Activity No. 0217-0000-14-115-L05-P, 1.5 contact hours; Knowledge-based activity. · 2014-09-26 · Curricular Track I: REMS and Regulation Updates to Promote Medication Safety

Curricular Track I: REMS and Regulation Updates to Promote Medication Safety Activity No. 0217-0000-14-115-L05-P, 1.5 contact hours; Knowledge-based activity.

Tuesday, October 14 10:15 a.m.–11:45 a.m. Convention Center: Grand Ballroom D

Moderator: Laura B. Borgelt, Pharm.D., FCCP, BCPS Professor, University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy & Pharmaceutical Sciences, Aurora, Colorado

Agenda

10:15 a.m. The Evolution of Risk Evaluation and Mitigation Strategies (REMS): Updates That Pharmacists Need to Know Katie Stabi, Pharm.D., BCPS Clinical Coordinator, Drug Use Policy and Compliance, Department of Pharmacy Services, University of Chicago Medicine, Chicago, Illinois

10:45 a.m. The Food and Drug Administration (FDA) and Institute for Safe Medication Practices (ISMP): Teaming Up to Reduce Medication Errors Rebecca H. Stone, Pharm.D., BCPS, BCACP Clinical Assistant Professor, University of Illinois Chicago, Chicago, Illinois

11:15 a.m. Applying Recent FDA Safety Communications into Your Everyday Practice Mandy C. Leonard, Pharm.D., BCPS System Director, Drug Use Policy and Formulary Management, Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio

Conflict of Interest Disclosures

Laura B. Borgelt: no conflicts to disclose. Mandy C. Leonard: no conflicts to disclose. Katie Stabi: no conflicts to disclose. Rebecca H. Stone: no conflicts to disclose.

© American College of Clinical Pharmacy 1

Learning Objectives

1. Briefly explain the goals and scope of Risk Evaluation and Mitigation Strategies (REMS). 2. Determine strategies for the implementation of the more complex REMS requirements. 3. Given patient specific information, design a successful REMS plan to perform the

required functions and provide appropriate information. 4. Evaluate the barriers and outcomes of implementing REMS, including information and

knowledge provided to patients and health care professionals. 5. Compare and contrast medication error reporting programs for the Food and Drug

Administration (FDA) and Institute for Safe Medication Practices (ISMP). 6. Using case examples, analyze the most common medication safety issues reported to

ISMP with successful practices to mitigate the error potential for each. 7. Apply the collaborative initiatives between the FDA Center for Drug Evaluation and

Research (CDER) and ISMP to prevent harm from medications. 8. Through the FDA’s Safe Use Initiative, design effective strategies for health care

providers and patients to collaboratively reduce medication errors. 9. Describe various Food and Drug Administration (FDA) drug safety communications,

including the MedWatch program. 10. Examine the risks and benefits of patients taking medications involved in FDA safety

communications. 11. Assess the significance of various FDA safety warnings based on evidence. 12. Develop appropriate therapeutic plans for patients impacted by a FDA safety warning.

Self-Assessment Questions Self-assessment questions are available online at www.accp.com/am

Curricular Track I: REMS and Regulation Updates to Promote Medication Safety


2014 ACCP Annual Meeting

REMS and Regulation Updates to Promote Medication SafetyKatie L Stabi, PharmD, BCPSOctober 14, 2014

Conflict of Interests

Nothing to disclose

Learning Objectives

Briefly explain the goals and scope of RiskEvaluation and Mitigation Strategies (REMS)

Evaluate the barriers and outcomes of implementingREMS, including information and knowledgeprovided to patients and health care professionals

Determine strategies for the implementation of themore complex REMS requirements

Given patient specific information, design asuccessful REMS plan to perform the requiredfunctions and provide appropriate information

REMS Programs

Strategy by the FDA to manage a known or potentialserious risk associated with a drug or biologicproduct

Support safe access to drugs that have knownserious risks and would otherwise be unavailable

REMS is “necessary to ensure that the benefits ofthe drug outweigh the risks of the drug”

Am J Health-Syst Pharm 2009;66(Suppl 7):S3-S5.

REMS Components

Medication guide (MedGuide)

Communication plan

Elements to assure safe use (ETASU)

Implementation system

Assessment

Am J Health-Syst Pharm 2009;66(Suppl 7):S3-S5.Hosp Pharm 2010;45(7):576-580.

Elements to Assure Safe Use

Prescribers have specific training, experience, or specially certified

Settings that dispense the drug are specially certified

Drugs dispensed to patients only in certain healthcare settings

Drug dispensed only with evidence or other documentation of safe‐use conditions

Patient can be subject to certain monitoring

Patient may be enrolled in a registry

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf Am J Health-Syst Pharm 2009;66(Suppl 7):S3-S5.



ETASU Inpatient Pharmacist Responsibility

Prescribers: specific training, experience, or certified

Verify certified prescribers

Hospital: certified None

Drug: dispensed only for inpatients None

Safe-use conditions: documentedVerify documents / labs completed /

additional requirements

Patient: monitoring required Verify monitoring completed

Patient: enrolled in a registryVerify patient enrollment / enroll

patient

Elements to Assure Safe Use REMS Programs

144

32

35

6

Released REMS REMS with ETASU

REMS without ETASU Shared System

N = 217; Updated 8/12/14http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm111350.htm

REMS Programs

0 1 1

99

33

6 41 5 8 7 5 4 23 6 94 5 3 5

0 0 1 1 2 2 00

20

40

60

80

100

2008 2009 2010 2011 2012 2013 2014

Num

ber

Year

Released REMS REMS with ETASU

REMS without ETASU Shared Systemhttp://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm111350.htm

N = 217; Updated 8/12/14

Barriers and Outcomes of Implementing REMS

Primary Barrier

Awareness

Knowledge

Education

Who needs it? Health Care Professionals

REMS Representatives

Addressed ETASU

Prescribers have specific training, experience, orspecially certified

Drug dispensed only with evidence or otherdocumentation of safe-use conditions

Patient can be subject to certain monitoring

Patient may be enrolled in a registry



Medical license = certified, right? Who is certified?

Ask prescriber Verify with REMS program

Call REMS program for list Call REMS program with possible prescriber names

REMS program hours Online database of certified prescribers

Information needed to log-in not available Incorrect information typed by REMS representative Need to know prescriber’s enrollment ID to verify

Outpatient requirement only, right?

Challenges of Certified Prescriber Requirement

Challenges of Documented Safe-use Conditions Risk:benefit discussion occurred

How is this verified? Enrollment form signed

How is this verified? Labs obtained

Documentation required? Patient enrolled in REMS

Prior to dispensing drug or start paper work? Medication guide dispensed

Who does this? Patient registered with REMS program

Which registry? Can an inpatient pharmacy even dispense the drug?

Outcomes of Successful REMS Implementation Staff educated Pharmacists able to explain requirements

Services consulted, as needed

Electronic support

Hospital specific REMS information readilyavailable

Patient able to obtain drug without interruption Order entry → Order verification → Dispensing

Strategies for Implementing REMS

Where to Start

Build a REMS infrastructure

Designate a coordinator Standardization, efficiency, reference

Prioritize programs Determine what is formulary

Determine true nonformulary, not stocked

Determine what needs to be home medication use

Identify ETASUs that affect inpatient use Not just if stocking and dispensing drug

If drug stocked, who signed all the paperwork?

Education Pharmacists Primary service groups

Determine required versus optional ETASUs Start with required Determine if optional ETASUs will be enforced

Create a Checklist / working document FDA REMS documents Company websites Contracts and information provided by wholesalers Representatives of REMS Programs contacted

Next Steps



Pharmacy Enrollment and Responsible Persons Duties

Procurement and Storage of Medication

Medication Guide Requirements and Process

Prescriber Enrollment and Pharmacy Notification

Patient Enrollment and Verification

Dispensing the Medication

Laboratory Monitoring

Electronic Software Updates

Additional Considerations

Patient Discharge

Checklist: REMS Program Considerations

Common Inpatient ETASU

Certified prescriber Facility specific list

Patient:Physician Acknowledgement Form Scan into medical record

Labs documented Display in drug file

Patient registration with REMS Alert verifying pharmacist

Electronic Support

Alerts in the medical record

Policies and procedures posted

Medical record support Scanned forms

Formulary software

Intranet

Alerts

Order Entry Alerts

Ordering instructions

Order Verification Alert

This drug has a Risk Evaluation and Mitigation Strategy (REMS) Program that requires a certified prescriber to place the order. Consult one of the following:

REMS Drug: Click here to verify all REMS requirements have been met.

Questions Embedded in Drug Record

Are you a certified prescriber?

Is the patient enrolled in the registry?

Have the XXX labs been completed?

Is this a continuation of home therapy?

Has the patient signed an enrollment form?

Is the patient of child bearing potential?

no yes

no yes

no yes

no yes

no yes

no yes

Case Scenario




The Food and Drug Administration (FDA) and Institute for Safe Medication Practices (ISMP): Teaming Up to Reduce Medication Errors

Rebecca Stone, Pharm.D., BCPS, BCACP

October 14th, 2014

Learning Objectives

1. Compare and contrast medication error reporting programs for the Food and Drug Administration (FDA) and Institute for Safe Medication Practices (ISMP).

2. Using case examples, analyze the most common medication safety issues reported to ISMP with successful practices to mitigate the error potential for each.

3. Apply the collaborative initiatives between the FDA Center for Drug Evaluation and Research (CDER) and ISMP to prevent harm from medications.

4. Through the FDA’s Safe Use Initiative, design effective strategiesfor health care providers and patients to collaboratively reduce medication errors.

Hierarchy

Institute for Safe Medication Practices(ISMP)

Food and Drug Administration(FDA)

MedWatch

Medication Errors

Reporting Program(MERP)

Vaccine Errors

Reporting Program(VERP)

Center for Drug Evaluation and Research(CDER)

Safe Use Initiative

(SUI)

Vaccine Adverse Event

Reporting system

(VAERS)

FDA: MedWatch

FDA Safety information and adverse eventreporting program Voluntary and confidential

Health care professionals

Consumers

FDA: MedWatch

What to reportAdverse events related to Prescription meds OTC meds Biologics Medical devices Special nutritional products Cosmetics Foods/beverages

What NOT to report Vaccines Investigational drugs Mandatory reporting by

regulated industry Dietary Supplements

ISMP: MERP & VERP

Non-profit organization adverse eventreporting program focused on system-basedcauses of medication and vaccine errors Voluntary and confidential

“Frontline practitioners” Consumer reporting system



ISMP: MERP & VERP

What to report Errors

Prescribing, transcribing, dispensing, administering, and monitoring

Wrong drug/strength/dose Look alike/sound alike Calculation or preparation

errors

Preventable adverse rxns Close calls Hazardous conditions

What NOT to report Adverse or allergic rxns Investigational drugs Mandatory reporting by

regulated industry Dietary Supplements

Where to report?

ISMPMedWatch

VaccinesClose callsSystem based errors

Medication Adverse RxnAllergic RxnMedical devices Foods/beverages CosmeticsSpecial nutritional products

All Medication ErrorsPreventable adverse Rxn

Hazardous conditions

Investigational drugsMandatory industry reporting

Dietary supplements

Patient case #1

TH is a 64 yo male with insulin dependent DM TH was seen at his primary care clinic by a medical resident for DM f/u

2 weeks ago.

He had been using a Lantus vial 30 units qhs. His poct A1C was 9.5%, fasting SMBG at goal, 2 hr postprandial SMBG all >200 mg/dl.

His provider prescribed Novolog Flexpen 5 units BID AC, continue Lantus 30 units qhs. There was limited time for patient education during his visit.

TH calls today and is triaged to the clinical pharmacist because he has been experiencing hypoglycemia in the early morning since he started using his new insulin.

ISMP ambulatory care high alert medicationsClasses/Categories Antiretroviral agents Oral chemotherapeutics Oral hypoglycemics Immunosuppressants Insulin Opioids Pediatric liquids Pregnancy Cat X

Specific agents carBAMazepine Chloral hydrate liquid UF and LMW heparins metFORMIN Methotrexate Midazolam liquid Propylthiouracil Warfarin

Patient case #1, cont’d

Further investigation by the PharmD revealsthat TH received NovoLIN N Flexpen, notNovoLOG Flexpen insulin as intended

Where did the error(s) occur?

What steps/tools can be utilized to reduce therisk of error(s)?

http://www.ismp.org/tools/default.asp [Accessed August 15, 2014]

ISMP Tools



http://www.ismp.org/tools/highalertMedications/default.asp [Accessed August 15, 2014]

ISMP Tools

http://www.ismp.org/tools/personal_med_form/default.asp [Accessed August 15, 2014]

ISMP Tools

http://www.ismp.org/tools/personal_med_form/default.asp [Accessed August 15, 2014]

ISMP Tools


Error analysis revealed that the NovoLOGFlexpen prescription was written correctlywhen entered, but was filled incorrectly by thepharmacy.

What tools are available from ISMP for errorrisk assessment during the dispensingprocess?

Risk of error evaluation

High-Alert Medication Modeling and Error-Reduction Scorecards (HAMMERSTM )

Free tool designed to help community pharmacies: Identify their unique set of system and behavioral risks

associated with dispensing certain high-alert medications

Estimate how often an error or adverse drug event reaches a patient

http://www.ismp.org/tools/HAMMERS/default.asp [Accessed August 15, 2014] http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm297644.htm#1 [Accessed August 15, 2014]



Collaboration: ISMP & FDA’s Center for Drug Evaluation and Research (CDER)

"As a part of its ongoing effort to fight [medication error] risks, [FDA] has entered into an agreement with ISMP to develop collaborative efforts to reduce preventable harm from medicines…”

"The collaboration is also designed to provide more informational and educational materials for both consumers and health care professionals.”

“The relationship will broaden FDA's ability to reach out to [consumers and health care professionals] when there are issueswith product safety and effectiveness."

http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm297644.htm#1 [Accessed August 15, 2014]

Collaboration established 2012

ISMP reviews all FDA MedWatch reportswhich contain information about medicationerrors

As a MedWatch partner, ISMP promotesFDA’s initiatives to reduce adverse drugreactions

Hierarchy

Institute for Safe Medication Practices

(ISMP)

Food and Drug Adminstration(FDA)

Medication Errors

Reporting Program(MERP)

Vaccine Errors

Reporting Program(VERP)


Pooled error report data

ISMP promotes findings to reduce adverse events

MedWatchSafe Use Initiative

(SUI)

Vaccine Adverse Event

Reporting system

(VAERS)

ISMP electronic newsletters

ISMP Medication Safety Alert!®

Acute Care edition

Community/Ambulatory Care edition

Nurse Advise-ERR

Long-Term Care Advise-ERR

Safe Medicine

ISMP QuarterWatch: Monitoring FDAMedWatch Reports

http://www.ismp.org/newsletters/default.asp [Accessed August 15, 2014]www.ismp.org/quarterwatch/default.aspx [Accessed August 15, 2014]

Patient Case #2

DR is a 32 yo F, pregnant at 25 wga, andwas diagnosed gestational DM today basedon her OGTT Her newly hired high risk OB/GYN provider wants

to start her on a weight based basal/bolus insulinregimen of NPH and regular insulin


The MD searches “insulin regular” and is presentedthe following options




DR’s OB/GYN provider was not aware of thedifferences between U-100 and U-500 insulin U-500 insulin was incorrectly selected The community pharmacist caught the error when

the dose in U-500 formulation was unable to beeasily measured in insulin syringes

What steps/tools can be utilized to reduce the riskof error(s)?

Medication Safety Alert!®

Specify problem based on recent errorreports and recommendation for avoidance

https://www.ismp.org/newsletters/acutecare/showarticle.aspx?id=62 [Accessed August 15, 2014]


Community pharmacist was aware ofincreasing U-500 insulin errors Tuberculin syringes recommend for U-500

Facility updated order entry

FDA: Safe Use Initiative

“The goal is to reduce preventable harm byidentifying specific, preventable medicationrisks and developing, implementing andevaluating cross-sector interventions withpartners who are committed to safemedication use.”

http://www.fda.gov/Drugs/DrugSafety/SafeUseInitiative/default.htm [Accessed August 15, 2014]

http://www.fda.gov/drugs/drugsafety/safeuseinitiative/ucm188762.htm [Accessed August 15, 2014].

Patient case #3

SG is a 22 yo male who presents to the University Health Center for a same day appointment with asprained ankle from an intramural kickball incidentyesterday. He endorses 6 out of 10 pain.

Home meds Albuterol inhaler 2 puffs q 4 prn SOB OTC loratadine 10 mg po daily OTC Nyquil two tbsp “for sleep if my roommate is being loud” OTC APAP 325 mg one po q 6 hr prn pain

Social history per patient Drinks two to three beers per day Smokes five cigarettes per day




Physical evaluation of SG by his PCP issupportive of a severe sprained anklediagnosis His PCP prescribes the following

Crutches stay off ankle Hydrocodone/APAP 5/325 mg, one po q4 hr prn pain, #30,

0 RF

When SG picks up his prescription what issuesshould be addressed during counseling?

APAP- Rx container labels

APAP liver injury related to overdose remainsa serious public health issue Consumers need to be able to

Identify products containing APAP Compare active ingredients on their Rx and OTC labels Take action to avoid 2 products with APAP

APAP – Rx container labels

National Council for Prescription DrugPrograms (NCPDP) and FDA collaboration Produced “NCPDP Recommendations for Improved

Prescription Container Labels for MedicinesContaining APAP” Eliminate active ingredient abbreviations Standardize liver pharmacy warning label Format with plain language and health literacy principles Stakeholder call to action

FDA has ongoing public education campaign

http://www.fda.gov/Drugs/DrugSafety/SafeUseInitiative/ucm188762.htm [Accessed August 15, 2014] http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the-CounterMedicines/SafeUseofOver-the-CounterPainRelieversandFeverReducers/ucm164977.htm#fact_sheets[Accessed August 15, 2014]

Patient case #3

Stakeholder call toaction

Utilize counseling toolsfor SG regarding thedangers of APAPoveruse

Refer SG to additionalself education “Know your dose” http://www.knowyourdose.org/

http://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the-CounterMedicines/SafeUseofOver-the-CounterPainRelieversandFeverReducers/UCM234237.pdf[Accessed August 15, 2014]

Summary

FDA’s MedWatch and ISMP’s MERP & VERP programsare appropriate pathways for medication error reporting

ISMP produces many provider and consumer MedicationSafety Tools and Resources for med error risk mitigation

The FDA and ISMP collaboration is designed to helpkeep healthcare providers (YOU!) informed regardingcurrent medication issues

The FDA’s Safe Use Initiative brings togetherstakeholders to implement large scale, cross-sectorinterventions at the national level to prevent med errors




Applying Recent FDA Safety Communications into Your Everyday PracticeMandy C. Leonard, Pharm.D., BCPSOctober 14, 2014

Conflict of Interests

No conflicts of interest to disclose.

Learning Objectives

Describe various Food and Drug Administration(FDA) drug safety communications.

Examine the risks and benefits of patients takingmedications involved in FDA safetycommunications.

Assess the significance of various safetywarnings based on evidence.

Develop appropriate therapeutic plans forpatients impacted by a FDA safety warning.

Food and Drug Administration (FDA)


Center for Biologics Evaluation and Research(CBER)

Monitors and reviews safety information for adrug’s (or biological product’s) life cycle

Post-marketing Diverse populations

http://www.fda.gov/downloads/Drugs/DrugSafety/UCM300946.pdf [Accessed August 15, 2014].

History

In 2004, FDA initiated planning of long-termsafety changes

In 2007, Food and Drug AdministrationAmendments Act (FDAAA) granted authorityto FDA for assuring drug safety Safety First Safe Use Strengthening Drug Safety Science Drug Safety Communications


Safety First

Establish equal priority to postmarket safety andpremarket safety

Create collaboration via a multidisciplinaryapproach within the Offices at the FDA Equal Voice Initiative

Implement FDAAA’s drug safety provisions Postmarket studies/clinical trials Required labeling changes REMS authorities Quarterly online reports




Safe Use

Reduce preventable drug harm caused byinappropriate use (e.g., unintentionaloverdose or inappropriate prescribing) Preventing acetaminophen toxicity Medication adherence Prescription opioids

http:www.fda.gov/Drugs/DrugSaefty/SafeUseInitiative/ucm188762.htm [Accessed August 15, 2014].http://www.fda.gov/downloads/Drugs/DrugSafety/UCM300946.pdf [Accessed August 15, 2014].

Drug Safety Science

Develop new drug safety tools Advance risk evaluation during drug

development Dedicate statistical analysis (biostatisticians) Expand epidemiology studies Understand and use pharmacogenomics Enhance adverse event surveillance Create The Sentinel Initiative


Enhance Communication

Use a systematic approach Communicate to public as early as possible Use single format for drug safety issues Drug Safety Communications (DSC)

Study most effective communication methods Publish articles in medical journals Gain advise and expert opinion on how to

communicate drug risks


Drug Safety Information-Guidance Important drug safety issue

Alter benefit-risk analysis; affects decision regardingprescribing or taking a drug

Serious adverse reactions identified after drugapproval

Medication errors Emerging drug safety issue

Has the potential to alter the benefit-risk analysis thatmay affect the decision regarding prescribing or takinga drug

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM295217.pdf[Accessed August 15, 2014]

Emerging Drug SafetyConcern- Identification Prompt review and analysis FDA Sponsors

Sources of data Spontaneous reports

MedWatch Vaccine Adverse Event Reporting System (VAERS)

Clinical trials Surveillance databases


Emerging Drug Safety Concern: Assessment

Factors considered before sending a communication Relative seriousness related to benefits Magnitude of risk Strength of evidence of causal relationship Extent of patient exposure Impact on specific populations (e.g., children/elderly) Potential for preventing or mitigating risk Alternative therapies




Emerging Drug SafetyConcern: Communication

Drug labeling Prescribing information Patient package inserts Medication Guides (MedGuides) Drug Facts label (over-the-counter products)

Drug Safety Communication (DSC)



Implemented in 2010 Specific tool used by FDA to communicate

important safety information of marketed drugs Targeted to both health care professionals and

the public Standardized and posted on FDA Web site Not a “Crisis Document” Public Health Alert



Summary of the safety issue and nature ofthe risk

Established benefit(s) of drug Recommended actions for both health care

professionals and the public Summary of data reviewed or in process of

being reviewed by FDA



Updates to Drug Safety Communications New information Timeliness Public reminder Decision




Ondansetron DSCs

Basis of original alert (9-5-11) Two published studies associated ondansetron with QT

prolongation Manufacturer required to conduct a thorough QT study to

determine degree of QT prolongation Current status

6-29-12: Preliminary results of manufacturer study prompted the removal of the 32 mg IV dose from product labeling

12-4-12: Final study results prompted removal of 32 mg IV product (pre-mixed injection) from the market

http://fda.gov/Drugs/DrugSafety/ucm271913.htmhttp://fda.gov/Drugs/DrugSafety/ucm310190.htmhttp://fda.gov/Drugs/DrugSafety/ucm330049.htm

DSC Review

Do not panic (not a “Crisis Document”) Tell others not to panic Designate a “quarterback” to manage Review detail of all pertinent DSCs Evaluate cited literature in the specific DSCs Search for additional published literature Obtain input from key stakeholders

DSC Review

Understand the specific impact at institutionlevel and/or patient level

Make recommendation to governing body athospital (e.g., P&T Committee), if needed

Create consistent communication about finaldecision

QT Prolongation Significance QTc interval: 420 msec

QTc interval > 500 msec is associated with significantrisk for torsade de pointes or TdP (2- to 3-fold higher) Individual changes < 30 msec

Clinically insignificant Individual changes between 30 and 60 msec

More likely to represent a drug effect and concern aboutpotential risk of arrhythmias

Individual changes > 60 msec Clinically significant

.Drew B, et al. Circulation 2010;121:1047-60Malik M, et al. Drug Saf 2001:24(5):323-51

De Ponti F, et al. Drug Saf 2002;25(4):263-86

Risks Factors for QT Prolongation

Congenital long QT syndrome (LQTS) Clinically significant bradycardia or heart

disease Electrolyte imbalances Sodium, potassium, magnesium, calcium

Impaired hepatic/renal function Pharmacokinetic or pharmacodynamic drug

interactions (acquired LQTS)

Drew B, et al. Circulation 2010;121:1047-60De Ponti F, et al. Drug Saf 2002;25(4):263-86



Literature Regarding QT Prolongation Risk of developing TdP is proportional to the degree of QT

prolongation

Patient variability: Intra-individual and inter-individual variability; individual metabolic capacity for a given drug

QT interval measurement: Definitions, variability in heart rate

Pharmacokinetics: Timing of ECG measurements compared to peak/steady state drug concentrations

Data analysis and interpretation: Different formulas to correct for the QT interval for heart rate and definition of clinicallysignificant change in QTc

Ondansetron: Primary Literature

Design Non-randomized, observational12-lead ECG evaluations (blinded)Baseline, 1-, 2-, 3-, 5-, 10-, and 15-minutes

Participants Droperidol (n=43); Ondansetron (n=42)Operative procedure (vascular, neurosurgery, ENT, orthopedics, gynecology)No QT-interval prolonging medications with risk of TdPQTc interval prolonged at baseline: 18/85 (21%) patients(> 450 msec in males; > 470 msec in females)

Objective To describe QTc interval changes associated with administration of low-dose droperidol (0.75 mg IV) or ondansetron (4 mg IV) to treat post-operative nausea and vomiting (PONV)

Charbit, et al. Anesthesiology 2005;102(6):1094-1100


Results •Mean maximal QTc interval prolongation:Droperidol: 17+9 msec at 2 minute (P<0.0001) Ondansetron 20+13 msec at 3 minute (P<0.0001)•Prolonged QTc interval:Droperidol (10/43); ondansetron (8/42)•Correlated with body temperature and duration ofanesthesia

Conclusions •Associated significant QTc interval changes•Low risk of proarrhythmias (TdP: n=0)•QTc interval > 500 msec (n=10)

PracticeConsiderations

Observational study designStatistical versus clinical significancePONV versus CINV patient population and dose


Design Prospective, placebo-controlled, double-blindFour cross-over periods (single dose)Droperidol alone (1 mg IV); Ondansetron alone (4 mg IV); Droperidol + ondansetron; Placebo12-lead ECG (at 1 minute intervals for the first 15 minutes, then at other set times through 10 hours)

Participants Healthy volunteers (n=16; 50% male)Normal QTc interval (< 440 males:< 450 females) and resting HR (55-70 bpm)

Objective To assess the effects of droperidol IV and ondansetron IV alone or in combination on the QTc interval duration

Charbit, et al. Anesthesiology 2008;109(2):206-12


Results •Compared with placebo, droperidol and ondansetron significantly prolonged the QTc interval Mean maximal QTc prolongation: droperidol (25+8 msec); ondansetron (17+10 msec); and droperidol + ondansetron (28+10 msec)

•Maximal QTc prolongation was significantly greater in droperidol and droperidol + ondansetron groups compared with ondansetron alone (P=0.014 and P=0.001, respectively)

•No difference between droperidol group and droperidol + ondansetron group (P=0.33)

•No ventricular arrhythmia noted during study


Conclusions Effect of droperidol on QTc prolongation was significantly greater than ondansetron

Droperidol alone and droperidol + ondansetron had similar effect (i.e., no additive effect) on QTc interval

No patient had QTc interval greater than 500 msec or a change from baseline > 60 msec

PracticeConsiderations

Prospective study (Harmonization E14 Guidelines for evaluation of proarrhythmic risk for non-cardiac drugs)Drug interaction studyStatistical versus clinical significancePONV versus CINV patient population and dose



Ondansetron: Manufacturer Data Study conducted by manufacturer (GlaxoSmithKline) Evaluated effect of ondansetron injection on cardiac

conduction in healthy volunteers (n=58) Baseline 12-lead ECG Holter 12-lead continuous recording device (24 hours) Randomized, blinded, four way cross-over design

Ondansetron 8 mg and 32 mg (15-minute infusion) Moxifloxacin 400 mg (tablet) – positive control Placebo

Communication with GlaxoSmithKline. Study 115458.2012 http://gsk- clinicalstudyregister.com [Accessed 3/26/13]

Ondansetron: Manufacturer Data Ondansetron 32 mg:placebo (change from baseline)

19.6 msec (90% CI; 17.64, 21.49) Ondansetron 8 mg:placebo (change from baseline)

5.84 msec (90% CI; 3.92, 7.76) Predicted mean QTc interval for ondansetron:

24 mg: 14 msec (upper limit 95% CI: 16.3 msec) 16 mg: 9.1 msec (upper limit 95% CI: 11.2 msec)

No subjects had QTc interval greater than 480 msec(or experienced change from baseline > 60 msec)

Thirteen (23%) of subjects had changes on QTc intervalbetween 30 msec and 60 msec

Ondansetron: RevisedProduct Labeling (11/2012)

Warnings and Precautions: Prolongs QTc interval in dose dependent manner ECG monitoring recommended in select patients

Dose Chemotherapy-induced nausea and vomiting (CINV):

Adults: Three 0.15 mg/kg doses up to a max of 16 mg per dose First dose 30 minutes before chemotherapy and subsequent

doses 4- and 8-hours after first dose (max of 16 mg per dose)

Ondansetron: Other Considerations

PONV and CINV: Different population, dose, risk Dose of ondansetron (higher doses) Route of administration (IV versus PO) Rate of administration (IV push versus infusion) Multi-medication (multi-modal) approach to N/V 5HT3 antagonist class effect Cost of medication Cost of baseline and/or frequent ECG monitoring

Ondansetron: Application

VL is a 47-year-old female with cancer who will beundergoing first course of moderately emetogenicchemotherapy. PMH: GERD, hypercholesterolemia, seasonal allergies Medications: famotidine, simvastatin, loratidine Other: Anxious over new cancer diagnosis; non-smoker

What would you recommend for the prevention of CINVand why?A= Ondansetron 16 mg IV + steroidB= Granisetron 1 mg IV + baseline/continuous ECG monitorC= Palonosetron 0.25 mg IV + steroidD= Avoid 5HT3 antagonists and use other antiemetics

Same DSC Review Process

Azithromycin and Risk of Potentially FatalHeart Rhythms

Zolpidem and Lower Recommended Doses Sildenafil (Revatio®) and Use in Pediatric

Patients with Pulmonary ArterialHypertension (PAH)

Codeine and use in pediatrics patients aftertonsillectomy and/or adenoidectomy



Summary

Drug safety communication is the single tool used by theFDA for communicating emerging drug safety information

Drug safety communications are not crisis documents

Process should be developed to evaluate the drug safety communication and other available data

Consistent response should be developed to respond toany inquiries from health care professionals or patients



Documents

Activity No. 0217-0000-14-115-L05-P, 1.5 contact hours; Knowledge-based activity. · 2014-09-26 · Curricular Track I: REMS and Regulation Updates to Promote Medication Safety