GAMECHANGERS IN PHARMACY

SUNDAY/11:00AM-12:30PM

ACPE UAN: 0107-9999-18-270-L01-P 0.15 CEU/1.5 hr

0107-9999-18-270-L01-T 0.15 CEU/1.5 hr

Activity Type: Application-Based

Learning Objectives for Pharmacists & Pharmacy Technicians:

Upon completion of this CPE activity participants should be able to:

1. List selected Gamechangers that affect your practice.

2. Describe reasons the selected Gamechangers were chosen and how they affect the way pharmacists care

for patients.

3. Describe possible solutions to the clinical problems listed.

4. Assess the clinical trials used to support this presentation.

5. Apply the information presented to your specific practice.

Speaker: Geoffrey C. Wall, PharmD, FCP, BCPS, CGP

Dr. Geoffrey C. Wall is a Professor with the Department of Clinical Sciences, College of Pharmacy

at Drake University and Director of the Drake Drug Information Center. His clinical practices

include the Internal Medicine and Medical Intensive Care Teaching Services at Iowa Methodist

Medical Center in Des Moines, IA. Dr. Wall received his Bachelor of Science in Pharmacy from

the University of Utah in 1992 and his Doctor of Pharmacy from Idaho State University in 1998.

He completed an ASHP-accredited Internal Medicine Specialty Residency at Scott and White

Memorial Hospitals and Clinics in 1999. He is Board-Certified in Pharmacotherapy and a

Certified Geriatric Pharmacist. He is a Fellow of the American College of Clinical Pharmacy. Dr.

Wall has written a number of peer-reviewed papers and textbook chapters on a variety of topics,

and has designed or participated in several clinical trials. His research interests include drug

treatment of gastrointestinal disorders, clinical evaluation of drug allergy and rheumatologic

disorders.

Speaker Disclosure: Geoffrey Wall reports that he is on the speaker’s bureau with Boehringer Ingelheim,

Janssen and La Jolla Pharmaceuticals. Off-label use of medications will be discussed during this presentation.

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Presented by:

Gamechangers in Pharmacy: 2018

Geoffrey C. Wall

Pharm.D., FCCP, BCPSProfessor of Pharmacy Practice, Drake UniversityInternal Medicine Medical Center

Des Moines, IA

Disclosure

• Geoff Wall reports:• A Speaker’s bureau member for Janssen, Boehringer Ingelheim, La Jolla Pharmaceuticals• Off-label use of medication will be discussed during this presentation.

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Learning Objectives

• Upon successful completion of this activity, participants should be able to:

1. List selected Gamechangers that affect your practice

2. Describe reasons the selected Gamechangers were chosen and how they affect the way pharmacists care for patients

3. Describe possible solutions to the clinical problems listed

4. Assess the clinical trials used to support this presentation

5. Apply the information presented to your specific practice

What Are Gamechangers

• Facets of clinical medicine that directly impact the everyday practice of the majority of “boots on the ground” pharmacists

• Some Gamechangers are specific to practice site• IV dug shortages, oral blockbuster drug goes generic

• Others are more general in scope• Affordable Care Act changes, landmark study published

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Examples of Gamechangers

• New, first-in-class drug released

• Vanguard or seminal study published

• Wide-impact practice guidelines

• Reported ADRs of widely used medications

• FDA regulations/warnings

• New or changing laws/policies

• Economic changes

Problem: How to determine a Gamechanger• Any one practitioner will always have bias of putting weight on the

factors that influence THEIR practice

• May be unaware of a fundamental change in another area of practice

• Evaluation of potential Gamechanger may be out of area of expertise

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Solution: Gamechanger Panel

• Representatives from hospital, community, long-term care with oversight by a pharmacist with expertise in regulatory affairs

• Independently select list of Gamechangers

• Meet and determine the top contenders via Modified Delphi Method

• Peer-reviews presentation data

Gamechanger 2018 Panel Brian Benson, PharmD, FASHP

Exec. Director of Pharmacy, Unity Point Health Jennifer Moulton, RPh

CEO, The Collaborative Education Institute Kristin Meyer, PharmD

Clinical Pharmacist, Iowa Veterans Home Cheri Schmit, RPh

Director of Clinical Pharmacy, GRX Holdings

Sarah Derr, PharmD Director, Medication Safety and Efficacy, Iowa Healthcare

Collaborative

Kristin Stover, PharmD Additional peer-review

Matt Pitlick, PharmD Executive Fellow, Iowa Pharmacy Association

CS1

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Gamechanger Ground Rules

• This list was compiled by the Panel• Your Gamechanger may not have been included

• Every effort made to be up-to date

• This presentation does not have “all the answers” in controversial areas

• Not listed in perceived order of importance

Gamechanger #1

• The 2018 IDSA guidelines for Clostridium difficille disease• I will avoid any poop jokes here…..

McDonald LC, et al. Clinical Infectious Diseases 2018; 66: e1–e48.

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Why needed?

• Although, thanks to infection control measures, CDAD infections have leveled off locally, such infections are still common

• Associated with ABX use and recurrences

• Still has the potential to cause severe, even life-threatening disease

• Multiple papers since the last guidelines had the potential to change practice

How Developed

• How developed: Expert panel used a PICO format to answer specific questions concerning CDAD. Then a systematic review was performed and a standardized assessment of evidence was completed.

• Level of evidence: Strong , Moderate, Low, Very low based on strength of data and safety vs efficacy and cost

• It should be noted that many recommendations do not have moderate-to-strong levels of guiding evidence

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Introduction

• Case definition: (1) the presence of diarrhea or evidence of megacolon or severe ileus and (2) either a positive laboratory diagnostic test result or evidence of pseudomembranes demonstrated by endoscopy or histopathology

• Risk factors for severe disease: Elderly, IBD, Transplant, Cancer, CKD/Dialysis

• ABX with highest association with CDAD: third-/fourth-generation cephalosporins , fluoroquinolones, carbapenems , and clindamycin

• Its worth noting that overall incidence rates of the above are similar

Diagnosis and Prevention

• Diagnosis: Test if new-onset ≥3 unformed stools in 24 hours (Weak Rec)

• Toxin A and B enzyme immunoassays (EIA) detects the actual toxins and should be used in combination with another test like PCR to improve sensitivity and specificity (Weak Rec)

• Remember Stool FA is PCR and does not detect toxin

• Do not perform repeat testing (within 7 days) during the same episode of diarrhea and do not test stool from asymptomatic patients, except for epidemiological studies ( >60% of patients may remain C. difficile positive even after successful treatment) (Strong Rec)

• Infection Control: Gowns and Gloves are a must. Continue contact precautions for at least 48 hours after diarrhea has resolved. Soap and water are preferred to alcohol based hand gels (Weak Rec)

• But hand gels are better than nothing!

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ATLAS ScoreParameter 0 points 1 point 2 points

Age < 60 years 60 – 79 years ≥ 80 years

Treatment with systemic antibiotics during CDI therapy (≥ 1 day)

No --------- Yes

Temperature ≤ 37.5°C 37.6 – 38.5°C ≥ 38.6°C

Leukocyte count (total)

< 16,000 16,000 –25,000

> 25,000

Albumin (serum)

> 35 g/L 26 – 35 g/L ≤ 25 g/L

Serum creatinine (as a measure of renal function)

≤ 120 μmol/L 121 –179 μmol/L

≥ 180 μmol/L

Miller et , al. BMC Infectious Diseases2013:148 https://doi.org/10.1186/1471-2334-13-148

Role of scoring systems?

• IDSA does NOT recommend any one severity scoring system and instead bases treatment decisions on presence of hemodynamic instability and recurrence

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Treatment• First episode: Vanco 125 po QID or fidaxomicin 200 mg

twice daily for 10 days (note metronidazole removal and no recommendations concerning assessment of severity of disease) (Strong Rec)

• Fulminant disease (hypotension or shock, ileus, or megacolon): vancomycin 500 mg orally QID OR 500 mg in approximately 100 mL normal saline per rectum every 6 hours as a retention enema + IV metronidazole 500mg q8h (Strong Rec)

• First Recurrence: Pulsed Vancomycin (eg, 125 mg 4 times per day for 10–14 days, 2 times per day for a week, once per day for a week, and then every 2 or 3 days (over 6 weeks) OR Fidaxomicin x 10 days (Weak Rec)

• Metronidazole removed because of several studies showing recurrence rates more common compared to PO vanco

Other Treatment Recommendations

• >1 Recurrence: FMT (Strong Rec) OR Tapered PO vanco ((eg, 125 mg 4 times per day for o 10–14 days, 2 times per day for a week, once per day for a week, and o then every 2 or 3 days or po vanco X 10 days followed by rifaximin 400 mg 3 times daily for 20 days or Fidaxomicin x 10 days (Weak Rec)

• No recommendation on prophylaxis in patients requiring other ABX at high risk of recurrence of CDAD, but one study suggested Vanco 125 po BID is reasonable

• No recommendations for probiotics for prevention or during treatment of CDAD

• No recommendation for withholding PPIs during treatment, but is probably reasonable unless patient has an absolute indication for PPI use like a recent GIB. H2RAs can be substituted during CDAD treatment

Van Hise HW, et al. Clin Infect Dis. 2016 Sep 1;63(5):651-3

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Some treatment pearls

• Remember COST!• PO vanco capsule cost is about $1000 for 14 days• A commercially available liquid was just given FDA approval

• Why could this a problem??

• 10 days of fidaxomicin = $3000• Numerous patient assistance programs exist from new manufacturer

• Chaser of Rifaximin = $1500• Most insurance companies will not pay as this is not an approved indication

• Cost of FMT• $3000, but freeze-dried encapsulated stool may be available this year…

• Cost of recurrence is about $15,000

While on the subject of ABX• FDA reinforces safety information about serious

low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes

• Strengthened warning about hypoglycemia—may be more common then generally thought

• NEW warnings about CNS adverse effects• disorientation, agitation, nervousness, memory impairment,

and delirium have all been reported

• TRY NOT TO USE THESE DRUGS FOR “COMMON” infections such as sinusitits or uncomplicated UTIs if possible

• Should have come up with this warning 20 years ago…..

https://www.fda.gov/Drugs/DrugSafety/ucm611032.htm. Accessed 11/5/18

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Gamechanger #2

• Update of the use of aspirin to prevent vascular disease events• After reading the studies you’ll need an aspirin for a headache….

Total Cardiovascular Disease Death Rates by State, Age Adjusted

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CVD and DM

• Risk of CV events is increased from 2- to 4-fold in type 2 diabetes1

• Aspirin is recommended for primary prevention in patients with type 2 diabetes in many guidelines, including AHA2,3

• Previous aspirin primary prevention trials have had diabetic subgroups but data were limited from European and North American populations4,5 and nonexistent from Japan

1. Haffner SM, et al. N Engl J Med. 1998;339:229-234; 2. American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4-S41; 3. AHA/ADA Scientific Statement. Circulation. 2007;115:114-126;4. Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86; 5. Sacco M, et al. Diabetes Care. 2003;26:3264-3272.

CVD and the Frail Elderly• The US Preventive Services Task Force 44 in 2016

noted that among individuals with a 10-year cardiovascular disease risk of 10% or higher based on the ACC/AHA pooled cohort equation, 3 the greatest benefit of aspirin was in those ages 50 to 59. In this age group, 225 nonfatal myocardial infarctions and 84 nonfatal strokes were prevented per 10,000 men treated, with a net gain of 333 life-years. Similar findings were noted in women.

• However, in those ages 60 to 69, the risks of harm begin to rise and the benefit of starting daily aspirin necessitates individualized clinical decision-making, with particular attention to bleeding risk and life expectancyOrakby AR, et al. Cleveland Clinic Journal of Medicine. 2018; 85:55-64

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• Well established over dozens of studies• Myocardial infarction [MI], stroke, and vascular death in patients

who have experienced an MI or a stroke. The absolute risk reduction for treatment over 2 years is 36 ± 5 per 1,000 in patients who have had an MI, 36 ± 6 per 1,000 in patients who have had a stroke or transient ischemic attack

• But in PRIMARY prevention the data is much less clear the benefit outweighs the risk—particularly of GI bleeding

• THREE new studies in the last year have clarified this conundrum • In general patients with moderate CV risk factors• In patients with DM• In patients over age 75

Secondary Prevention

Fanaroff AC et al. Int J Cardiol. 2017;241:87-96.

• R, DB, PC, international study, n = 12, 546

• Inc: Men age > 55, Women age> 60 + 3 CV risk factors: HLP, HTN, Smoking, + FH

• COULD be on treatment for modifiable risk factors

• Exc: known vascular disease, including CV or stroke, CHF, or high risk for bleeding, DM patients, on antiplatelet or anticoagulants for another reason

• Intervention: ASA 100mg daily (EC) or matching placebo,

• Median follow-up: 60 months

• Outcomes:• Efficacy: composite outcome: MI, CVS, USA, CV death,

TIA• Safety: Major bleeding by GUSTO criteria

The ARRIVE study

Gaziano JM, et al. Lancet 2018; 392: 1036–46

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Selected Baseline Characteristics

Aspirin (n=6270)

Placebo (n=6276)

% Male 70.5 70.4

% Smoker 28.8 28.5

SBP, Mean, mm Hg

145 145

Mean Framingham

Score

13.9 14.1

Outcomes

• No difference in any efficacy outcome

• NNH = 197

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The ASPREE Study• R, PC trial to determine if use of aspirin in healthy, community-dwelling older

adults would prolong healthy life span, free from dementia and persistent physical disability

• INC: Australia and the U.S. patients > age 70 (or ≥65 years of age among blacks and Hispanics in U.S. arm) WITHOUT dementia or serious physical disability

• EXC: known diseases that would limit life span to < 5 years, known CV disease of stroke history

• Intervention: ASA 100mg daily or placebo

• Trial ended at average 4.7 years follow-up, n = 19,114

• Outcomes: • Efficacy: disability-free survival, death from any cause• Safety: Major bleed

• Stratified numerous ways, including age and weight

McNeil JJ, et al. N Engl J Med 2018;379:1499-508.

Selected Baseline Characteristics

Aspirin (n=6270)

Placebo (n=6276)

% Male 43.6 43.6

Age 74 or >, mean, yrs

50.5 49.7

HTN % 74.2 74.5

BMI, mean 28.1 28.1

% Frail 58.8 58.8

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Outcomes

• No difference in primary outcome or any secondary outcome

• Incidence of major bleed 3.8% vs 2.8% (p < 0.001), NNH = 100

• No difference in death from any cause

• R, DB, PC, U.K. study, n = 15, 480

• Inc: Any patient with DM over age 40 without known CV disease who did not have another indication for antiplatelet or anticoagulant therapy

• Exc: Likely to not complete a 5 year study, C/I to ASA

• Intervention: ASA 100mg daily (EC) or matching placebo

• 2X2 factoral design also look at omega-3 fatty acids

• Median follow-up: 7.4 years

• Outcomes:• Efficacy: 1st serious vascular event, which was defined as a

composite of MI, CVA, Death from vascular cause, TIA• Safety: Major bleeding

The Ascend study

Bowman L, et al N Engl J Med 2018;379:1529-39.

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Selected Baseline Characteristics

Aspirin (n=7740)

Placebo (n=7740)

% Male 62.6 62.5

Age, yr, mean 63.2 63.3

BMI, Mean 30.8 30.6

Statin Use, % 75.6 74.9

Outcomes

ASA reduced vascular events by 12% but increased risk for major bleed by 29%NNT = 91, NNH = 111

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And while we are on the subject….• Is body weight a factor in ASA effectiveness?

• Recent patient data level review of several studies looking at ASA use in primary prevention

• Trials were eligible if they randomly assigned > 1000 participants to daily or alternate-day aspirin versus no aspirin

• Patient level data extracts from original databases• Results: Found that low dose ASA was effective only in patients up to 70

kg (p-interaction=0·0072), while higher dose (325mg+) was effective only in patients above 70 kg (p-interaction=0·0072)

• Explanation of these findings is largely unknown as antiplatelet effects of ASA occur at low doses

• I WOULD NOT SWITCH OBESE PTS TO HIGH DOSE ASA BASED ON THIS INFORMATION

Rothwell, PM et al. Lancet 2018; 392: 387–99

So what does it all mean?

• Secondary prevention with ASA is still unequivocally beneficial • BUT• Million of primary prevention patients take ASA for “heart health” that

are gaining no benefit and perhaps harm by doing so

• Pharmacist’s role:• Ask patients about their CV risk before recommending ASA to all older

patients

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Gamechanger #3

• Legislative Update (Iowa)

• Big changes from the statehouse

Technician Role

• ARC4030C

• Proposed law allowing technicians to transfer noncontrolledprescriptions and receive transfers of noncontrolled prescriptions

• Proposed law allowing technicians to dispense medications to patients that do not need counseling while a pharmacist is on a “break of limited duration”

• All at the discretion of the pharmacist on duty

CS2CS4

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Expanded Tech Roles

• Usually requires additional:• Experience• Education• Training• Competencies (including analytical and problem-solving skills)

• Certification• Competence Assessment• Supervision of pharmacists• State Board of Pharmacy approval• Liability issues??• Pharmacist resistance??

CS3CS5

What do you Value?

• Statement 1: We need a competent and capable technician workforce to allow pharmacists to perform patient care activities

• Statement 2: If techs can dispense, I will be out of a job

• Statement 3:??

CS10

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Pharmacy-Interns

• ARC4091C

• Proposed amendment that removes limitation of number of interns being supervised under one pharmacist concurrently

Naloxone

• Pharmacists must complete at least 1-hour of ACPE-approved CE related to naloxone prior to dispensing naloxone

• Prior to dispensing naloxone pursuant to the statewide protocol, provide training and education to the patient

• Written materials shall not be in lieu of direct pharmacist consultation with the patient

• After, the pharmacist shall notify the patient’s primary health care provider of the transaction

• If the patient does not have a primary health care provider, the authorized pharmacist will provide a written record of the naloxone provided to the patient and advise the patient to consult a physician

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Naloxone Formulations AvailableProduct Route of

Adminis-tration

AvailableStrengths

Dosing Advantage Price per Dose*(7/2015)

FDA Status

Auto-injector

IM 0.4mg/ml 0.4mg No training requiredEasy to useNo assemblyDecreased risk of needle stick

$345 Yes

Multi-useVial

IM, IV, SC 0.4mg/ml 0.4mg Multiple doses $11.84 Yes

Single Dose Vial

IM, IV, SC 0.4mg/ml 0.4mg Individual dose $18.99 Yes

Prefilled Syringe

Intranasal 1mg/ml 1mg Easy to useDecreased risk of needle stick

$19.80 Yes

Tobacco Cessation• Pharmacists must complete at least 1-hour of ACPE-

approved CE related to nicotine replacement tobacco cessation product utilization

• Prior to dispensing tobacco cessation products pursuant to the statewide protocol, provide training and education to the patient

• After, the pharmacist shall notify the patient’s primary health care provider of the transaction

• If the patient does not have a primary health care provider, the authorized pharmacist will provide a written record of the naloxone provided to the patient and advise the patient to consult a physician

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Cannabis

• 5 dispensaries in Iowa opening Dec. 1st

• ARC4085C• Approved 10/3/18

• Any drugs approved by the FDA which contain cannabidiol (CBD) derived from cannabis and no more than 0.1 percent tetrahydrocannabinols (THC) are placed into Schedule V Controlled Substances

• Physician must fill out application form and certify that patient is suffering from a ‘debilitating condition’

• Medical cannabis card is valid for 1 year from approval date and may be cancelled at any time

Cannabis Cont.• Patients may NOT smoke medical cannabidiol or

consume ‘edibles’• Tablet, Capsule, Liquid, Tincture, Sublingual, Topical forms,

Nebulizable inhaled forms, rectal/vaginal forms

• 90-day supply max of each product, as determined by dispensary staff/manufacturers/literature

• No physicians or pharmacists on staff

• Manufacturers are required to collect and dispose of excess cannabidiol from dispensaries, including medical cannabidiol that was returned to a dispensary from a patient or primary caregiver

• Provider FAQ• https://www.legis.iowa.gov/docs/iac/chapter/641.154.pdf

CS6

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Gamechanger #4

• 2018 ADA/EASD Guidelines for the treatment of DM 2

• Improved macrovascular outcomes—but at a cost??

Mohamed S, et al. JAMA. 2017;318:132-145.

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Can DM drugs by themselves reduce CV risk? Apparently Yes• FDA-approved for reduced CV risk

• SGLT-2 inhibitors• Empagliflozin (Jardiance)• Canagliflozin (Invokana)

• GLP-1 agonists• Liraglutide (Victoza)

? Class effect

Literature Review

• What’s the evidence?• Canagliflozin (CANVAS trial 2017)

• Included 10,142 participants with DMII• 30 years old w/ ASCVD• 50 years old with two + CV risk factors (see below)• Randomized to 300mg daily, 100mg daily, or placebo

• Results• Reduced combined risk of MI, stroke, and CV death by 14%

• (hazard ratio [HR], 0.86; 95% CI, 0.75 - 0.97; P < .0001 for noninferiority, P = .0158 for superiority).

• Patients with CVD risk reduction =18% • (HR, 0.82; 95% CI, 0.72 - 0.95)).

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Literature Review

• What’s the evidence (cont.)• Empagliflozin (EMPA-REG 2015)

• Enrolled 7,020 patients with DMII• Patients were 18 years +• BMI < 45• GFR > 30 mL/min/1.73m2

• Randomized to Empagliflozin 20mg, 10mg, or placebo

• Results• Reduced risk of death from MI or CV causes by 13%

• (HR 0.86; 95.02% confidence interval [CI], 0.74 to 0.99; P

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Considerations

• SGLT-2 Inhibitors• FDA Black Box: Increased risk of amputation

• Well noted HR 1.98 in CANVAS trial

• Renal insufficiency• CrCl < 30 mL/min use is contraindicated

• GLP-1 Agonists• FDA Black Box: Increased risks of thyroid cancer

• Avoid use in patients with personal/family hx of thyroid cancer

Considerations

• Some drugs may worsen CV outcomes

• 2nd Generation Sulfonylureas• FDA warning of worsened CV outcomes based on studies with Tolbutamide

• Thiazolidenones• FDA Black Box: Increased risk of HF

• Both Pioglitazone (Actos) and Rosiglitazone (Avandia)

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Medication/Class Impact on CV Outcomes

Recs for Use in DM2 patients with

CVD

Insulin Neutral Use if failed 2+ therapies or

diagnosis A1C ≥ 10%

Metformin ↓ MI risk First line therapy

Sulfonylureas Overall neutral, may ↑risk of MI

Use if other therapies cost

prohibitive

GLP-1 Liraglu de ↓CVD, others neutral

Consider liraglutideearly, esp in obese

patients

DPP-IV Saxagliptin ↑ HF others neutral

Avoid saxagliptin in HF

SGLT2 Class ↓ CVD, CV death, ACM

Consider early in these patients

Recommendations

Gale SE, et al. Pharmacotherapy 2018;38:739-57

Gamechanger #5

• The Updated Beer’s Criteria 2018

• No, not that kind of beer’s list

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Introduction

• What is the Beers Criteria (aka the Beers List)???

• List of POTENTIALLY inappropriate medications for use in older adults

• Published by the American Geriatrics Society

• Originally created in 1991 by the late geriatrician, Mark Beers, MD

History of the Beer’s List• Beers Criteria: History and Utilization

• Original 1991 – Nursing home patients

• Updates• 1997 All older adults; adopted by CMS in 1999 for nursing home regulation• 2003 Era of generalization to Med D, NCQA, Healthcare• Effectiveness Data and Information Set (HEDIS)• 2012 Further adoption into quality measures• 2015 Introduction of drug‐drug interactions (DDI), renal dosage tables, how to

use, and alternatives papers• 2018: Updated list completed

Marcum ZA, et al. Am J Geriatr Pharmacother. 2012;10:151–159.

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Key Changes to Beer’s 2018*

• Glimepiride – sulfonylureas to avoid• Try to avoid SU in the elderly if possible*

• SNRIs – avoid in patients with history of falls or Fractures• One study found increased risk of both compared to other antidepressants*

• ASA for primary prevention of CV disease – age to use with caution lowered to >70 yrs

• See previous Gamechanger*

• Rivaroxaban for treatment of VTE or a fib in adults >75 yrs• GI bleeding increased compared to warfarin & other NOACs

• DPP‐4 inhibitors in patients with heart failure • Tramadol added to drugs associated with SIADH or hyponatremia

Key Changes to Beer’s 2018

• Cotrimoxazole (trimethoprim-sulfamethoxazole)• Increased risk of hyperkalemia in pts Drug Interactions

• Additions:• Opioids + benzodiazepines• Opioids + gabapentinoids• Some antibiotic interactions• Concomitant drugs that can increase potassium• Modification:

• Simplified CNS depressant interactions• Avoid 3 or more concomitantly

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Gabapentanoids and ADRs

• Pregabalin and the Risk for Opioid‐Related Death

• Design: Nested case–control study

• Sample: 1417 cases with fatal opioid overdose matched with 5097 controls (median age 48) •

• Results: Any recent pregabalin use increased the risk of overdose• Adj. OR 1.68; (95% CI, 1.19 to 2.36)

• Those taking > 300mg/d of pregabalin had higher risk• Adj. OR, 2.51; (95% CI 1.24‐5.06)

Gomes T, et al. Ann Int Med 2018; DOI: 10.7326/M18‐1136

Dosing of Gabapentin/Pregabalin in the elderlyGabapentinoid Renal Dosing

Drug est CrCl (ml/min) Max. Dosage (mg)

Gabapentin 30‐59 600 bid

15‐29 300 bid

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“Start Low and Go Slow…”• Start one medication at a time.

• Start with a low dose and increase gradually.

• Once daily is usually best.

• Monitor for response and adverse effects.

• Assess adherence with regimen.

“…But, Go All The Way!”• Be conservative, but don’t miss the target!

• What is your goal? Are you achieving it?

• Can you keep increasing the dose or are you limited by side effects?

• Are you observing a clinical benefit at lower doses?

• Consider stopping if you can’t “go all the way” and the benefit is not clear.

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“Deprescribing”

“Systematic process of identifying and discontinuing drugs in instances in which

existing or potential harms outweigh existing or potential benefits within the

context of an individual patient’s care goals, current level of functioning, life

expectancy, values, and preferences.”

JAMA Intern Med. 2015;175(5):827-834

“Deprescribing” Should Be Considered

• New symptom or clinical syndrome suggestive of ADE

• Advanced disease, terminal illness, extreme frailty

• High-risk drugs or combinations

• Preventive drugs for scenarios associated with no increased risk despite stopping drug

• Stopping alendronate after 5 years of treatment results• Stopping statins for primary prevention

• Patient/family willing to participate in shared decision

JAMA Intern Med. 2015;175(5):827-834

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“Deprescribing”• Instruct patient to bring all medications to visit

(prescription and non-prescription)

• What Are Current Indications for Each Drug?

• Is the Patient Actually Taking the Drug?

• Does the Likely Benefit of the Drug Outweigh Its Potential for Harm?

• This is where looking at the Beers Criteria can have the most clinical impact

• Time to benefit for preventive medications

JAMA Intern Med. 2015;175(5):827-834

Gamechanger #6

• The 2018 CHEST guidelines on antithrombotic therapy in atrial fibrillation

More Choices = More problems??

Liip GYH, et al. CHEST 2018; 154:1121-1201

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Background

• In the “old days” the CHEST guidelines were a tome released published every 3-4 years

• The “bible” of antithrombotic therapy

• Now, like other medicine groups periodic guidelines are released more frequently

• NEW guidelines in AF needed because of the NOACs and data surrounding their use

• Note that the rate of AF is tied to an aging population so incidence of AF is expected to dramatically increase

• Focused only on antithrombotic therapy in AF

Methodology

• Designed in a Clinical Question/Answer format

• Evidence-Based results is the highest priority

• In depth process for procuring/analyzing data

• “Consensus” recommendations given lower priority

• Systematic reviews/meta-analyses included

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Recommendation Grading

• Overall Recommendations• Grade 1 = Benefits clearly outweigh risks, strongest recommendation• Grade 2 = Less clear risk/benefit ratio

• Methodologic Quality• Grade A = RCTs with clear results• Grade B = RCTs with inconsistent results, or poor quality• Grade C = Observational studies, other data

• Grades combined in final score

Key recommendations for Pharmacists

• 1- Use the CHADS2Vasc Score AS WELL as the HAS-BLED scoring systems to assess benefit and risk of antithrombotic therapy (strong, mod)

• “A high HAS-BLED score (> 3) is rarely a reason to avoid anticoagulation” but warrants closer follow-up

• 2-Do NOT use ASA or ASA + Clopidogrel for stroke prevention in AF (Strong, Mod)

• WHY? Only the SPAF-1 study suggested ASA is beneficial for AF no other subsequent study has been able to demonstrate this AND risk for bleeding—especially ICH—is nearly as high with ASA as with warfarin

Lancet. 2006;367(9526):1903-1912.Circulation. 1991;84(2):527-539.

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Key recommendations for Pharmacists

• 3-NOACs are now PREFERRED over warfarin for AF (Strong, Mod)

• Generally all of these drugs have been found to be at least as efficacious as warfarin and generally safer—especially in ICH

• 4-In patients on warfarin a TTR of > 70% should be targeted, (Consensus only)

• If cannot maintain this, switch to NOAC if possible

• 5-In AF patients in which aspirin is concomitantly used with antithrombotic therapy use baby ASA + a PPI to minimize gastropathy (Weak, low)

• In stable CVD a patient started on antithrombotic therapy can OMIT ASA—no extra benefit and increased risk for bleeding

Circulation. 2014;129:1577-1585

Key recommendations for Pharmacists

• 3-NOACs are now PREFERRED over warfarin for AF (Strong, Mod)

• Generally all of these drugs have been found to be at least as efficacious as warfarin and generally safer—especially in ICH

• 4-In patients on warfarin a TTR of > 70% should be targeted, (Consensus only)

• If cannot maintain this, switch to NOAC if possible

• 5-In AF patients in which aspirin is concomitantly used with antithrombotic therapy use baby ASA + a PPI to minimize gastropathy (Weak, low)

• In stable CVD a patient started on antithrombotic therapy can OMIT ASA—no extra benefit and increased risk for bleeding

Circulation. 2014;129:1577-1585

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Key recommendations for Pharmacists

• 6-In AF patients after acute ischemic stroke, start anticoagulation within 2 weeks of even—but exact time unknown (consensus)

• 7-In patients with Chronic Kidney Disease• Stage III (CrCl 30-59 mL/min), Warfarin or label adjusted

NOAC can be used • Stage IV (CrCl 15-30 mL/Min) Warfarin or selected NOACs:

rivaroxaban 15 mg QD, apixaban 2.5 mg bid, edoxaban 30 mg QD, dabigatran 75 mg bid) can be used

• Stage V (CrCl < 15 mL/min or dialysis) warfarin is preferred (all low (all recs, weak, very Low)

Bottom line

• New CHEST guidelines on antithrombotic therapy is out—all 1200 pages of it!

• If you work with these patients at least being familiar with the summary document is important

• Not everyone is on board with these guidelines---but they will almost certainly become the standard by which treatment is determined in this area of medicine

• If you work in anticoagulation management, brew a lot of coffee and get ready to read….

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Gamechanger #7

• Drug Pricing update: CIVIA, Hyperinflation and “brown bagging” it

What Is Brown or White bagging?• “White bagging” refers to the distribution of patient‐specific

medication from a pharmacy, typically a specialty pharmacy, to the physician’s office, hospital, or clinic for administration. It is often used in oncology practices to obtain costly injectable or infusible medications that are distributed by specialty pharmacies and may not be available in all non‐specialty pharmacies.

• “Brown bagging” refers to the dispensing of a medication from a pharmacy (typically a specialty pharmacy) directly to a patient, who then transports the medication(s) to the physician’s office for administration.

• Clear bagging - People have started using the term to refer to when you dispense a drug from your own specialty Rx or outpatient RX to be administered at a system owned facility, clinic, or infusion center.

NABP White paper: White and Brown Bagging Emerging Practices,

Emerging Regulation. Accessed 11/6/18

CS7

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How Common is it?• Several Reports suggest that—especially in oncology—”brown

bagging” is done approximately 30% of the time

• As specialty pharmacies continue to grow—and third parties adopt this model—”brown bagging” will be expected to grow

• BUT, very few state boards of pharmacy even define the practice, let alone provide guidance or rules for its proper use

• In particular outpatient infusion centers may be particularly affected• In the brown bag model, the administering pharmacy is expected to dispense,

keep records, monitor the patient, and dispose of (often chemotoxic) remnant of the infusion FOR FREE

https://www.drugchannels.net/2013/09/payers-want-specialty-drug-distribution.html. Accessed 11/8/18

But you know who likes “brown bagging”?• Physicians offices: They don’t have costs associated with

purchasing and stocking expensive medications nor have to bill third parties for reimbursement, BUT, is paid for professional services associated with the drug’s administration.

• Third parties: Negotiate lower prices with specialty pharmacies

• Does it help with adherence??

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Problems

• Outpatient/Inpatient pharmacies who stock infusion centers and the infusion centers themselves are not reimbursed for usual and proper pharmacy practice

• A patient may have to transport chemotoxic medications—especially important in the age of USP 800

• Are appropriate storage criteria made in transport?

• Lack of coordination/communication between specialty pharmacy and hospital/physician office/infusion center can lead to wrong doses, or other errors

• Does “track and trace” play a role here??

CS9

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BOP action

• NABP paper discusses issues• Cost issues listed above• Specialty pharmacy is still the pharmacy of record who dispensed medication

to patient– responsibility for record keeping, MUE, patient counseling and education, the provision of disposal instructions, etc should be theirs

• Communication issues should be anticipated and polices adopted to avoid

• State boards of Pharmacy• New regulations? New Rules?

• Third parties• Separate contracts or communications between payers and administration

facility?

Hyperinflation in Generic Drug Prices

Elsevier White Paper: The impact of rising generic drug prices on U.S. Supply Chain. Accessed 11/10/18

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Some Deflation since 2014 but not enough

We know why…

• Fewer generic houses = less competition• Drugs with a projected small market attract fewer competitors

• Supply issues and shortages

• Market Consolidation and Monopolistic Pricing

• Safety issues result in drug removal and less competition

• Lagging FDA approval process

• Unapproved Drugs Initiative of the FDA• Neostigmine, colchicine, vasopressin, others

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It isn’t just community pharmacies

• Example: Sodium Nitroprusside• For decades one of the DOC for hypertensive emergencies

• Despite the risk of cyanide poisoning

• In 2014, Marathon Pharmaceuticals purchased the rights to the drug from Hospira and increased the price from ∼$50 per vial to ∼$215 per vial

• In 2015, SNP was purchased by Valeant Pharmaceuticals, and the price was increased further to ∼$650 per vial,

• In late 2016, Sagent Pharmaceuticals introduced another generic SNP product to market with an average wholesale price (AWP) of $900 per vial.

Alternatives to SNP

• Nicardipine? Labetalol? Hydralazine?

• All have pros and cons—and must be approached on an individual basis

• Nicardipine• Equivalent to SNP for post op hypertension and hypertensive emergencies• May lower intracranial pressure

• Labetalol• Blunted affect on HR compared to traditional beta-blockers• Effects may be more long lasting and more difficult to titrate

• Hydralazine• Not given as an IV drip• Reflex tachycardia can be a problem

Neutel JM, et al. Am J Hypertens. 1994;7:623–628

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Potential Solutions?

• Compounding generic• Obvious barriers include: facilities, quality control, manufacturing rules, etc

• Select alternative therapy• Barriers: Does one exist?, Safety issues? Cost issues?

• Work with prescribers to examine patients taking the drug proactively to see if it can be stopped temporarily or changed to something else

• Example: nadolol for portal hypertension, Digoxin for atrial fibrillation

• No one answer will solve every issue

Should hospitals enter the generic drug market?• NY Times reported that a group of 300 nonprofit hospitals, led by

Intermountain Healthcare and including Ascension, Trinity Health and SSM are planning to enter the generic drug manufacturing market

• Stemming from price increases in 2013-2014 & shortages in 2015-2017

• 77 drugs currently listed by the FDA are experiencing API (active pharmaceutical ingredient) shortages or have had manufacturing process interruptions

• Of the top 50 products dispensed in the hospital channel (which make up roughly 10% of hospital pharmaceutical sales), 42 are injectables

Nephron Research, Should Hospitals Enter the Generic Market? (Part II), January 2018. Accessed 11/7/18

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Civica Rx• Not-for-profit generic drug company• 120 health organizations representing about a third of the nation’s

hospitals have contacted Civica Rx and expressed a commitment or interest in participating with the new company

• Has identified 14 hospital-administered generic drugs as the initial focus of the company’s efforts

• It will be an FDA approved manufacturer and will either directly manufacture generic drugs or sub-contract manufacturing to reputable contract manufacturing organizations

• First Priority: to stabilize the supply of essential generic medications administered in hospitals

https://intermountainhealthcare.org/news/2018/09/not-for-profit-generic-drug-company-officially-established-named-civica-rx/. Accessed 11/11/18

Questions above Civica Rx• What drugs will be targeted for manufacture?

• When will they be released?

• What does the FDA say about this• Surprisingly not much to date

• How will then maintain supply and development lines?

• How does the supply chain work?• What wholesalers? OR direct to pharmacies?

• Total cost impact?• Their own FAQ says some costs may go up

• Other drugs in the future?

Civica Rx Operations FAQ. Accessed 11/11/18

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Bottom Line

• Brown bagging can put undue and unfair expense on the facilities administering the drug, and has a lot of logistic issues as well

• Rapid shifts in the generic price market has left both pharmacies and drug manufacturers in a state of uncertainty—to say nothing of patients

• Generic drug hyperinflation is often driven by drug shortages• Innovative solutions such as Civica Rx may provide solutions—if they can

actually get product to market

• Inventory control an issue for both community and hospital pharmacy

Gamechanger #8

• Update on Penicillin and beta-lactam allergy

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Penicillin Allergy

• Approximately 10-15% of hospital patients claim this allergy• Positive skin reactions in one study in children was 10%

• About 90% of patients who had a childhood reaction to PCN become tolerant to the molecule by adulthood and will have a negative skin test

• Only drug allergy with standardized testing (Type I reactions only)

Cetinkaya, et al. Pediatr Allergy Immunol 2004;15:278-80Khan DA, et al. Drug allergy. J Allergy Clin Immunol 2010, 125: S126-37

But we have lots of other antibiotics, right?

• Inpatients with a reported history of PCN allergy (n = 52,000 in a large database):

• More hospital days than controls (about 1 day)• More total exposure to ABX and days on ABX• Significantly more vancomycin, quinolone and clindamycin use (p < 0.001)

Macy E, et al. J Allergy Clin Immunol. 2014;133:790-6

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Reported Reactions to PenicillinPopulation: 5063 STD Clinic Outpatients

Other (29%)

Uncertain (9%)

Anaphylaxis (7%)

Urticaria (35%)

Exanthem(20%)

Gadde J, et al. JAMA. 1993;270:2456-63

Cross-Reactivity With Other Beta-Lactams• Cephalosporins

• Side chains determine cross-reactivity—see later slides

• Carbapenems• Imipenem originally thought to be about 50% cross-

reactive• Prospective and retrospective data suggests that any

carbapenem has little or no cross reactivity in PCN allergic patients

• Monopenems (aztreonam) safe in PCN allergyMcConnell, et al Clin Infect Dis 2000;31:1512-4Wall GC, et al. J Chemother 2014; 26:150-3Romano A, et al. Ann Intern Med. 2007;146:266-9. Romano A, et al. N Engl J Med. 2006;354:2835-7. Gaeta F, et al J Allergy Clin Immunol. 2014 Nov 22.pii: S0091-6749(14)01481-X. doi: 10.1016/j.jaci.2014.10.011

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Cephalosporin Cross-Reactivity

• N = 128 patients with IgE reaction + skin reactivity

• Skin tested with various cephalosporins then oral challenges

• Results: 14/128 (11%) had positive skin tests for cephalosporins—mostly to first generation drugs

• About 1% for 3rd and 4th generation cephalosporins

• More recent study found almost same results in T-cell/delayed reactions such as DRESS syndrome

Romano A, et al. Ann Intern Med 2004;141:16-22

Buinomo A, et al. J Investig Allergol Clin Immunol. 2014;24:331-7

Side chain relationships between PCNS and Cephs

Kim HE, et al. Allergy Asthma Immunol Res. 2014; 6: 485–495

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Side chain relationships between different Cephs

Kim HE, et al. Allergy Asthma Immunol Res. 2014; 6: 485–495

Bottom line on Cross-reactivity

• If poor history or non-threatening reaction history any cephalosporin may be used in a patient with a claimed PCN allergy

• If recent and life-threatening reaction would be cautious with 1stgeneration cephalosporins only.

• Carbapenems have no cross-reactivity

• Use side-chains to help determine beta-lactam to use

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PCN Allergy Skin Test

• The ONLY standardized drug allergy test • 99% Negative predictive value (NPV)• Safe even in extremely allergic patients IF scratch testing used first• Can be used “preemptively” for future uses of ABX• Relatively simple procedure

Annals of Allergy, Asthma & Immunology 1999:83:665-700

The impact of penicillin skin testing on clinical practice and antimicrobial stewardship

• ID fellows trained to administer and interpret PCN skin testing

• 146 patients tested who have history of past IgE mediated reaction

• Tested no matter the acuity (ED, ICU, Medical Floors, Surgery, L&D)

• 145 tested negative and had antibiotics changed based on results

• Estimated $82,000 saved just on this cohort of patients

• Same group found it very hard to “remove” allergy from EHR

Journal of Hospital MedicineVolume 8, Issue 6, pages 341-345, 3 APR 2013 DOI: 10.1002/jhm.2036http://onlinelibrary.wiley.com/doi/10.1002/jhm.2036/full#jhm2036-fig-0001

Aztreonam most commonly given before test, Pip/TazoAfter

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What about pharmacists?

• Depending on state law and training YES pharmacists ARE performing allergy assessment and skin testing in a variety of settings and in a variety of models

• Rph alone, or with RNs, MDs, residents, etc.

• Check with your state board!

• Training for pharmacists by pharmacists does exist

Jones BM, et al. Am J Health Syst Pharm. 2017 15;74:232-237

Conclusions

• A lot of information I know

• Perhaps a Focus on:• Areas that impact your practice• Variations that may change these recommendations• The “bottom line” slides

• PLEASE give us feedback • Gamechangers for 2019?

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Geoff.wall@drake.eduTwitter: @nuwavepharm

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Gamechangers Cover Page.pdfWall- Gamechangers.pdf