Pharmacy News

Entries for April 2020

Controversy Behind Selinexor’s Approval

By Polly Luo, Pharm.D. candidate 2020, University of Michigan, Ann Arbor

Patients with multiple myeloma often develop relapsed or refractory multiple myeloma (RRMM) and have a median overall survival rate of 1.3 to 3.5 months.1 Selinexor was approved July 3, 2019, for adults patients with RRMM who are penta-exposed and triple class refractory to at least two proteasome inhibitors, two immunomodulatory agents and an Anti-CD38 monoclonal antibody.2 Selinexor is a selective inhibitor of nuclear export that binds to the nuclear export protein (XP01) that mediates the nuclear export of proteins and upregulates certain malignancies.1,3 By binding to XP01, the accumulation of tumor suppressor proteins amplifies the tumor suppressor function, leading to apoptosis in cancer cells and sparing normal cells. The Food and Drug Administration (FDA) granted accelerated approval of selinexor based off part two of the Selinexor Treatment of Refractory Myeloma (STORM) trial which represents the largest, most heavily treated patient population to date.4 This approval, however, was not without controversy.

The STORM trial was a phase 2b, multicenter, single-arm, open-label study of 123 patients with RRMM.1,3 All patients were refractory to at least one immunomodulatory drug, one proteasome inhibitor, daratumumab and glucocorticoids. The study was permissive with the allowance of patients that had baseline thrombocytopenia, neutropenia and reduced renal function. All patients received oral selinexor (80 mg) and dexamethasone (20 mg) twice weekly for a 28-day cycle.1,3 The overall response rate was studied as the primary endpoint. The secondary endpoints included duration of response (DUR), overall survival (OS), progression free survival (PFS) and safety. A partial response or better was seen in 26 percent of patients and the median OS of these patients was 15.6 months.1,3 The overall median survival of the patient population was 8.6 months. The median DUR was 4.4 months and the median PFS was 3.7 months. During this study, 28 patients died from disease progression or an adverse event. The most common adverse events included thrombocytopenia (73 percent), fatigue (73 percent), nausea (72 percent) and anemia (67 percent).1,3 Serious adverse events occurred in 63 percent of the population with pneumonia and sepsis as the most common. Around 88.6 percent required at least one dose modification due to a treatment emergent adverse events (TEAEs).4 The efficacy and safety outcomes were similar across all evaluated subgroups, including the most treatment resistant group that included 83 patients who were refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide and daratumumab.1,3

FDA’s Oncologic Drugs Advisory Committee (ODAC) voted to wait for the findings of the phase 3 trial before deciding on an approval.4 The recommendation of ODAC is considered but is non-binding. In a surprising turn of events, the FDA approved selinexor, but due to the severe toxicities and modest benefit seen in the STORM study, the drug was not approved for all RRMM patients. It is indicated only for adult patients who are refractory to at least two proteasome inhibitors, two immunomodulatory agents and an Anti-CD38 monoclonal antibody (ie, the characteristics of the most heavily pretreated 83-patient subset in the STORM trial). It was concluded that this group represents a population who, for all intents and purposes, has no available therapy, and therefore, the benefit-risk profile of selinexor is acceptable in this population. This indication was approved under an accelerated approval and continued FDA approval requires additional clinical trials to verify clinical benefits.5 The approval was controversial because there were several issues noted for this trial. Selinexor’s activity as a monotherapy in the phase 1 trial was not demonstrated and the isolated effects of selinexor is undetermined.4 All patients in the trial experienced at least one adverse event thus toxicity is a concern. The proposed starting dose in phase 2 was not well tolerated because 88.6 percent of patients required at least one dose modification due to TEAEs.4 Lastly, the time frame between previous treatments and selinexor was unknown. Medications can have a lingering effect in the body long after the patient is finished with their therapy. There is reason to question if there were lingering effects from previous therapies.

Several clinical trials are in progress for selinexor. Of note, the results of the phase 3 BOSTON study assessing the use of selinexor with bortezomib and low-dose dexamethasone versus bortezomib plus low-dose dexamethasone are set to be released in early 2020.6 In addition, a phase 2 trial assessing the safety and efficacy of at least two different doses of selinexor, a hepatic impairment trial and a drug interaction trial results are set to be available in late 2021.5

References:

1. Chari, A., Vogl, D. T., Gavriatopoulou, M., et al (2019). Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple Myeloma. New England Journal of Medicine, 381(8), 727-738.

2. Food and Drug Administration. (2019). FDA grants accelerated approval to selinexor for multiple myeloma. Retrieved from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selinexor-multiple-myeloma

3. Karyopharm Therapeutics. (2018).  Results of the Pivotal STORM Study (Part 2): Deep and Durable Responses with Oral Selinexor plus Low Dose Dexamethasone in Patients with Penta-Exposed and Triple Class Refractory MM [PDF file]. Retrieved from https://www.karyopharm.com/wp-content/uploads/2019/01/STORM-ASH2018-Final-2Dec18-1.pdf

4. Food and Drug Adminstration. (2019). FDA Briefing Document [PDF file]. Retrieved from https://www.fda.gov/media/121667/download

5. Food and Drug Adminstration. (2019). FDA approval letter [PDF file]. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/212306Orig1s000ltr.pdf

6. Karyopharm Therapeutics. (2019). Clinical Trials. Retrieved from https://www.karyopharm.com/patient-resources/clinical-trials/

Posted in: Professional Practice
Gram Negative Bacteremia Treatment Updates

Jean Huang, Pharm.D., Alyssa Divens, Pharm.D., Heba El-Ghoroury, Pharm.D., Kelsey Olmack, Pharm.D., St. Joseph Mercy Hospital, Ann Arbor

Bacteremia remains a major contributor to morbidity and mortality, accounting for approximately 80,000 deaths each year.1 With a cost of nearly $17,000 per patient, there is also a large financial burden.2 While initial use of intravenous antibiotics remains the standard of care, there has been a general lack of published data to support an optimal treatment duration and use of oral versus intravenous antibiotics with regard to patient outcomes. In the absence of treatment guidelines, patients often experience prolonged lengths of stay, are recommended longer durations of therapy and are placed at higher risk of nosocomial complications in order to continue inpatient intravenous antibiotic treatment. Over the last few years, new data has become available that supports shorter treatment durations and de-escalation to oral antibiotics, most notably for enterobacteriaceae bloodstream infections secondary to urinary sources. In light of increasing antimicrobial resistance, it is more important than ever to reduce unnecessary use of antibiotics.

A recent meta-analysis conducted by Tansarli et al. reviewed five studies that compared durations of therapy for enterobacteriaceae bacteremia, four of which were retrospective analyses and one randomized controlled trial.3 First, the authors examined all-cause mortality differences between ≤10 days of treatment versus >10 days of treatment. At 30 days, they found no difference in all-cause mortality between the treatment courses (1,374 patients; RR = 0.99; 95 percent CI, 0.69 to 1.43). Similarly, 90-day mortality showed no difference between treatment durations (1,750 patients; RR = 1.16; 95 percent CI, 0.81 to 1.66). When discussing clinical cure, there was also no significant difference between the two treatments when studies were pooled (81.6 percent versus 81.4 percent, respectively; 1,080 patients; RR = 1.02; 95 percent CI, 0.96 to 1.08). Additionally, four of the studies provided data on relapse of bacteremia at 30 or 90 days from the completion of antibiotic therapy. At 90 days there was no significant difference between treatment durations (1,750 patients; RR = 1.08; 95 percent CI, 0.69 to 1.67) as well as at 30 days (RR = 0.56; 95 percent CI, 0.19 to 1.64). 

Coinciding with the recent evidence suggesting shorter treatment durations for gram-negative bacteremia, the literature also seems to support de-escalation from intravenous to oral antibiotics. In a recently published systematic review and meta-analysis, Punjabi et al. reviewed eight retrospective studies that compared step-down oral therapy for enterobacteriaceae bacteremia.4 The study included data for 2,289 patients, 65 percent of whom were transitioned to oral fluoroquinolones, 7.7 percent to trimethoprim-sulfamethoxazole, and 27.2 percent to beta-lactams. The authors found no significant difference in all-cause mortality in patients de-escalated to either group of oral antibiotics (OR = 1.13; 95 percent CI, 0.69 to 1.87), but they did find an increased risk of infection recurrence in patients transitioned to oral beta-lactams versus fluoroquinolones (OR = 2.05; 95 percent CI, 1.17 to 3.61). Of note, factors such as underdosing of and decreased adherence due to frequency of dosing of beta-lactams may have contributed to the increased recurrence. Although the optimal oral antibiotic upon de-escalation still requires further investigation, recent evidence supports the use of step-down oral therapy for enterobacteriaceae bacteremia in regard to patient outcomes.

Bacteremia is a high risk infection that leads to increased mortality, healthcare costs and utilization of hospital resources. Without clear direction from national guidelines, practitioners must evaluate available literature in order to optimize patient care. Two main areas of interest in bacteremia treatment include length of treatment and transitioning from intravenous to oral therapy. As described, the literature supports limiting treatment to 10 days of therapy as well as transitioning to oral antibiotics when medically appropriate. Since literature updates focus on bacteremia caused by enterobacteriaceae from urinary sources, clinicians should continue to evaluate a variety of resources to determine the most effective treatment of all types of bacteremia.

References:

  1. Goto M, Al-Hasan MN. (2013). Overall burden of bloodstream infection and nosocomial bloodstream infection in North America and Europe. Clin Microbiol Infect, 19, 501-9.
  2. Riu M, Chiarello P, Terradas R, et al. (2017). Incremental cost of nosocomial bacteremia according to the focus of infection and antibiotic sensitivity of the causative microorganism in a university hospital. Medicine (Baltimore), 96(17):e6645.
  3. Tansarli G, Andreatos N, Pliakos E, et al. (2019). A Systematic Review and Meta-analysis of Antibiotic Treatment Duration for Bacteremia Due to Enterobacteriaceae. Antimicrob Agents Chemother, 63(5):e02495-18.
  4. Punjabi C, Tien V, Meng L, et al. (2019). Oral Fluoroquinolone or Trimethoprim-sulfamethoxazole vs. ß-lactams as Step-Down Therapy for Enterobacteriaceae Bacteremia: Systematic Review and Meta-analysis. Open Forum Infect Dis, 6(10):ofz364.
Posted in: Professional Practice
Providing Feedback to Students and Residents

Marilen C. Martinez, Pharm.D., BCPS, Henry Ford Macomb Hospital, Clinton Township

Feedback is an essential component of experiential training for student pharmacists and residents. The American Society of Health-System Pharmacists (ASHP) Accreditation Standards for PGY-1 Residency note that preceptors must provide ongoing feedback to residents about how they are progressing and how they can improve. It should be frequent, immediate, specific and constructive.1 Activities that can trigger feedback include presentations, answering drug information questions, making recommendations during rounds, patient counseling sessions or the completion of a project. Feedback is essential to learning, however student pharmacists and residents may not recognize that feedback has been provided. Preceptors may be providing feedback on a regular basis, but the trainees may not perceive it that way. At the beginning of the rotation, it is important to discuss how feedback will be provided to mitigate any confusion.

It is notable to distinguish the difference between feedback and evaluation. Although used similarly, they can serve two different purposes. Both provide information to the trainee to improve her or his performance and can encourage self-assessment. Feedback, or formative assessment, is an ongoing evaluation of the trainee and can be used to provide information on actions that were directly observed. Evaluation, or summative assessment, is used to measure the trainee’s achievement of a goal, usually at the end of an activity or rotation. Feedback is most typically thought of as an informal, short discussion, compared to evaluation which is thought of as a formal, extended discussion. Feedback reinforces good practices, corrects mistakes and modifies behavior, all while working toward the goals of the experience. Evaluation usually grades the experiences and reviews how goals were met. It also provides suggestions for future experiences.2,3

There are several approaches to providing feedback. A commonly used approach is the Feedback Sandwich which provides positive feedback, followed by a corrective statement, then closes with another piece of positive feedback. This method may be helpful to ‘soften the blow’ of the constructive criticism so the trainee may be able to accept the negative feedback and avoid becoming defensive. Another approach is the Pendleton Four-Step Model, where 1) the trainee states what is good about her or his performance, 2) the preceptor states areas of agreement and elaborates on good performance, 3) the trainee describes areas of improvement, and 4) the preceptor states what could be improved. This approach allows for the trainee to self-evaluate her or his performance and develop a self-awareness of her or his own strengths and weaknesses. The last approach is the Situation-Behavior-Impact (SBI) Feedback Tool that was developed by the Center for Creative Leadership and has three distinct parts. The first is situation, which is when the preceptor defines when and where a performance was addressed so the feedback is put into context of a specific setting and time of reference. The second part is for the preceptor to describe specific behavior that was witnessed directly without assumptions or subjective judgement of that behavior. The third and final part is impact, where a preceptor describes how the behavior affected the trainee or the patient.2

Even with these feedback techniques, providing difficult or negative feedback to a trainee can be challenging. constructive feedback may be necessary when the trainee has displayed unprofessional behavior, is unprepared for rotational activities, or has not completed an assignment. Another preceptor or program director present when providing negative feedback may be considered. The preceptor may reframe the bad news, for example if a trainee is not meeting expectations, as an opportunity for improvement. The preceptor should be direct about the issue and should provide a stepwise plan to improve the trainee’s performance. It is important to allow the trainee to provide her or his own thoughts about the negative feedback. Lastly, the preceptor should point out what is working well along with what needs additional work.2

Feedback is crucial for a pharmacy trainee’s learning but often there are obstacles and challenges when providing feedback. By providing timely feedback with specific examples, preceptors can improve their skills and trainees may have a great appreciation for the quality of guidance that was offered.

References:

1. American Society of Health-System Pharmacists. ASHP accreditation standards for residencies in pharmacy practice. https://www.ashp.org/-/media/assets/professional-development/residencies/docs/pgy1-residency-accreditation-standard-2016.ashx?la=en&hash=9FF7C76962C10562D567F73184FAA45BA7E186CB (accessed 2020 Feb. 20).

2. Soric MM, Schneider SR, Wisneski SS. The effective pharmacy preceptor. Bethesda, MD: American Society of Heath-System Pharmacists, 2017.

3. Grover B, Hayes BD, Watson K. Feedback in clinical pharmacy education. Am J Health-Syst Pharm. 2014;71:1592-6.

Posted in: Professional Practice
MSHP Student Pharmacist Luncheon at the 2020 Annual Convention & Exposition

Peggy Malovrh Pharm.D., BCPS, Sparrow Hospital, Lansing

The annual MSHP Student Luncheon was held Saturday, Feb. 22, 2020, during the MPA Annual Convention & Exposition (ACE) in Detroit. With 130 registered, the function was well attended by student pharmacists from all three colleges of pharmacy in Michigan, as well as a few out-of-state students. Each table had the capacity of eight students and a MSHP leader. Students from each academic year of school participated and it was really nice to see the networking among schools and year of study.

Curtis Smith, current MSHP president, welcomed the student pharmacists and thanked everyone for coming. Guests at each table took some time to introduce themselves, share their personal career experience, and past experiences at the ACE meeting and MSHP student luncheon. The pharmacist table leader also shared their own career path, talking about pros and cons of their area of practice and how they ended up in their current position. There was lively discussion among the tables, including a great ice breaker of guessing the names of medication. Without peeking, a student would hold a card to their forehead containing the name of a medication. Clues were given until the medication was identified. It was very impressive, seeing the rapid discovery of the correct answer after only a few clues, even by the first-year pharmacy students.

During dessert and coffee, a serious conversation was held at my table on the under-staffing issues at larger pharmacies and how it impacts patients and pharmacists alike. The shortage of licensed technicians seemed to be a common denominator among the group. Maximizing technology and expanding technician roles were other identified solutions. Other tables discussed such topics as the opioid crisis, drug shortages and the impact on health care, provider status and collaborative practice agreements.

Before concluding, each table held a raffle for an Amazon gift card, and participants parted ways on a very positive note, many making arrangements to meet again later that evening during the Annual Awards Banquet through the Michigan Pharmacy Foundation (MPF) Adopt-A-Student program.

It was encouraging to hear all the student pharmacists voice their commitment to the profession and resolution to continue to be actively involved in local, state and national associations. Many students expressed interest in pursuing a residency and some were interested in learning more about fellowships with manufacturers.

Regardless of the various career paths, it was clear that all of these student pharmacists have a passion for patient care and making a difference in the lives of their patients.

Posted in: Member News
MSHP Member Spotlight: Matthew Rico, Pharm.D.

Matthew Rico, Pharm.D.
PGY1 Pharmacy Practice Resident
Ascension Genesys Hospital
Grand Blanc

Something interesting about yourself that you would like to share: When I retire after a successful career in pharmacy, I think it would be awesome to own a coffee shop! 

Describe Your Role/Day In the Life: As a resident, I have learned how to function in many different practice areas within the pharmacy department at Genesys to prepare for the rest of my career. I have had the opportunity to become involved with many different committees at Genesys, such as the P&T Committee, Antimicrobial Stewardship Committee, and the ICU/Telemetry Task Force. Additionally, Ascension has offered me opportunities to become involved with statewide and national antimicrobial stewardship committees to impact patient care across their network of hospitals. I hope to move on to a PGY2 in Infectious Diseases next year! 

Why are you an MSHP/MPA Member: MSHP has provided me with a platform to meet some of the most influential people in the state of Michigan. I have really enjoyed working with members of the Antimicrobial Stewardship Committee to learn about how to further stewardship practices at many different institutions. Making connections with pharmacy leaders who have the drive to make change is an invaluable resource to me and I'm very thankful to be a part of MSHP! 

Recent Accomplishments: I graduated from Ferris State University College of Pharmacy in May 2019 with High Distinction. Additionally, I had the privilege to write an article on the updated CAP Guidelines for the MSHP Monitor in March. 

Posted in: Member News
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