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Opioid REMS Update Kevin L. Zacharoff, MD, FACIP, FACPE, FAAP


Disclosures  Grant/Research Funding: Endo Pharmaceuticals, Actavis  Salary: Inflexxion


Learning Objectives Recognize the increase in abuse and risks associated with opioid prescriptions Describe the proposed class-wide opioid REMS program approved by the FDA Identify the goals of the new class-wide opioid R EMS program


Opioid Risk  Old definition – The potential for opioid analgesia adverse effects • Constipation • Nausea/Vomiting • Dry mouth • Itching • Sweating

– Respiratory Depression


Opioid Risk  New definition – Adverse effects – Aberrant drug-related behavior • Abuse • Misuse • Diversion • Addiction

– Unintended Deaths


Opioid Risk  An increase in prescription opioid misuse and mortality associated with opioid use has been observed1  The reasons for this can be attributed to many different factors: • The use of opioids as part of a comprehensive treatment plan has gained significant traction2 • The number of opioid prescriptions have increased over the last 20 years • The number of people suffering from chronic pain has increased and continues to increase • Educational deficits of non-expert health care providers with regard to safe and appropriate use of chronic opioid therapy

1. Office of Applied Studies, Substance Abuse and Mental Health Service Administration:

Results from the 2004 National Survey on Drug Use and Health. Rockville, MD: Department of Health and Human Services, 2005 2. The American Academy of Pain Medicine, the American Pain Society: The use of opioids for the treatment of chronic pain: A consensus statement from the American Academy of Pain Medicine and the American Pain Society. Clin J Pain 13:6-8, 1997


Stakeholders  We are all stakeholders – Physicians – Nurses – Pharmacists – Dentists – Law Enforcement Officials – Hospitals – EDs, Clinics – Insert your name here______________________


Far-Reaching Public Health Impact of Widespread Opioid Analgesic Abuse/Misuse  Mental impairment leads to other types of unintentional injuries – Falls and fractures among elderly – Motor vehicle crashes involving “drugged driving”

 Substance abuse leads to intentional injuries

– Drug-related self harm and drug-crime related interpersonal violence

 Intravenous use leads to infections

– HIV transmission to injection of dissolved tablets – Hepatitis C: “Graduating” from oxycodone to injected heroin

 Reproductive health effects

– Congenital defects associated with opioid exposure in utero – Newborn withdrawal syndrome – Infertility from chronic heavy use

 Family Stability

– Primary reason for needing to shelter children Family stability statistic from DCF, 2010


New York Shooting: Four Dead In Pharmacy Massacre June, 2011


Unintentional Overdose Deaths Involving Opioid Analgesics, Cocaine, and Heroin

Source: CDC Public Health Grand Rounds 2.18.2011 Data from the National Vital Statistics System. http://wonder.cdc.gov, multiple cause dataset


Unintentional and Undetermined Intent Drug Overdose Death Rates by State, 2007

Source: CDC Public Health Grand Rounds 2.18.2011


Nonmedical Use of Prescription Pain Medications  Ages 12 and older: The 2009 estimate of 5.3 million current nonmedical users is up 20% from the 2002 estimate of 4.4 million – Ages 12-17: The rate of current nonmedical use increased 17%, from 2.3% to 2.7%

 Initiation

– As a class of drugs, the nonmedical use of prescription pain medications continues to have more new users in the past year than any other class – In 2009, there were 2.6 million new users, 2.2 million of which were for nonmedical use of pain relievers

 Reasons

– Most young people who misuse prescription medications report that they obtain the drugs from friends or family. Many of these medications, particularly prescription painkillers, sit unused and unsecured in medicine cabinets, thereby making them readily available – Unfortunately, young people often mistakenly think these drugs are safer than so-called “street drugs” Data from Nat’l Survey on Drug Use and Human Health. 2009. http://www.oas.samhsa.go


Public Health Impact of Opioid Analgesic Use: For Every 1 Overdose Death There Are 9

Abuse treatment admissions

35

ED visits for misuse or abuse

161

People with abuse/dependence

461

Nonmedical users 0

50

100

150

200

250

300

350

400

450

500

Slide from CDC Grand Rounds 2.18.11. Treatment admissions are for primary use of opioids from the Treatment Exposure Data Set. Abuse dependence and nonmedical use are from the Natl Survey on Drug Use and Health https://dawninfo.samhsa.gov/default.asp Emergency department (ED) visits are from DAWN (Drug Abuse Warning Network)


It Gets Worse  National Survey on Drug Use and Health - 2009 – In 2008, more than 13% of all Americans age 12 and older have used a prescription pain medication non-medically at least once in their lifetime – More than 2 million Americans age 12 and older initiate non-medical use of a prescription pain reliever each year; this rate has remained unchanged for the past 5 years – Most non-medical users of prescription pain medications obtained it from a single healthcare provider or clinical setting


Dependent on Prescription Drugs, Even Before Birth

By ABBY GOODNOUGH and KATIE ZEZIMA New York Times Published: April 9, 2011


Distribution of Prescription Opioid Analgesics by Health Care Setting Hospital Outpatient Surgical Specialty Offices 8% 10% Medical Specialty Offices 13%

Emergency Departments 39% Primary Care Offices 30%

Raofi S, Schappert SM. Medication therapy in ambulatory medical care: United States, 2003–04 National Center for Health Statistics. Vital Health Stat 13(163). 2006.


When are opioids indicated?  It depends… – If the pain is moderate to severe and: • Has significant impact on function • Has significant impact on quality of life • Non-opioid pharmacotherapy has been tried and failed • Patient agreeable to close monitoring* i.e., warfarin

 “To write prescriptions is easy, but to come to an understanding with people is hard.”1

1. Frank Kafka, Country Physician


In 2012…… It depends….. –Who you talk to •Is the pendulum swinging the other way? •Are opioids ever the right answer? –Did we go too far? –More harm than good?

•What is the long-term efficacy of chronic opioid therapy? –FDA Workshop May 30-31, 2012


The Opioid Pendulum

Opiophobia

Opiophilia


Safe and Appropriate Use What does this mean? –Risk factors • What does risk mean?

–Prior experiences –Comfort level of all parties involved –Education –The Law

Have guidelines worked?


Risk Evaluation and Mitigation Strategies REMS


What are REMS?  Risk Evaluation and Mitigation Strategies – On September 27, 2007, the President signed into law the Food and Drug Administration Amendments Act of 2007 (FDAAA) – NEW Authorization for FDA to require certain drug manufacturers to submit a proposed REMS if the FDA determines that a REMS is

necessary to ensure that the benefits of a drug outweigh the risks of the drug


The Past  Before FDAAA was enacted, FDA required that a small number of drug and biological products have  Risk Minimization Action Plans (RiskMAPs): – A strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits – Developed for products that had risks that required additional risk management strategies beyond describing the risks and benefits of the product in labeling


The Present  NOW that FDAAA has given FDA the authority to require REMS when necessary to ensure that the benefits of a drug outweigh the risks, FDA anticipates that: – A product that would previously have been approved with a RiskMAP will, instead if deemed to be appropriate by the FDA, be approved with a REMS

 REMS ARE ENFORCEABLE – Manufacturer’s will pay if they are not followed – It all ends up at the doorstep of healthcare providers and patients


REMS Goals  The desired safety-related health outcome or the understanding by patients and/or healthcare providers of the serious risk(s) associated with a certain medication – Stated in a way to achieve maximum risk reduction  Examples: – Healthcare providers are aware of how to assess patients appropriately to determine the risk/benefit ratio – Patients taking drug “X” should be aware of the serious risks relative to potential benefits


REMS Goals  The desired safety-related health outcome or the understanding by patients and/or healthcare providers of the serious risk(s) associated with a certain medication – Stated in a way to achieve maximum risk reduction

 Examples: – Healthcare providers are aware of how to assess patients appropriately to determine the risk/benefit ratio – Patients taking drug “X” should be aware of the serious risks relative to potential benefits


Think Thalidomide


Opioid REMS  Prescription opioids continue to be an increasing problem with respect to adverse events & abuse  Prescription opioid abuse contributes to crime & violence  Inadequate patient supervision following prescription of opioids, leading to: – Overdose – Iatrogenic addiction – Continued dosing in patients who no longer need treatment – Recreational use (including high school and college students)


“The Letter” about REMS  Written to all manufacturers of extended-release/long-acting opioids from the FDA – This letter is to inform you (insert manufacturer’s name) that the Agency has determined certain opioid products, including DRUG NAME, will be required to have Risk Evaluation and Mitigation Strategies (REMS), to ensure that the benefits of the drugs continue to outweigh the risks of: • Use of certain opioid products in non-opioid-tolerant individuals • Abuse • Overdose, both accidental and intentional

– The REMS will include elements to assure safe use to ensure that prescribers, dispensers, and patients are aware of and understand the risks and appropriate use of these products


The FDA’s Statements  “The agency has long been concerned about adverse events associated with this class of drug and has taken steps in cooperation with drug manufacturers to address these risks. We intend to use the agency’s REMS authority under the Food and Drug Administration Amendments Act of 2007 (FDAAA) to mitigate the risks of these drugs”  “Opioid drugs have benefit when used properly and are a necessary component of pain management for certain patients”  “Opioid drugs have serious risks when used improperly”  “Despite these efforts (RiskMAPs), the rates of misuse and abuse, and of accidental overdose of opioids, have risen over the past decade”


The REMS Rationale  “The FDA believes that establishing a REMS for opioids will reduce these risks, while still ensuring that patients with legitimate need for these drugs will continue to have appropriate access”  “The REMS would be intended to ensure that the benefits of these drugs continue to outweigh certain risks”


Opioid REMS What does (or will) it all mean?


Opioid REMS  Outstanding Questions – Weak? – Strong? – Unfair? – Restrictive? – Appropriate? – Effective? – Long-acting, extended-release vs. short-acting, immediate-release? – When? – How will effectiveness be measured?


“Class-wide” Opioid REMS Some Important Questions  Is it truly “class-wide”?  Does the higher incidence of non-medical use occur with immediate-release, or extended-release formulations? – Does it matter?

 Will forcing requirements on prescribing the extended-release meds just push people towards writing for more of the shortacting ones?  Will that possibly worsen the problem?


Unintended Consequences?  Decreased access to these pain medications for legitimate medical purposes  Shifts in prescribing to opioids not covered by the REMS and other pain medications  Healthcare providers “opting out” of pain management due to burdensome certification requirements  Negative impact on the care of disparate groups of chronic pain patients, such as those in rural areas, the poor, ethnic and racial minorities, and women


Industry Working Group (IWG)  A group independent of the FDA was formed and consisted primarily of the affected medication’s sponsors, advocacy and policy groups, and other non FDA stakeholders  Met regularly to provide a forum to work collaboratively with other stakeholders in order to develop a REMS plan that would satisfy the goals of the FDA  These goals needed to include key components of the REMS, as well as a mechanism to measure how effectively the REMS would be able to achieve its desired goals over time


What’s Happening?  On April 19, 2011, the White House made an announcement at a press conference about its new program targeting abuse and misuse of prescription pain medications  On April 20 2011, the FDA announced the implementation of its proposed REMS  Decisions need to be made about incorporating the best available metrics to measure the impact of REMS, as well as whether this will be a true “class-wide” REMS, covering all opioid medications


Education  A large part of the REMS will emphasize education – Draft blueprint for education released 11/4/11

“Health care professionals who prescribe extended-release (ER) and long-acting (LA) opioids are in a key position to balance the benefits of prescribing ER/LA opioids to treat pain against the risks of serious adverse outcomes including addiction, unintentional overdose, and death. Opioid misuse and abuse, resulting in injury and death, has emerged as a major public health problem” FDA


Education  “After notifying the sponsors of long-acting and extended-release (LA/ER) opioid drugs that they were required to submit a risk evaluation and mitigation strategy (REMS), FDA has been working with the sponsors that market these products on the required REMS”  “The central component of the Opioid REMS is an education program for prescribers (e.g., physicians, nurse practitioners, physician assistants) so that LA/ER opioid drugs can be prescribed and used safely”  “FDA expects the prescriber training to be conducted by accredited, independent continuing education (CE) providers, without cost to the healthcare professionals, under unrestricted grants to accredited CE providers funded by the sponsors”


The Blueprint  Outlines that prescribers should: – Understand how to assess patients for treatment with ER/LA opioids – Be familiar with how to initiate therapy, modify dose, and discontinue use of ER/LA opioids – Be knowledgeable about how to manage ongoing therapy with ER/LA opioids – Know how to counsel patients and caregivers about the safe use of ER/LA opioids, including proper storage and disposal – Be familiar with general and product specific drug information concerning ER/LA opioids


Patient Assessment Consideration of risks involved with ER/LA opioids and balance these against potential benefits –Risks of concern include: • Overdose due to the high dosage of opioid available as an ER/LA formulation • Intentional abuse by patient or household contacts • Addiction • Interactions with other medications and substances • Inadvertent exposure to household contacts (e.g., children)


Initiating Therapy, Modifying Dosing, and Discontinuing Use of ER/LA Opioids  Awareness of federal and state regulations  Consideration that dose selection is critical  Knowledge about conversion from IR to ER/LA, and from one ER/LA to another  Issues surrounding cross-tolerance  Equianalgesic dosing concepts and monitoring  Necessity for tapering when decision is exit strategy


Managing Ongoing ER/LA Therapy  Clear establishment of goals of treatment

– Regular re-evaluation for pain, function, and QOL

 Use Patient-Provider Agreements (PPA) – Not mandated

 Assurance that patients are adherent to treatment plan  Monitor patients for aberrant behaviors

– Awareness – Interview – PDMPs – Screening for substance abuse/behaviors (e.g., SOAPP, ORT) – Understand the role of drug-screening (e.g., UDS) – Medication reconciliation at each visit


Managing Ongoing ER/LA Therapy Management of adverse effects Re-assessment of efficacy and tolerance Re-assessment of appropriateness of continuation of chronic opioid therapy Re-assessment of underlying pain condition


Counseling of Patients and Caregivers  Product-specific information  Directions for safe and appropriate use  Explicit warning against modification of formulation (e.g., crushing, chewing)  Caution about use of other CNS depressants concomitantly  Symptoms of withdrawal  Warning about sharing  Safe storage  Disposal  Adverse effects


General Information about ER/LA Opioids  General characteristics  Toxicity  Drug interactions  Examples: – Respiratory depression – Constipation – Drug-drug interactions

 Tolerance  Specifics about formulation (e.g. oral, transdermal)


Specific Information About ER/LA Opioids  Knowledge related to the molecule  Dose form/strength  Dosing interval  “Key” instructions to convey to patients  Major drug interactions  Use in opioid-tolerant patients  Drug-specific adverse events  Morphine equivalency


What’s Next?  Implementation of REMS educational programs  DEA Registration linked to education  Don’t forget patient education  PDMPS  Disposal programs  Enforcement


Opioid REMS Update