the most appropriate partial-fill code was entered into the comments field for these scenarios. As such, there is no way to distinguish precisely how many of these partial fills were escalated to a supervisory level for a decision.

The positive fiscal impact noted from the implementation of this project should not be viewed as the only utility for such guidance. Though not directly measured within the confines of this project, a reduction in pharmacy staff time spent on partial-fill prescriptions will likely result in shorter pharmacy wait times, line lengths, and streamlining of pharmacy workflow. When the pharmacy staff is free to work on pressing issues rather than on continually educating veterans on the partial-fill or refill process, many will benefit. Veteran satisfaction was not directly measured during this project but could be an interesting topic to review as a future study.

Each VA facility is unique, with its own challenges for implementation of a project such as this. Nevertheless, the incorporation of a formal guidance and education process, perhaps adapted to the indi vidual facility’s needs may be considered for overall pharmacy operations QI.

Limitations

During the preliminary data collection period, FVAMC and its catchment area were impacted by a natural disaster, Hurricane Matthew. Based on a review of the text entered into the comments field for all partial fills, about 4% of the partial fills completed in the preliminary phase can be attributed to the hurricane. The effects of this hurricane may have potentially increased the number of partial fills completed in the preliminary phase compared with that in the postintervention phase, due to the number of veterans who were temporarily or permanently displaced from their homes. This increase in partial fills and associated expenses preintervention likely caused a slightly higher cost savings to be reflected in the postimplementation phase than what would have traditionally been observed without extenuating factors.

Several other limitations must be considered for this QI project. The implementation phase, during which all education and training was completed, was only 1 month. A longer implementation period and more opportunities to educate veterans and staff might have created a greater impact on the results. Additionally, because there were no data collected on New Patient Orientation attendance for this project, it is unclear exactly how many veterans received refill-process education through this outlet.

Though all staff members were trained on the appropriate process, it was discovered during interim analysis that several pharmacists were not following the partial-fill guidance, potentially negatively impacting the results. It is likely that staff would have benefited from continual reeducation of the process throughout the entirety of the project, as the restriction of partial filling was a novel concept to many. In addition to continual reeducation of current employees, any new hires would likely need this information as part of initial training.

Cost variance in the type of partial fills completed between the preliminary and postintervention phases also may have negatively impacted the results. The postintervention phase contained 2 high-cost classes of drugs (antivirals and immunoglobulins) that received multiple partial fills but were not partialed in the preliminary phase, which increased the raw drug cost in the postintervention phase.

Conclusion

The implementation of partial-fill and process education to FVAMC staff and veterans proved beneficial in reducing the expenditures and workload associated with partial-fill prescription processing. The continued use of the updated partial-fill guidance will provide a standardized approach for pharmacy staff when completing partial-fill prescriptions.

Facilities may consider annual reeducation on their guidance through a local TMS module, as well as occasional process reminders during staff meetings to improve staff adherence to the guidance. Moreover, the sustained incorporation of improved refill process education to new patients and with every prescription pickup could help guide the FVAMC veteran population to use pharmacy services more effectively. The adoption of such procedures may be useful for VA facilities’ health care system looking to maximize the use of funding provided for prescription services as well as improve veterans’ understanding of how to appropriately order prescription refills.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE: EPIVIR-HBV (LAMIVUDINE)

• Added to warning September 2017

WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

EPIVIR-HBV is not approved for the treatment of HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment.

INVOKANA (CANAGLIFLOZIN)

• Added section to warning July 2017

WARNING: LOWER LIMB AMPUTATION

• An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.

Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

INVOKAMET (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Risk of Lower Limb Amputation

• In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.

INVOKAMET XR (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
  malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/ pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
• Steps to reduce the risk of and manage metforminassociated lactic acidosis in these high risk groups are provided in the full prescribing information.
• If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Risk of Lower Limb Amputation

• An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
• Monitor patients receiving INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

JEVTANA KIT (CABAZITAXEL)

• Edited warning September 2017

WARNING: NEUTROPENIA AND HYPERSENSITIVITY

Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.

THYRO-TABS (LEVOTHYROXINE SODIUM)

• Added section to warning August 2017

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS

Thyroid hormones, including THYRO-TABS, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.

In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.

Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

REGLAN (METOCLOPRAMIDE HYDROCHLORIDE)

• Edited warning August 2017

WARNING: TARDIVE DYSKINESIA

• Reglan can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage.
• Discontinue Reglan in patients who develop signs or symptoms of TD. In some patients, symptoms may lessen or resolve after Reglan is stopped.
• Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE: EPIVIR-HBV (LAMIVUDINE)

• Added to warning September 2017

WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

EPIVIR-HBV is not approved for the treatment of HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment.

INVOKANA (CANAGLIFLOZIN)

• Added section to warning July 2017

WARNING: LOWER LIMB AMPUTATION

• An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.

Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

INVOKAMET (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Risk of Lower Limb Amputation

• In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.

INVOKAMET XR (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
  malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/ pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
• Steps to reduce the risk of and manage metforminassociated lactic acidosis in these high risk groups are provided in the full prescribing information.
• If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Risk of Lower Limb Amputation

• An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
• Monitor patients receiving INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

JEVTANA KIT (CABAZITAXEL)

• Edited warning September 2017

WARNING: NEUTROPENIA AND HYPERSENSITIVITY

Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.

THYRO-TABS (LEVOTHYROXINE SODIUM)

• Added section to warning August 2017

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS

Thyroid hormones, including THYRO-TABS, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.

In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.

Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

REGLAN (METOCLOPRAMIDE HYDROCHLORIDE)

• Edited warning August 2017

WARNING: TARDIVE DYSKINESIA

• Reglan can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage.
• Discontinue Reglan in patients who develop signs or symptoms of TD. In some patients, symptoms may lessen or resolve after Reglan is stopped.
• Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE: EPIVIR-HBV (LAMIVUDINE)

• Added to warning September 2017

WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

EPIVIR-HBV is not approved for the treatment of HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment.

INVOKANA (CANAGLIFLOZIN)

• Added section to warning July 2017

WARNING: LOWER LIMB AMPUTATION

• An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.

Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

INVOKAMET (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Risk of Lower Limb Amputation

• In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.

INVOKAMET XR (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

• Edited warning August 2017

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION

Lactic Acidosis

• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
  malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/ pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
• Steps to reduce the risk of and manage metforminassociated lactic acidosis in these high risk groups are provided in the full prescribing information.
• If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Risk of Lower Limb Amputation

• An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
• Monitor patients receiving INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

JEVTANA KIT (CABAZITAXEL)

• Edited warning September 2017

WARNING: NEUTROPENIA AND HYPERSENSITIVITY

Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.

THYRO-TABS (LEVOTHYROXINE SODIUM)

• Added section to warning August 2017

WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS

Thyroid hormones, including THYRO-TABS, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.

In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.

Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

REGLAN (METOCLOPRAMIDE HYDROCHLORIDE)

• Edited warning August 2017

WARNING: TARDIVE DYSKINESIA

• Reglan can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage.
• Discontinue Reglan in patients who develop signs or symptoms of TD. In some patients, symptoms may lessen or resolve after Reglan is stopped.
• Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use.

Successful treatment of pneumonia depends on timely diagnosis and administration of antibiotics. Multidrug-resistant organisms (MDROs) complicate antibiotic therapies by rendering some antibiotic agents ineffective. Inappropriate initial therapy has been associated with a more than 2-fold increase in the risk of mortality.¹ Because culture results are not available immediately, clinicians prescribe antibiotics empirically and must rely on guidelines and knowledge of risk factors associated with MDRO infection to make these selections.

Treatment guidelines exist for hospital-acquired and ventilator-associated pneumonia (HAP/VAP) and community-acquired pneumonia (CAP) to assist with empiric antibiotic selection. For HAP/VAP, 2 to 3 antibiotics with a broad-spectrum of activity are used due to increased prevalence of MDROs in hospitals, whereastreatment of CAP involves more narrow coverage because bacteria that cause this infection typically have fewer antibiotic resistances.^2,3 The HAP/VAP guidelines stratify the risk of pneumonia due to the presence of a MDRO acquired during a hospitalization. However, neither the CAP nor HAP/VAP guidelines offer risk-stratification guidance for nonhospitalized patients who develop pneumonia but who may have become colonized with a MDRO during a previous hospitalization or from another exposure to a health care facility.

Health care-associated pneumonia (HCAP) was first described in the 2005 American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) nosocomial pneumonia guidelines and was associated with criteria intended to aid clinician identification of nonhospitalized patients at risk for MDRO pneumonia, which warranted empiric broad-spectrum antibiotic therapy.² According to these guidelines, patients were classified as having HCAP if they had been hospitalized for at least 48 hours in the past 90 days, admitted from a nursing home, received recent intravenous antibiotics, had hemodialysis in the past 30 days, had a history of home infusion therapy or wound care, received intravenous chemotherapy, or had a family member with MDRO colonization.

Since publication of the 2005 guidelines, HCAP has been criticized as being a poor predictor of MDRO infection. A 2014 meta-analysis of 24 studies investigated the discriminating ability of HCAP and reported that the specificity and sensitivity for MDRO infections was 71.2% and 53.7%, respectively.³ In 2016, the ATS/IDSA guidelines were updated to remove HCAP due to the risk of antibiotic overprescribing.⁴

Literature Review

Although criteria previously defining a patient as having HCAP have been shown to be a poor discriminator of MDRO pneumonia as a whole, MDRO infections still pose a threat to nonhospitalized patients who have exposure to the health care system. A literature review was performed to identify independent HCAP risk factors that may increase the risk of MDRO pneumonia infecting a nonhospitalized patient needing empiric broad-spectrum antibiotic therapy. All included studies were prospective or retrospective observational cohort studies that performed logistic regression analyses to assess the association between MDRO isolation and the previously defined HCAP risk factors (Table 1).

Five studies examined the risk of MDRO infection in patients with a previous hospital admission of 2 days or more in the past 90 days. Shindo and colleagues found a significant increase in MDRO infections by about 2-fold (adjusted odds ratio [AOR], 2.1; 95% confidence interval [CI], 1.2-3.4).⁵ Shorr and colleagues found a 4-fold increase in likelihood of identifying a MDRO in HCAP (AOR, 4.2; 95% CI, 2.9-6.3).⁶ Nseir and colleagues and Jung and colleagues found similar results (AOR 3.9, 95% CI 1.7-8.8; AOR 2.7, 95% CI 1.3-5.5, respectively).^7,8 Conflicting results were reported by Gross and colleagues who did not find a significant relationship between previous hospitalization and MDRO isolation (AOR 1.2, 95% CI, 0.5-3.2).⁹

In patients with pneumonia admitted from a nursing home, MDRO infection risk also was evaluated in these 5 studies. Shorr and colleagues, Nseir and colleagues, and Gross and colleagues found significant AORs of 2.7 (95% CI 1.7-4.3), 2.0 (95% CI 1.1-3.7), and 4.2 (95% CI 1.6-11.3), respectively.^6,7,9 Shindo and colleagues (AOR 1.1; 95% CI, 0.6-2.0) and Jung and colleagues (AOR 1.9, 95% CI, 0.5-6.9) found this risk factor not significant.⁵

Receipt of antibiotics within the previous 90 days was assessed in 3 studies. Shindo and colleagues, Nseir and colleagues, and Gross and colleagues all found significant AORs of 2.5 (95% CI 1.2-4.0), 2.3 (95% CI 1.2-4.3), and 2.9 (95% CI 1.1-7.5), respectively.^5,7,9 Antibiotic therapy within the previous 90 days is an established risk factor for MDRO pneumonia, and the 2016 ATS/IDSA guidelines consider this a risk factor for HAP and VAP, including pneumonia caused by methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa.⁴

The impact of hemodialysis in the previous month on acquisition of MDRO pneumonia was investigated in 4 studies. Shindo and colleagues, Jung and colleagues, and Gross and colleagues concluded that this risk factor was not significantly related to MDRO infection, reporting AORs of 2.2 (95% CI 0.5-9.7), 2.8 (95% CI 0.9-9.2) and 0.7 (95% CI 0.1-5.1), respectively.^5,8,9 Shorr and colleagues, however, found a significant AOR of 2.1 (95% CI 1.0-4.3).⁶

Shindo and colleagues investigated the impact of home infusion therapy on acquisition of pneumonia due to a MDRO and reported a nonsignificant AOR of 0.8 (95% CI 0.4-1.8).⁵ Gross and colleagues also found a nonsignificant AOR of 0 (P = .1).⁹ In the Shindo and colleagues study, resistance was found in 107 of 679 patients who did not receive infusion therapy, and 12 of 55 patients who were receiving infusion therapy.⁵ Gross and colleagues reported that home-infusion therapy was received by 0 of 20 patients with MDRO infection and 4 of the 501 patients without MDRO infection.⁹

Shindo and colleagues reported that home wound care was not found to be significantly related to MDRO pneumonia as well as did Gross and colleagues: AORs of 3.8 (0.8-18.4) and 1.4 (95% CI 0.5-4.4), respectively.^5,9 Jung and colleagues examined IV chemotherapy in the past 30 days, and found this to not significantly impact the odds of MDRO isolation (AOR = 0.62, 95% CI 0.2-1.8).⁸ No data were available reflecting the risk of a family member with a MDRO.

Limitations

The variables on which logistic regression were performed differed among the studies. Therefore, results cannot be averaged or compared quantitatively, as AORs varied, depending on the variables included. In addition, data were drawn from multiple geographic locations that may impact MDRO prevalence within each patient population. Finally, this review examines the utility of the risk factors formerly included in HCAP. However, other risk factors for MDRO pneumonia outlined by the ATS/IDSA guidelines still should be considered when evaluating patient risk. The 2016 guidelines recommend local incidence of resistant strains be considered when initiating empiric therapy. Review of medical records for previous positive cultures and duration of current hospitalization also should be considered. Although the 2016 ATS/IDSA HAP guidelines are not intended for immunosuppressed patients, this risk factor also may be taken into account.

Conclusion

Review and synthesis of published literature found previous hospital admission (of ≥ 2 days in the past 90 days), admission from a nursing home, and IV antibiotic therapy in the last 90 days to be independent risk factors for identification of MDRO pneumonia in previously nonhospitalized patients (Table 2). Additionally, although no data were found to support this risk factor, existence of an in-home (close contact) source of MDROs would provide ample opportunity for transmission, so evaluation of known exposure to MDROs from contacts should be considered. When choosing empiric antibiotic therapy for patients admitted to the hospital for treatment of pneumonia, consideration of patient history and risk factors that may contribute to infection with a MDRO are recommended.

Successful treatment of pneumonia depends on timely diagnosis and administration of antibiotics. Multidrug-resistant organisms (MDROs) complicate antibiotic therapies by rendering some antibiotic agents ineffective. Inappropriate initial therapy has been associated with a more than 2-fold increase in the risk of mortality.¹ Because culture results are not available immediately, clinicians prescribe antibiotics empirically and must rely on guidelines and knowledge of risk factors associated with MDRO infection to make these selections.

Treatment guidelines exist for hospital-acquired and ventilator-associated pneumonia (HAP/VAP) and community-acquired pneumonia (CAP) to assist with empiric antibiotic selection. For HAP/VAP, 2 to 3 antibiotics with a broad-spectrum of activity are used due to increased prevalence of MDROs in hospitals, whereastreatment of CAP involves more narrow coverage because bacteria that cause this infection typically have fewer antibiotic resistances.^2,3 The HAP/VAP guidelines stratify the risk of pneumonia due to the presence of a MDRO acquired during a hospitalization. However, neither the CAP nor HAP/VAP guidelines offer risk-stratification guidance for nonhospitalized patients who develop pneumonia but who may have become colonized with a MDRO during a previous hospitalization or from another exposure to a health care facility.

Health care-associated pneumonia (HCAP) was first described in the 2005 American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) nosocomial pneumonia guidelines and was associated with criteria intended to aid clinician identification of nonhospitalized patients at risk for MDRO pneumonia, which warranted empiric broad-spectrum antibiotic therapy.² According to these guidelines, patients were classified as having HCAP if they had been hospitalized for at least 48 hours in the past 90 days, admitted from a nursing home, received recent intravenous antibiotics, had hemodialysis in the past 30 days, had a history of home infusion therapy or wound care, received intravenous chemotherapy, or had a family member with MDRO colonization.

Since publication of the 2005 guidelines, HCAP has been criticized as being a poor predictor of MDRO infection. A 2014 meta-analysis of 24 studies investigated the discriminating ability of HCAP and reported that the specificity and sensitivity for MDRO infections was 71.2% and 53.7%, respectively.³ In 2016, the ATS/IDSA guidelines were updated to remove HCAP due to the risk of antibiotic overprescribing.⁴

Literature Review

Although criteria previously defining a patient as having HCAP have been shown to be a poor discriminator of MDRO pneumonia as a whole, MDRO infections still pose a threat to nonhospitalized patients who have exposure to the health care system. A literature review was performed to identify independent HCAP risk factors that may increase the risk of MDRO pneumonia infecting a nonhospitalized patient needing empiric broad-spectrum antibiotic therapy. All included studies were prospective or retrospective observational cohort studies that performed logistic regression analyses to assess the association between MDRO isolation and the previously defined HCAP risk factors (Table 1).

Five studies examined the risk of MDRO infection in patients with a previous hospital admission of 2 days or more in the past 90 days. Shindo and colleagues found a significant increase in MDRO infections by about 2-fold (adjusted odds ratio [AOR], 2.1; 95% confidence interval [CI], 1.2-3.4).⁵ Shorr and colleagues found a 4-fold increase in likelihood of identifying a MDRO in HCAP (AOR, 4.2; 95% CI, 2.9-6.3).⁶ Nseir and colleagues and Jung and colleagues found similar results (AOR 3.9, 95% CI 1.7-8.8; AOR 2.7, 95% CI 1.3-5.5, respectively).^7,8 Conflicting results were reported by Gross and colleagues who did not find a significant relationship between previous hospitalization and MDRO isolation (AOR 1.2, 95% CI, 0.5-3.2).⁹

In patients with pneumonia admitted from a nursing home, MDRO infection risk also was evaluated in these 5 studies. Shorr and colleagues, Nseir and colleagues, and Gross and colleagues found significant AORs of 2.7 (95% CI 1.7-4.3), 2.0 (95% CI 1.1-3.7), and 4.2 (95% CI 1.6-11.3), respectively.^6,7,9 Shindo and colleagues (AOR 1.1; 95% CI, 0.6-2.0) and Jung and colleagues (AOR 1.9, 95% CI, 0.5-6.9) found this risk factor not significant.⁵

Receipt of antibiotics within the previous 90 days was assessed in 3 studies. Shindo and colleagues, Nseir and colleagues, and Gross and colleagues all found significant AORs of 2.5 (95% CI 1.2-4.0), 2.3 (95% CI 1.2-4.3), and 2.9 (95% CI 1.1-7.5), respectively.^5,7,9 Antibiotic therapy within the previous 90 days is an established risk factor for MDRO pneumonia, and the 2016 ATS/IDSA guidelines consider this a risk factor for HAP and VAP, including pneumonia caused by methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa.⁴

The impact of hemodialysis in the previous month on acquisition of MDRO pneumonia was investigated in 4 studies. Shindo and colleagues, Jung and colleagues, and Gross and colleagues concluded that this risk factor was not significantly related to MDRO infection, reporting AORs of 2.2 (95% CI 0.5-9.7), 2.8 (95% CI 0.9-9.2) and 0.7 (95% CI 0.1-5.1), respectively.^5,8,9 Shorr and colleagues, however, found a significant AOR of 2.1 (95% CI 1.0-4.3).⁶

Shindo and colleagues investigated the impact of home infusion therapy on acquisition of pneumonia due to a MDRO and reported a nonsignificant AOR of 0.8 (95% CI 0.4-1.8).⁵ Gross and colleagues also found a nonsignificant AOR of 0 (P = .1).⁹ In the Shindo and colleagues study, resistance was found in 107 of 679 patients who did not receive infusion therapy, and 12 of 55 patients who were receiving infusion therapy.⁵ Gross and colleagues reported that home-infusion therapy was received by 0 of 20 patients with MDRO infection and 4 of the 501 patients without MDRO infection.⁹

Shindo and colleagues reported that home wound care was not found to be significantly related to MDRO pneumonia as well as did Gross and colleagues: AORs of 3.8 (0.8-18.4) and 1.4 (95% CI 0.5-4.4), respectively.^5,9 Jung and colleagues examined IV chemotherapy in the past 30 days, and found this to not significantly impact the odds of MDRO isolation (AOR = 0.62, 95% CI 0.2-1.8).⁸ No data were available reflecting the risk of a family member with a MDRO.

Limitations

The variables on which logistic regression were performed differed among the studies. Therefore, results cannot be averaged or compared quantitatively, as AORs varied, depending on the variables included. In addition, data were drawn from multiple geographic locations that may impact MDRO prevalence within each patient population. Finally, this review examines the utility of the risk factors formerly included in HCAP. However, other risk factors for MDRO pneumonia outlined by the ATS/IDSA guidelines still should be considered when evaluating patient risk. The 2016 guidelines recommend local incidence of resistant strains be considered when initiating empiric therapy. Review of medical records for previous positive cultures and duration of current hospitalization also should be considered. Although the 2016 ATS/IDSA HAP guidelines are not intended for immunosuppressed patients, this risk factor also may be taken into account.

Conclusion

Review and synthesis of published literature found previous hospital admission (of ≥ 2 days in the past 90 days), admission from a nursing home, and IV antibiotic therapy in the last 90 days to be independent risk factors for identification of MDRO pneumonia in previously nonhospitalized patients (Table 2). Additionally, although no data were found to support this risk factor, existence of an in-home (close contact) source of MDROs would provide ample opportunity for transmission, so evaluation of known exposure to MDROs from contacts should be considered. When choosing empiric antibiotic therapy for patients admitted to the hospital for treatment of pneumonia, consideration of patient history and risk factors that may contribute to infection with a MDRO are recommended.

Successful treatment of pneumonia depends on timely diagnosis and administration of antibiotics. Multidrug-resistant organisms (MDROs) complicate antibiotic therapies by rendering some antibiotic agents ineffective. Inappropriate initial therapy has been associated with a more than 2-fold increase in the risk of mortality.¹ Because culture results are not available immediately, clinicians prescribe antibiotics empirically and must rely on guidelines and knowledge of risk factors associated with MDRO infection to make these selections.

Treatment guidelines exist for hospital-acquired and ventilator-associated pneumonia (HAP/VAP) and community-acquired pneumonia (CAP) to assist with empiric antibiotic selection. For HAP/VAP, 2 to 3 antibiotics with a broad-spectrum of activity are used due to increased prevalence of MDROs in hospitals, whereastreatment of CAP involves more narrow coverage because bacteria that cause this infection typically have fewer antibiotic resistances.^2,3 The HAP/VAP guidelines stratify the risk of pneumonia due to the presence of a MDRO acquired during a hospitalization. However, neither the CAP nor HAP/VAP guidelines offer risk-stratification guidance for nonhospitalized patients who develop pneumonia but who may have become colonized with a MDRO during a previous hospitalization or from another exposure to a health care facility.

Health care-associated pneumonia (HCAP) was first described in the 2005 American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) nosocomial pneumonia guidelines and was associated with criteria intended to aid clinician identification of nonhospitalized patients at risk for MDRO pneumonia, which warranted empiric broad-spectrum antibiotic therapy.² According to these guidelines, patients were classified as having HCAP if they had been hospitalized for at least 48 hours in the past 90 days, admitted from a nursing home, received recent intravenous antibiotics, had hemodialysis in the past 30 days, had a history of home infusion therapy or wound care, received intravenous chemotherapy, or had a family member with MDRO colonization.

Since publication of the 2005 guidelines, HCAP has been criticized as being a poor predictor of MDRO infection. A 2014 meta-analysis of 24 studies investigated the discriminating ability of HCAP and reported that the specificity and sensitivity for MDRO infections was 71.2% and 53.7%, respectively.³ In 2016, the ATS/IDSA guidelines were updated to remove HCAP due to the risk of antibiotic overprescribing.⁴

Literature Review

Although criteria previously defining a patient as having HCAP have been shown to be a poor discriminator of MDRO pneumonia as a whole, MDRO infections still pose a threat to nonhospitalized patients who have exposure to the health care system. A literature review was performed to identify independent HCAP risk factors that may increase the risk of MDRO pneumonia infecting a nonhospitalized patient needing empiric broad-spectrum antibiotic therapy. All included studies were prospective or retrospective observational cohort studies that performed logistic regression analyses to assess the association between MDRO isolation and the previously defined HCAP risk factors (Table 1).

Five studies examined the risk of MDRO infection in patients with a previous hospital admission of 2 days or more in the past 90 days. Shindo and colleagues found a significant increase in MDRO infections by about 2-fold (adjusted odds ratio [AOR], 2.1; 95% confidence interval [CI], 1.2-3.4).⁵ Shorr and colleagues found a 4-fold increase in likelihood of identifying a MDRO in HCAP (AOR, 4.2; 95% CI, 2.9-6.3).⁶ Nseir and colleagues and Jung and colleagues found similar results (AOR 3.9, 95% CI 1.7-8.8; AOR 2.7, 95% CI 1.3-5.5, respectively).^7,8 Conflicting results were reported by Gross and colleagues who did not find a significant relationship between previous hospitalization and MDRO isolation (AOR 1.2, 95% CI, 0.5-3.2).⁹

In patients with pneumonia admitted from a nursing home, MDRO infection risk also was evaluated in these 5 studies. Shorr and colleagues, Nseir and colleagues, and Gross and colleagues found significant AORs of 2.7 (95% CI 1.7-4.3), 2.0 (95% CI 1.1-3.7), and 4.2 (95% CI 1.6-11.3), respectively.^6,7,9 Shindo and colleagues (AOR 1.1; 95% CI, 0.6-2.0) and Jung and colleagues (AOR 1.9, 95% CI, 0.5-6.9) found this risk factor not significant.⁵

Receipt of antibiotics within the previous 90 days was assessed in 3 studies. Shindo and colleagues, Nseir and colleagues, and Gross and colleagues all found significant AORs of 2.5 (95% CI 1.2-4.0), 2.3 (95% CI 1.2-4.3), and 2.9 (95% CI 1.1-7.5), respectively.^5,7,9 Antibiotic therapy within the previous 90 days is an established risk factor for MDRO pneumonia, and the 2016 ATS/IDSA guidelines consider this a risk factor for HAP and VAP, including pneumonia caused by methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa.⁴

The impact of hemodialysis in the previous month on acquisition of MDRO pneumonia was investigated in 4 studies. Shindo and colleagues, Jung and colleagues, and Gross and colleagues concluded that this risk factor was not significantly related to MDRO infection, reporting AORs of 2.2 (95% CI 0.5-9.7), 2.8 (95% CI 0.9-9.2) and 0.7 (95% CI 0.1-5.1), respectively.^5,8,9 Shorr and colleagues, however, found a significant AOR of 2.1 (95% CI 1.0-4.3).⁶

Shindo and colleagues investigated the impact of home infusion therapy on acquisition of pneumonia due to a MDRO and reported a nonsignificant AOR of 0.8 (95% CI 0.4-1.8).⁵ Gross and colleagues also found a nonsignificant AOR of 0 (P = .1).⁹ In the Shindo and colleagues study, resistance was found in 107 of 679 patients who did not receive infusion therapy, and 12 of 55 patients who were receiving infusion therapy.⁵ Gross and colleagues reported that home-infusion therapy was received by 0 of 20 patients with MDRO infection and 4 of the 501 patients without MDRO infection.⁹

Shindo and colleagues reported that home wound care was not found to be significantly related to MDRO pneumonia as well as did Gross and colleagues: AORs of 3.8 (0.8-18.4) and 1.4 (95% CI 0.5-4.4), respectively.^5,9 Jung and colleagues examined IV chemotherapy in the past 30 days, and found this to not significantly impact the odds of MDRO isolation (AOR = 0.62, 95% CI 0.2-1.8).⁸ No data were available reflecting the risk of a family member with a MDRO.

Limitations

The variables on which logistic regression were performed differed among the studies. Therefore, results cannot be averaged or compared quantitatively, as AORs varied, depending on the variables included. In addition, data were drawn from multiple geographic locations that may impact MDRO prevalence within each patient population. Finally, this review examines the utility of the risk factors formerly included in HCAP. However, other risk factors for MDRO pneumonia outlined by the ATS/IDSA guidelines still should be considered when evaluating patient risk. The 2016 guidelines recommend local incidence of resistant strains be considered when initiating empiric therapy. Review of medical records for previous positive cultures and duration of current hospitalization also should be considered. Although the 2016 ATS/IDSA HAP guidelines are not intended for immunosuppressed patients, this risk factor also may be taken into account.

Conclusion

Review and synthesis of published literature found previous hospital admission (of ≥ 2 days in the past 90 days), admission from a nursing home, and IV antibiotic therapy in the last 90 days to be independent risk factors for identification of MDRO pneumonia in previously nonhospitalized patients (Table 2). Additionally, although no data were found to support this risk factor, existence of an in-home (close contact) source of MDROs would provide ample opportunity for transmission, so evaluation of known exposure to MDROs from contacts should be considered. When choosing empiric antibiotic therapy for patients admitted to the hospital for treatment of pneumonia, consideration of patient history and risk factors that may contribute to infection with a MDRO are recommended.