Fact: Prescription drugs are complicated, and they are getting more complicated every day.
Issues with complex drugs and side effects is not just a concern for the healthcare provider, it directly impacts the patient and caregiver, too. We’ve all heard the long list of adverse effects and warnings that unfold during a primetime ad on TV. But how do the FDA and healthcare providers address these very serious drug concerns in a patient-centered approach? Is there a proactive program to help follow these adverse drug effects in known risky drugs? How does technology factor into keeping patients safe from serious drug side effects? Can these programs be easily implemented by providers and the healthcare system?
The answers are not straightforward. A program from the FDA known as the Risk Evaluation and Mitigation Strategy (REMS) aims to address many of these questions. With drug safety a top concern, The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require a REMS from manufacturers to ensure that the health benefits of REMS drug or biological products outweigh their risks, which can be severe in all of the affected drugs.
What is the goal of the REMS program?
- A REMS is a strategy to manage known or potential serious risks associated with a drug product and is required by the FDA to ensure that the benefits of a drug outweigh its risks.
In fact, FDA has many other individual risk management programs that may be more familiar: patient package inserts, medication guides, restricted access, MedWatch, and the DEA classification of controlled substances. However, REMS employ risk minimization strategies beyond the typical package insert labeling — that long piece of paper that you receive with each prescription.
REMS may allow a much needed drug to remain on the market that otherwise might be too risky to approve. An example is the drug alosetron (Lotronex), used for severe diarrhea-predominate irritable bowel syndrome (IBS) in women who fail all other possible treatments. Lotronex was actually removed from the US market in November 2000 due to safety concerns with serious, but rare, side effects, including ischemic colitis. However, Lotronex was allowed back on the market after development of a risk management program by the manufacturer. Today, Lotronex falls under a REMS program to educate provider and patient about the serious risk of severe constipation and ischemic colitis with Lotronex treatment.
FDA has also launched an upgraded website — REMS@FDA — to allow easier electronic access for all stakeholders — patients, prescribers, and healthcare systems — to the individual elements of the REMS.
Components of a REMS
REMS require certain risk mitigation components, which can include any or all of these:
- A Medication Guide or Patient Package Insert
- Communication Plan
- Elements to Assure Safe Use (ETASU)
- Implementation System
For drugs in REMS programs, a Medication Guide may be dispensed with the medicine and is written in understandable, plain language for the patient. A Medication Guide is provided in addition to the regular Consumer Medication Information. A Communication Plan is developed by the manufacturer to inform and educate healthcare providers about drug risks, and might include Dear Healthcare Provider letters, targeted information about implementation or safety measures, or information directed through professional societies about drug risk and safe use. An Element to Assure Safe Use (ETASU) is considered the most extensive component of a REMS program and involves specific actions that healthcare professionals must execute prior to prescribing, dispensing, or continuing the drug. Of close to 80 approved REMS as of July 2016, 43 incorporate an ETASU. Finally, the Implementation System requires the manufacturer to take steps to monitor and evaluate those healthcare providers responsible for ETASU components.
Examples of REMS Requirements
Most drugs that have REMS are placed in a single REMS program developed by a single manufacturer. However, the FDA can require several drug companies to work together on REMS programs for similar drugs — called a Shared System REMS (SSSR) — to increase efficiency and lower the logistical burden of having multiple REMS for the same product. The manufacturers share the Elements to Assure Safe Use (ETASU), their REMS database and educational website, patient registries, and call center. There is only one REMS document and set of materials.
A brief look at various examples of drugs and drug classes that are involved in REMS can help to provide clarity for patients about how this program works and why it’s needed. All drugs in the REMS program have devastating side effects that need prevention and possible monitoring. However, different drugs may require different components of the REMS program. To view a complete list of REMS, visit the REMS@FDA page on the FDA website, www.fda.gov.
The iPledge program may be one of the best known REMS programs, which involves Isotretinoin (Absorica, Amnesteem, Claravis, Myorisan, Sotret, Zenatane) for severe recalcitrant nodular acne. Isotretinoin is part of a shared system REMS. REMS are required with isotretinoin because there is a very high risk that severe birth defects will result if pregnancy occurs while taking isotretinoin, even if the drug is taken only for short while.
How does the iPledge program work? Isotretinoin is available only from a certified pharmacy under a special program called iPLEDGE. Patients must be registered in the REMS and have two negative pregnancy tests before starting isotretinoin, and a negative test each month while taking isotretinoin. Patients are also required to use two forms of birth control to prevent pregnancy while taking isotretinoin. Females cannot donate blood while taking isotretinoin and must continue birth control for at least one month after stopping isotretinoin. There are many other specific requirements that the patient, prescriber, pharmacist and pharmacy must meet as well, and the REMS program spells all of this out clearly. Ultimately, the goal is to prevent pregnancy in the female to prevent devastating birth defects in a child.
Zinbryta (daclizumab) is an interleukin-2 receptor blocking antibody approved in May 2016 for the treatment of relapsing forms of multiple sclerosis (MS) in adults. Zinbryta can cause severe, possibly fatal liver injury, liver failure, autoimmune hepatitis and other serious immune mediated disorders. Because of these serious events, FDA requires a REMS program to ensure safe use.
As with most REMS programs, multiple stakeholders are involved in process. Prescribers, patients, pharmacies, and drug wholesalers are all included to ensure safe use of the drug. With Zinbryta, patients must enroll in the REMS program, review the patient guide, receive patient counseling, and have a blood test — all before starting Zinbryta — as well as monthly during treatment and monthly for 6 months after stopping treatment. Other stakeholders, like the pharmacy and physician, have special requirements they must fulfill, too. Prevention of possible fatal liver injury is the intent.
Chantix is a smoking cessation medicine used together with behavior modification and counseling support to help patients stop smoking. The goal of the Chantix REMS is to inform patients about the potential serious risk of psychiatric (mental health) side effects, such as mood or behavior changes, confusion, anxiety, panic attacks, hallucinations, agitation, or thoughts about suicide.
With Chantix, a Medication Guide is given with each prescription a patient receives at the pharmacy, and they should review it. In addition, the manufacturer must submit REM assessments to the FDA at various time intervals. The objective is to recognize serious behavioral changes before the patient is endangered.
Addyi, approved in August 2015, is used to treat decreased sexual desire in women who have not gone through menopause and who have never had low sexual desire in the past. The goal for the REMS program is to make the patient aware of the increased risk of hypotension (low blood pressure) and syncope (fainting) associated with Addyi due to a drug interaction with alcohol.
Addyi is available only from a certified pharmacies. For the Addyi REMS, patients must complete the Patient-Provider Agreement Form and receive counseling from the prescriber on not using alcohol with drug. In addition, the pharmacist must counsel the patient on not using alcohol with Addyi with each prescription refill. Additional requirements must be fulfilled by prescribers, pharmacies and wholesalers. The goal here is to be sure the patient abstains from alcohol to prevent a serious fall or accident.
- Extended-Release and Long-Acting (ER/LA) Opioid Analgesics
The news is crowded with overdose death reports due to opioid abuse, and addressing prescription narcotic addiction is a top health care initiative for government regulators. Long-acting (LA) and extended-release (ER) opioids are pain medications usually intended to be used in patients in need of chronic, long-term pain control and who have previously received increasing levels of narcotics. The amount of opioid analgesic contained in an ER tablet can be much more than the amount of opioid analgesic contained in an immediate-release tablet because ER tablets are designed to release the opioid analgesic over a longer period of time. These drugs are extremely potent and dangerous if not properly prescribed and monitored. Adverse outcomes may include addiction, unintentional overdose, and death.
The Extended-Release and Long-Acting (ER/LA) Opioid Analgesics REMS Program, a shared system REMS, includes these multiple drug products that could lead to dangerous blood levels of opioids if not used properly. Examples of brand name drugs in the ER/LA Opioid Analgesic REMS include: Embeda, Exalgo, Hysingla ER, Kadian, Oxycontin, Zohydro ER, and many other long-acting narcotics. Generic names include ER/LA forms of hydromorphone, fentanyl, oxycodone, oxymorphone, and morphine, among others.
The goal of the long-acting opioid REMS is to reduce serious side effects and outcomes due to inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics while still maintaining patient access to these much needed pain medications. Prescriber education on all ER/LA opioid analgesics, patient counseling, and a unique Medication Guide for each ER/LA opioid analgesic drug product are the principal components of this REMS.
Lost in Translation: REMS Challenges and Fixes
The REMS program is not without its critics and challenges. Currently, there are over 70 REMS in place. Complexity varies, as does the components and stakeholder prerequisites. It is difficult for health care professionals to sift through the required components and for patients to understand the safety risks. There have been concerns that these programs are too cumbersome, disconnected, and time-consuming for health care professionals to implement. A physician that did not initiate the medication may encounter patients who are enrolled in REMS programs.
Other REMS challenges include:
- No electronic integration into patient health records (EHRs) disrupts the work flow of providers and pharmacies.
- Lack of standardization and utilization of best practices across the entire REMS system.
- Variations among REMS make training and adaptability difficult.
- Pharmacy difficulty in verifying physician certification in REMS programs.
How is the FDA addressing these REMS burdens?
The FDA has developed a new FDA page REMS@FDA as one important response to these concerns. The page includes upgrades such as:
- A searchable table of REMS programs.
- Individual listings of actions required by all stakeholders, including patients, providers, pharmacies, and wholesalers.
- Electronic links to relevant information such as drug labeling, REMS websites, and specific REMS educational materials.
- Downloadable REMS data.
- Historical documents and most recent update dates.
- An mobile-friendly design.
- Options for email delivery of REMS news.
Another important upgrade currently in process is the addition of Structured Product Labeling, or “SPL”, which is a data standard for prescription drug information. SPL data will allow healthcare providers, health systems and specialty pharmacies to incorporate and access REMS requirements within the patient electronic health record (EHR).
The FDA has adopted SPL formatting as a priority project. It is hoped that REMS SPL availability will add a significant boost to patient safety and help to ease the burden and confusion often encountered with implementation of these programs.
What are other benefits of SPL?
As noted by The Office of Program and Strategic Analysis at the FDA, REMS SPL will capture the important data elements required by the REMS, such as:
- Who is the stakeholder that must meet the REMS requirement: such as the prescriber, dispenser, patient and/or health care setting?
- When should the action be put into place: for example, at certification, prescribing, dispensing, and administration?
- What is the activity: that is, patient counseling, completing an enrollment form, or lab testing?
- Which reference material is needed to meet the requirement of the REMS: such as an enrollment form, medication guide, or educational pamphlet?
SPL data will be centralized and distributed from the manufacturer to stakeholders such as patient, healthcare provider and pharmacies through the FDA. SPL data will make it easier for healthcare providers and others to implement REMS by:
- Clarifying the REMS requirements for stakeholders.
- Allowing REMS to be integrated into other existing electronic health record (EHR) and information technology systems.
- Allowing “triggers” for EHRs, pharmacies, and health systems to perform safety checks.
- Allows easier development of a standardized REMS.
- Facilitating review and tracking of REMS.
- Supporting analytics for REMS research and assessment.
FDA initiated an SPL pilot program in 2015 and is gathering data on the REMS program from stakeholders to continue to upgrade and strengthen this important drug safety initiative for high risk drugs.
Drugs are complicated and side effects can be serious, so it’s important for everyone — healthcare regulators, physicians, pharmacists, nurses and especially patients — to understand these high risk medications, implement communication and educational strategies, stay informed of program changes, and talk to each other. With an updated REMS@FDA web page and integration of SPL, REMS communication should get easier, but drug safety always has been — and always will be — a team effort.
The U.S. Food and Drug Administration (FDA). A Brief Overview of Risk Evaluation & Mitigation Strategies (REMS). Accessed July 21, 2016 at http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM328784.pdf
The Federal Register. Electronic Submission of Final Approved Risk Evaluation and Mitigation Strategies and Summary Information in a Standard Structure Product Labeling Format: Pilot Project. 10/06/2015.
Traynor K. Health Care Providers Want Electronic, Standardized REMS Programs. Pharmacy News.9/1/2013 ASHP. Accessed 7/21/2016 at http://www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=3938
Barlas S. FDA Intensifies Drive to Reduce REMS Burden. P&T. 2016;41:103-05, 119. Accessed 7/21/2016 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745637/
APHA. Letter to Division of Dockets Management, FDA. June 3, 2016. Re: Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee (FDA-2016-N-0820)
Cierniak K. REMS: Today vs. Tomorrow. April 21, 2016. REMS Logic Website. Accessed 7/26/2016 at http://remslogic.com/rems-today-vs-tomorrow/
Posted 7/26/2016: Leigh Anderson, BS, PharmD