Bacon-wrapped Pharmacovigilance

with a side of Genomics

topped with an Alert Reduction

FDB Conference

November 5, 2014

Optimizing Patient Care and Reducing Alert Fatigue.

Objectives

• Pharmacovigilance – definition and practice

• Identify potential ADR’s from the FDB database

• Integrating Pharmacovigilance into the workflow - identifying patients at risk for adverse clinical events

• Pharmacogenomic monitoring in MEDITECH

• Utilizing FDB resources for Pharmacogenomic data

• AlertSpace® overview

• Potential Alert reduction as a result of Pharmacovigilance

• Outcomes – end user satisfaction, cost savings, optimized care

Leveraging MEDITECH’s Pharmacy application with sophisticated rules to

monitor patient information and prevent potential adverse clinical events to

medications  

Bacon-wrapped

Pharmacovigilance

Pharmacovigilance

Pharmacovigilance (PV or PhV), also known as Drug Safety, is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical products

Pharmacovigilance activities include:

• Collecting and managing data on the safety of medicines

• Looking at the data to detect 'signals' (any new or changing safety issue)

• Evaluating the data and making decisions with regard to safety issues

• Pro-active risk management to minimise any potential risk associated with the use of the medicine

• Acting to protect public health (including regulatory action)

• Communicating with and informing stakeholders and the public

• Audit, both of the outcomes of action taken and of the key processes involved.

First DATA Bank

Data is their Middle Name

Renal Dosage Adjustment

Black Box Warnings

Genomic Data

Drug Disease

……..

Clinical Decision Support

Decision Support focuses on making

the appropriate choices for a therapy

at a given point in time

FDBRenal Adjustment Data

Pro-active Decision Support

Patients with impaired renal function must have their drug therapy carefully monitored to avoid adverse drug events.

– Dose the patient properly – Monitor the patient for any adverse response

CrCl Rule (from the archives)

Rule provides the end user with an estimated creatinine clearance for appropriate patients (site determined age and CRCL parameters) when entering drugs that may have an impact on renal compromised patients. The display includes not only the estimated creatinine clearance but also all the demographic information utilized in the calculation and a trend of the serum creatinine levels with specimen dates and times. Further utilization of the customer defined screens within the pharmacy module provides a suggested dose for the medication based on the calculated creatinine clearance.

MEDITECH Medication Screen CDS

• PHA DRUG type screen• Medication Specific Information• Attached in PHA parameters• Same for all formulary items

Medication CDS sample – Page 2 (9 pages available)

Page 2 – with data

Clinical Evidence transfer from Clinician to System

Sample CrCl Order Rule Display

PHA.DRUG CDS(current)

Global Rules are attached in the Customer Defined Parameters

Other Medication Rules

Black Box Warning (w/link)

This medication contains a Black Box Warning, please review additional information uses web link

Duplicate Generic 2 hr check

This is a more “in your face” duplicate generic checkShould also be built as POM Rule – attached to specific medications

eMAR / BMV RULES

• Override setting for particular sites or location with the use of RULES

• Replace common medication comments related to administration with rules – i.e. do not exceed amount of acetaminophen in 24 hours - use rules to total acetaminophen content and display for user administering medication when approaching do not exceed amount – additional rule with BMV could prevent administration if certain amounts exceeded.

• Prevent administration that could cause a potential ADE.

Acetaminophen 24 hour rule

Displays cumulative acetaminophen dose for past 24 hrs once past trigger value

Check Number of Doses and Levels

This rule displays the number of doses administered and previous levels if done.

Black Box Warning (eMAR)

Black Box Warning – POM

Dose Restriction Rule

Uses Drug CDS top control partial doses of oral forms

Restrict to Specialist MD

Designed to limit ordering of medication to specific physicians

Pharmacovigilance activities include:

• Pro-active risk management to minimise any potential risk associated with the use of the medicine

Vigilance Survey

• What are you doing now?

• What else should you be doing?

• What will it take to get to the next level?

Vigilance

• Determine what needs to be “watched”

• Establish Surveillance Opportunities

• Understand the clinical parameters

• Evaluate the system’s ability to capture and relay data

• Batch vs. Real-time surveillance –(levels of sophistication)

Opportunities

• Renal Dosing• Antimicrobial Therapy Monitoring• A.D.E. / Black Box Warning

Monitoring• Drug Disease Interactions• Pharamcogenomic contraindications

Methodology

• The system contains patient specific data.

• The Clinician works with specific triggers of evidence.

• By embedding the triggers into the system it can provide surveillance to streamline the clinician processes

Understanding

  By leveraging Data with sophisticated clinical rules and reports to identify potential drug problems, monitor laboratory values and alert the clinician to potential patient risks.  You can reduce potential adverse events and improve patient outcomes

Added Sophistication

• Utilizing Rules linked to fields on a Customer Defined Screen (CDS).

• Activating rules by selecting appropriate fields on the CDS.

ADE Monitoring

• Medications can be classified on the Drug CDS as those causing specific ADE’s. Multiple ADE’s can be associated with a single formulary item.

• A Rule is created for each potential ADE. • By answering “Y” to the ADE query “Potential

ADE (Y/N)” and associating the appropriate ADE’s at the “ADE:”the rule will be invoked.

ADE Monitoring

• Medications can be classified on the Drug CDS as those causing specific ADE’s. Multiple ADE’s can be associated with a single formulary item.

• A Rule is created for each potential ADE. • By answering “Y” to the ADE query “Potential

ADE (Y/N)” and associating the appropriate ADE’s at the “ADE:” prompt, these refill rules will be invoked and display on the refill list.

Clinical Evidence transfer from Clinician to System - Triggers

ADE Monitoring

• Medications can be classified on the Drug CDS as those causing specific ADE’s. Multiple ADE’s can be associated with a single formulary item.

• A Rule is created for each potential ADE. • By answering “Y” to the ADE query “Potential

ADE (Y/N)” and associating the appropriate ADE’s at the “ADE:” prompt, these refill rules will be invoked and display on the refill list.

Clinical Evidence transfer from Clinician to System - Triggers

Using a CDS Query to invoke a Global Rule

By answering “Y” to the ADE query “Potential ADE (Y/N)” and associating the appropriate ADE’s at the “ADE:” prompt, these refill rules can be invoked and display on the refill list

Multiple ADE responses can be entered for a specific formulary item

Clinical Parameters (sample triggers)

CDIFF Positive Stool culture for C.diff

PC<50000 Platelet count less than 50,000

PTT>100 PTT greater than 100 seconds

INR>6 INR greater than 6

Retcount>2 Absolute reticulocyte count greater than 2%

Bili>10 Seum bilirubin greater than 10 mg/dL

ALT>150 Serum ALT > 150 Units/L

IncreaseCR Increasing Creatinine

IncreaseALT Increasing ALT(20%)

Hyperkalemia Serum Potassium greater than 6.5 mmol/L

ADE Monitoring

• Global rules will indicate a potential ADE and the order that may be causing the adverse effect.

Sample ADE Rule; This rule will display patient with cyclosporine > 500 receiving

cyclosporine drug; [f rx med]^M,"PHA.ADEGRP"^GRP,"CYCLOSPRNE"^CDS,IF{[f z.get.cds.resp](M,GRP,CDS) ""^RES, [f rx nth ver Res-RES]("CYCL1",1)^RES,RES#”1,”^RESDT,RES#”2,”^RESTM,RES#"0,"^RES,IF{RES>500 "Potential ADE, cyclosporine serum level = "^MSG,MSG_RES_” on “_RESDT_” @ “_RESTM^MSG,Q(MSG,RESDT,RESTM);[f rx reject]};[f rx reject]};

Sample Custom Keywordz.get.cds.resp %PHA.RX.zcus.tig.npr.rx.rules.M.get.resp(; This program will get the ADE group Response from the formulary

Dictionary; A - Med; B - Query; C - Response to check for;A^PHA.DRUG.mnemonic,B^PHA.DRUG.query,""^PHA.DRUG.query.mult.q^FND,DO{@Next(PHA.DRUG.query.mult.q)&'FND

IF{@PHA.DRUG.query.mult.resp=C 1^FND}},FND;

Added Sophistication

An NPR Report printed to the screen that promotes the ability to provide real-time intervention on patients when time may be of the essence.

Real-time Display

Right Arrow for Detail of Order

Order Type CDSAn Additional field can be added to the order type CDS. The CDS is attached in the Order Type dictionary

Sample Order Type CDS

Once a user puts in a review Date and Time, the order will drop off the view board and resets the RX so that a new reported lab will trigger it to appear on the board again if indicated.Review notes added to note any changes or notes for that date.

Micro – CS Surveillance

• Displays if patient has been on antimicrobial therapy greater than x days (x customer defined)

• Warns if patient is on antibiotic and micro reports resistance to that antibiotic

• Warns if micro reports positive growth but patient not on Antibiotic

Querie Responses - Abx

Microbiology Warning

Additional Vigilance

• Change in patient weight > X%

• Warns if patient creatinine clearance changes by greater than X amount

• Pharmacogenetic Monitoring– IN.CYP2C10

• Poor Metabolizer for Plavix.

a side of

Genomics

BACKGROUND

Single Nucleotide Polymorphisms (SNP’s)

• Human genome contains between 30,000 and 40,000 distinct genes.

• Genetic variation most commonly occurs as random variations between the nucleotide sequences of different individuals

• Single base-pair substitutions that occur with a frequency of greater than or equal to 1% in a population are referred to as single nucleotide polymorphisms (SNP’s)

• To date 1.4 million SNP’s have been identified• More than 60,000 occur in the coding regions of

proteins• Genes that code for the CYP enzymes 2A6, 2C9,

2C19, 2D6 and 3A4 have shown to be polymorphic with functional variations on a significant percentage of ethnic groups.

• The most common and best studied polymorphisms to date are those that affect drug pharmacokinetics and pharamcodynamics

Variability in Drug Response

• Pharmacokinetics– Absorption– Distribution– Metabolism– Excretion

• Pharmacodynamics– Drug target response

Genomic Discussion Points

MEDITECH

Better Management of Cardiac Medications: Anticoagulants and Cytochrome P450 CYP2C19

– variations in this have a 3.58 times greater risk for major adverse cardiovascular events such as death, heart attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers.

New England Journal of Medicine

Better Pain Management : Opiates and P450 CYP2D6

– 80% of patients reporting ADRs were shown to have poor CYP2D6 metabolism

– Some methadone patients seeking higher doses were Ultra Metabolizers: proof that they were not exhibiting drug-seeking behavior

American Academy of Pain Medicine

Focus on Low Hanging Fruit

CYP2D6 - CYP2C19• CYP2D6 is involved in the metabolism of:

– Codeine (pro-drug)– Prozac– Zoloft– Paxil– Effexor– Hydrocodone– Amitriptyline– Claritin– Cyclobenzaprine– Tagamet– Tamoxifen (pro-drug)

• CYP2C19 is associated with the metabolism of:– Carisoprodol– Diazepam– Dilantin– Premarin– Prevacid– Plavix

By analyzing the variation in the two genes, the test predicts whether an individual will metabolize these drugs more quickly or more slowly than average. These variations can help the physician identify how a patient's metabolism works. If the test reveals that a patient metabolize drugs rapidly or slowly, the doctor may consider adjusting your drug dosages or switching to a non 2D6 or 2C19 metabolized drug. This information can help to maximize the likelihood of therapeutic effectiveness and minimize the risk of adverse drug reactions.

Breast Cancer Recurrence: Tamoxifen and Cytochrome P450 2D6

– Recent research has shown that 7-10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their unique genetic make-up. These women have a version of a gene called Cytochrome P450 2D6, which reduces the effectiveness of tamoxifen and increase their chance of breast cancer recurrence. 

Federal Drug Administration

• EVB Order Set for Cardiac Stent to include genetic testing for P450 2C19 (CYP2C19)

Bringing into Standard Practice Using CPOE , Evidence Based Order Sets (EVB) and Clinical

Decision Support:

Clinical Decision Support - Rules

• Suggest ordering appropriate Genetic Screening – if not already on Genetic Profile (Include reason for testing )

• Review Genetic Profile* and warn user regarding potential adverse effects (i.e. Warfarin – bleeding)

• Suggest alternate therapy when appropriate (i.e. Effient vs Palvix or H2 antagonist vs PPI)

Pharmacogenomic Rules may meet the “rules” requirement for “Meaningful Use”

New C/S Capabilities

*Incorporation of Problem List with Pharmacy Conditions will allow Drug Disease interactions from FDB Data

FDB Data

Warfarin- two genes below

Clopidogrel (Plavix) DNA Test - CYP2C19

Several recent landmark studies have proven the importance of 2C19 genotyping in treatment using clopidogrel or Plavix. Researchers have found that patients with variations in a gene called cytochrome P-450 2C19 (CYP2C19) have a 3.58 times greater risk for major adverse cardiovascular events such as death, heart attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers. The abstract is available in the online verison of the New England Journal of Medicine.

Workflow - Stent

1. Patient Identified as a candidate for cardiac stent.

2. Order Set contains order for screening for Cytochrome P450 2C19 Genotype test

3. CY2C19*2/*2

4. Patient Id’ d as poor metabolizer – added to “Problem List”

5. Drug – Disease Interaction displayed

• Orthopedic EVB Order Sets and Post Surgical

Pain:Pre-Op EVB Order Set to include genetic

testing for P450 CYP2D6

Patients Id ‘d as poor metabolizers will receive warning when orders for Hydrocodone selected. Switch to Hydromorphone (Drug –Disease Interaction Display) 

Workflow - Ortho

Who Should Be Tested

The CYP2C19 test for clopidogrel or Plavix is considered appropriate for any patient taking or considering this medication.

REDUCING ADRS AND SAVING MONEY

More than 50% of Americans have gene based variations that can be tested for and that increase the risk of an ADR.

The wide use of DNA Drug Sensitivity Testing has the potential to save tens of thousands of lives, prevent hundreds of thousands of serious events that initiate or extend hospital stays, and save hundreds of millions of dollars in health care costs. Fifty-nine percent of drugs most commonly cited in ADR studies are processed by enzymes with genes known to have poor metabolizer variants. This is compared to 7% of a random selection of the top selling drugs. (JAMA 286:2270 2001).

Currently available tests help predict a patient's response to many prescription, OTC (over-the-counter) and herbal medicines including those used to treat depression, anxiety, seizures and psychoses; blood pressure, anticoagulation and other heart medicines; anti-diabetic agents, and many pain relievers.

Many known drug drug interactions are based on a knowledge of the drug metabolizing systems that have a high level of genetic variation. When those variations are present in individuals taking more than one drug the chance of having an adverse drug reaction is greatly increased.

Hospitalized psychiatric patients who are poor metabolizers cost $4,000 - $6,000 more in medical care compared to patients with an average metabolizer genotype. ALL antidepressants and antipsychotics are processed by enzymes with a high incidence of poor metabolizers. Journal of Clinical Psycopharmacology 20:246 2000

Review – What We Know

• We know that genetic differences can affect drug response in patients

• We have identified specific SNP’s that produce specific responses

• We can now identify patients that have specific Genotypes

• Where do we go from here?

Conclusion As more patients have genetic profiles performed and

more information is available about medications and their interactions with different genetic profiles, we will be able to tailor a regimen with specific medications and doses for the patient based on the patient’s genetic make-up. This customization will be in addition to other commonly acceptable variables used today (age, weight, sex). The Hippocratic Oath states first do no harm. With genetic testing, many of the worst side effects from medications may be more predictable and can prevent patient deaths from occuring.

topped with an Alert Reduction

AlertSpace®

Once we have established a robust surveillance process, we can use alertspace to filter warnings related to clinically surveyed parameters.

i.e. If drug A is ordered with drug B there is an increased risk of drug B reduced renal function.

If we are continually surveying the renal function we can notify the physician if this occurs rather than on order entry.

AlertSpace® Overview - FDB

Questions / Discussion

Bruce Matthias R.Ph., PresidentThe IN Group, Inc.Bruce.Matthias@theingroup.com