Shopping Cart

INTRODUCTION

Approximately 70% of Americans take at least 1 prescription drug, more than 50% take 2, and 20% take 5 or more.¹ As a result, unanticipated drug safety problems can evolve into a public health problem. For example, an unacceptable number of cardiovascular events linked to rofecoxib (Vioxx) led to its withdrawal in 2004.² After a 2006 Institute of Medicine drug safety report was delivered to the United States Congress,³ the Federal Food, Drug, and Cosmetic Act, was amended by the Food and Drug Administration Amendments Act of 2007 (FDAAA). FDAAA authorized the United States (U.S.) Food and Drug Administration (FDA) to require drug manufacturers to submit a structured plan, known as a risk evaluation and mitigation strategy (REMS), to ensure that certain drugs' benefits would outweigh their risks.⁴ From 2008 to May 31, 2012, FDA approved REMS programs for 33% of biologics and 8% of chemical entities available on the market.⁵

Health care systems initially had limited involvement in REMS design. In its initial guidance documents, FDA stated that it would attempt to avoid undue burdens that REMS programs may impose on the health care system to improve drug safety. However, nearly 9 years later, the Office of the Inspector General at the Department of Health and Human Services and several pharmacy and medical organizations have raised concerns about REMS.^6-9 They question the increased burden REMS programs have imposed on the health care system; patient access to potentially beneficial drugs; the current evaluation process for existing and future REMS; and the lack of compensation for resources necessary to fulfill REMS requirements. When considering the continually changing REMS environment and emphasis of the 1992 Prescription Drug User Fee Act (PDUFA) on expediting the drug approval process, health care professionals need to remain up to date on the current state of REMS. This article reviews REMS components, pharmacy's role and responsibilities, and concerns about the evolution of REMS and existing safeguards.

FDAAA AND REMS COMPONENTS

Following implementation of PDUFA, concerns developed about the rapid market entry of drugs before their safety was scrutinized fully. In response, FDA developed RiskMAPs in 2003 for drugs that required more than routine safety monitoring and product labeling.¹⁰ A RiskMAP was a safety program designed to meet specific objectives for a drug to minimize known risks and preserve benefits.¹¹ However, RiskMAPs were only part of the drug approval process, and no provisions were in place that would allow FDA to enforce RiskMAP commitments after drugs gained market entry.¹² Subsequently, FDAAA enabled FDA to approve drug safety programs such as REMS at drug approval or after market entry when new safety information became available (Table 1).

Table 1. Risk Minimization Tools: REMS and RiskMAPs
Criteria	REMS	RiskMAP
Dates of activity	2007–present	2003–2007
Important documentation	Food and Drug Administration Amendments Act (FDAAA), 2007	Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment; Development and Use of RiskMAPs, 2005
Are monetary penalties in place for noncompliance?	Yes	No
Are assessments required to demonstrate improved drug safety?	Yes	No
Does FDA have the authority to intervene and recommend/mandate risk-based strategies to ensure safe use?	Before OR after regulatory approval of the drug or biologic agent	At the time of regulatory approval of the drug or biologic
Source: Reference 15
Abbreviations: FDA, Food and Drug Administration; REMS, risk evaluation and mitigation strategy; RiskMAPS, risk minimization action plan.

FDA may use several sources of postmarketing information to initiate or modify REMS including peer-reviewed biomedical literature, clinical trials, MedWatch, and the FDA Sentinel Initiative, which is a national strategy for drug and medical product safety.¹³ An example of FDA postmarketing authority occurred in June 2014 after severe hypoglycemic episodes were reported when pramlintide acetate (Symlin) was used in conjunction with mealtime insulin in patients with type 1 diabetes mellitus.¹⁴ After reviewing drug surveillance data, FDA instructed AstraZeneca, the drug's manufacturer, to develop and distribute a communication plan to select health care providers and medical societies as part of a newly designed pramlintide REMS Program. The program's overarching goal was to inform health care providers about the following:

• The increased risk of severe hypoglycemia associated with the use of pramlintide-insulin cotherapy, particularly in patients with type 1 diabetes mellitus
• The importance of insulin dose reduction with cotherapy (remind clinical providers to counsel and instruct patients on insulin dose reduction to minimize the risk of hypoglycemia)
• Proper patient selection (pramlintide acetate is contraindicated in patients with hypoglycemia unawareness, confirmed gastroparesis, and hypersensitivity to any of its product components)

FDA may mandate the development of preapproval and postapproval REMS for a drug or drug class and may deem a drug misbranded or impose civil monetary penalties when strategies are ignored. A responsible person—defined in the law as “the person who submitted a covered [new drug] application or the holder of the approved such application”—who violates a REMS requirement is subject to a penalty of $250,000 per violation, not to exceed $1 million in a single proceeding. Subsequent infractions may trigger penalties of $1 million per 30-day period and $10 million per proceeding.¹¹

FDA determines that a REMS program is necessary based on several factors, including the following¹⁶: (1) the seriousness of the disease or condition to be treated; (2) the size of the population expected to use the drug; (3) the drug's expected benefit with respect to the disease or condition; (4) the expected or actual duration of treatment; (5) the seriousness of known, potential, or previous adverse events that may be associated with the drug; and (6) whether the drug is a new molecular entity.

Depending on the medication's risks, REMS programs may include several different elements, (Table 2). It may include a medication guide (MedGuide) to provide information for safe, effective use of a drug; a patient package insert; a communication plan that is sent to health care providers highlighting safety concerns or ideal prescribing practices of a drug or biologic agent (eg, Internet-based education materials or presentations by medical liaisons); elements to assure safe use (ETASU), which may include specialized training for health care providers, limitations on dispensing, and patient monitoring; an implementation system; or a combination of these components. Additionally, to ensure that REMS programs successfully decrease the drug's known risk(s), FDA creates a timetable for submission of assessments for drug manufacturers. This means manufacturers must assess each individual program within 18 months, 3 years, and 7 years after the REMS is approved. FDA may require frequent evaluations to ensure a medication's benefits outweigh its risks.¹¹

Table 2. Different Elements Included in Risk Evaluation and Mitigation Strategies

Medication guide Patient package insert Communication plan to disseminate information to health care professionals Elements to assure safe use Implementation system to monitor and evaluate the program's success Timetable for submission of assessments (required for all REMS programs)

Source: Reference 11

Abbreviation: REMS, risk evaluation and mitigation strategy.

Drug manufacturers may voluntarily supply FDA with periodic evaluations of an individual REMS program and propose revisions to existing medication safeguards. The rosiglitazone REMS is an example of this process. After FDA determined that the ischemic cardiovascular risk associated with rosiglitazone-containing products was unacceptably high, it developed and adopted the rosiglitazone REMS program with ETASUs in 2010. However, a subsequent review of long-term, prospective, randomized controlled clinical trials of rosiglitazone compared with metformin and sulfonylureas showed no differences in overall mortality or major adverse cardiovascular events. This led FDA to remove¹⁷: (1) myocardial infarction warnings from rosiglitazone-containing drugs' labeling; (2) the requirement that prescribers become certified before prescribing the drug; (3) the requirement that pharmacies become certified before dispensing the drug; and (4) the requirement that patients enroll in the rosiglitazone REMS program.

FDA is required to evaluate the ETASUs for a minimum of 1 drug annually to determine whether the additional risk-based strategies ensure the following⁶: (1) the drug is used safely; (2) the strategies are not barriers to patient access to the drug; and (3) to the extent practicable, the burden to the health care system is minimized. However, a report published by the Office of the Inspector General at the Department of Health and Human Services showed that FDA completed only 1 evaluation of 32 possible ETASUs during the first 3 years after FDAAA enactment.⁶ As a result, FDA cannot demonstrate that the other 31 programs meet statutory requirements or minimize patient burden . This lack of data remains a point of contention for health care professionals, pharmacy and medical organizations, and managed care organizations.⁷

MEDICATION GUIDES

Pharmacists encounter a specific drug safety element—Medication Guides, or MedGuides—in daily practice, and need to differentiate between MedGuides as labeling and MedGuides as part of a REMS. MedGuides are paper handouts that include patient-friendly language about safe and appropriate medication use. MedGuides are considered part of product labeling and are included in REMS programs if 1 or more of the following circumstances exist¹⁸:

• Labeling of the drug could help prevent serious adverse events.
• The drug has a serious risk about which patients should be notified because information about the risk could affect a patient’s decision to start or continue to use the drug.
• The drug is important to health, and patient adherence to the drug’s directions for use is important for its effectiveness.

In 2011, FDA changed its policy for REMS programs that contain only MedGuides. The new policy stated that REMS programs will include MedGuides only when (1) the program includes other risk-based safety strategies such as communication plans, or (2) FDA determines that having the MedGuide without a REMS (that is, as a labeling requirement only) would be inadequate to ensure a drug’s benefits outweigh the risks.¹⁸

If FDA determines that additional information may help minimize a serious risk associated with the drug, it may require a patient package insert (PPI) in addition to a MedGuide. However, FDA expected that it would infrequently require both a MedGuide and a PPI. In most cases, FDA expects to include MedGuides when REMS programs include ETASUs. Additionally, the new policy included procedures for drug manufacturers to ask the FDA to remove MedGuides from REMS when they could demonstrate MedGuides would not ensure that the drug's benefits outweigh the risks. As a result, FDA has released more than 50% of drugs having MedGuides as the only medication safeguard from REMS requirements.¹⁹ However, even when a MedGuide is released from the REMS requirement, it continues to be part of the approved product labeling unless FDA approves a supplement stating otherwise.¹

Pharmacists and other health care professionals have expressed concerns about MedGuides' content, indicating that REMS materials often omit information about alternative therapies or fail to provide information at the literacy level appropriate for select patients.⁸ At an American Society of Clinical Oncology workshop, Flesch-Kincaid grade level analyses, which evaluate comprehension difficulty,²⁰ were applied to select REMS education materials. The analyses showed that REMS educational materials for darbepoetin alfa (Aranesp) were written at grade 8.2 level, lenalidomide (Revlimid) at grade 9.6 level, and fentanyl (Onsolis) at college level.⁸ Patient information materials should be written at a fifth to sixth grade level to address issues with low health literacy.

In addition to MedGuide content, health care professionals have other concerns. They have been confused about appropriate MedGuide distribution. MedGuides are not required when patients are admitted to a hospital ward, unless the patient or caregiver requests it, or the MedGuide is part of a REMS program mandating its distribution (such as a REMS with ETASUs); however, requirements for MedGuide distribution to outpatients are more complex (Table 3).¹⁸ Pharmacists and other health care providers can be confused about the rules that apply in different situations.

Table 3. MedGuide Distribution Requirements By Patient Location
Patient Location	Patient or Caregiver Requests a MedGuide	MedGuide Provided Each Time Drug is Dispensed	MedGuide Provided at First Dispensing	MedGuide Provided When Educational Materials are Updated	Drug is Part of ETASU With Requirements for MedGuide Distribution
Inpatient wards	MedGuide required	MedGuide NOT required	MedGuide NOT required	MedGuide NOT required	MedGuide required per REMS
Outpatient clinics (including infusion centers)	MedGuide required	MedGuide NOT required	MedGuide required	MedGuide required	MedGuide required per REMS
Outpatient (including retail pharmacy)	MedGuide required	MedGuide required	MedGuide required	MedGuide required	MedGuide required per REMS
Source: Reference 18
Abbreviations: ETASU, element to assure safe use; MedGuide, medication guide; REMS, risk evaluation and mitigation strategy.

COMMUNICATION PLANS

FDA may determine that important information related to a drug should be disseminated directly to health care providers by communication plans. These plans are intended for health care providers, not patients. Communication plans may include a dear-health-care-professional letter (DHCPL), a presentation by a medical liaison, or Internet-based education materials. Communication plans may encourage clinicians to implement risk-based strategies into clinical practice, emphasize drug safety protocols such as monitoring laboratory tests, or share information about serious adverse events that have been reported.¹¹ Fingolimod (Gilenya), an oral drug used to treat relapsing forms of multiple sclerosis, is approved by FDA, and has a communication plan as its only REMS component. Its communication plan is designed to educate health care providers about the serious risks associated with its use, including the potential for bradyarrhythmias and atrioventricular block at treatment initiation, infections, macular edema, respiratory and hepatic effects, and fetal risk.²¹ The initial communication plan developed by Novartis, the drug manufacturer, included 4 elements²¹:

• A dear-health-care-professional letter
• Dear-professional-society letter
• Guide to important safety information; and
• REMS Internet site with drug safety and prescribing information

Each component of fingolimod's communication plan includes information about the correct distribution, safe use, and REMS pregnancy registry. When FDA requires communication plans as part of a REMS program, the information must typically be disseminated within the first 60 days after initial REMS approval.¹¹ However, FDA mandated the DHCPL, dear-professional-society letter, and guide to important safety information for fingolimod be mailed directly to providers within 30 days of the initial REMS approval (September 21, 2010) and annually for 5 years. In addition, the complete fingolimod REMS had to remain available at the REMS Internet site until the 5-year anniversary of the initial approval.

Despite communication plans' stated purpose, it is unclear if they are effective. Results from company-sponsored surveys that were performed by FDA as part of 16 REMS assessments showed that a median of 28% of recipients (range, 13%–82% recipients) remembered receiving the DHCPL. Only 72% of recipients who remembered receiving the DHCPL reported reading all or most of the letter.²² These results highlight an educational gap that pharmacists can help improve by providing educational materials, effective counseling, and important drug information to patients and their caregivers.

ELEMENTS TO ASSURE SAFE USE AND IMPLEMENTATION SYSTEMS

When FDA determines that MedGuides and/or communication plans are insufficient to minimize serious risks associated with a drug, it may require drug manufacturers to develop ETASUs. As defined in FDAAA, ETASUs are more extensive safety strategies and may include 1 or more of the following components¹¹:

(1) Health care providers who prescribe the drug must have specific training or experience or become specially certified.

(2) Pharmacies, practitioners, or health care settings that dispense the drug must become specially certified.

(3) The drug is dispensed to patients only in specific health care settings, such as hospitals.

(4) The drug is dispensed only to patients who have evidence or other documentation of safe-use conditions such as laboratory test results.

(5) Each patient using the drug is subject to specific monitoring.

(6) Each patient using the drug must be enrolled in a registry.

Since July 2014, 90% of current REMS with ETASUs have included an implementation system to monitor and evaluate their execution.¹⁹ ETASUs often are the most burdensome of requirements and can affect all participants in the medication distribution process, including hospitals, wholesalers, individual health care providers, and managed care organizations. Common roles and responsibilities assumed by those who participate in ETASUs include¹¹:

• The drug manufacturer may be required to monitor and evaluate the overall implementation system including wholesalers, pharmacies, and health care providers who are responsible for implementing specific ETASUs and reporting those findings to FDA.
• REMS programs may require certification of wholesalers and distributors who disseminate the drug to ensure that the drug is sent to credentialed pharmacies and health care settings, and patients who meet specific REMS criteria.
• Pharmacies may be evaluated to determine whether credentials for selected REMS programs are posted in the pharmacy.²³
• Physicians, nurses, and pharmacy personnel may be required to complete educational training, participate in registries, and collect and evaluate data before prescribing or dispensing select medications.
• Managed care organizations may be required to align therapeutic protocols to ensure that the drugs are cost-effective and appropriately used, and to design benefit plans that include restricted drug distribution systems to ensure continuity of care.

Between 2000 and 2010, many clinical studies and meta-analyses showed shortened overall survival and/or increased risk of tumor progression or recurrence in patients with cancer who were receiving erythropoiesis stimulating agents (ESAs).²⁴ In February 2010, FDA approved a REMS program known as Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs (the ESA APPRISE Oncology Program) to decrease risks in these patients.²⁵ It incorporated 3 ETASUs into the ESA APPRISE Oncology Program: (1) health care provider certification, (2) hospital certification, and (3) documentation of safe-use conditions, as follows²⁴:

1. To become specially certified in the ESA APPRISE Oncology Program, each health care provider must enroll by:
   • Reviewing the prescribing information for ESAs,
   • Completing the ESA APPRISE Oncology Program Training Module for Health Care Providers,
   • Completing and signing the ESA APPRISE Oncology Program Enrollment Form and submitting it to the ESA APPRISE Oncology Program Call Center, and
   • Agreeing to counsel each patient about the risks of ESAs by reviewing and signing the ESA APPRISE Oncology Program Patient and Health Care Provider Acknowledgment Form (and providing a copy of the form to the patient).
2. For hospitals to become specially certified, a hospital designee (pharmacy director or other appointed designee) must enroll in the ESA APPRISE Oncology Program and agree to:
   • Complete the ESA APPRISE Oncology Program Training Module for Hospital Designees,
   • Assume the authority and responsibility to internally coordinate and oversee the ESA APPRISE Oncology Program requirements in the hospital, and
   • Oversee the establishment of a system, order sets, protocols, or other measures designed to ensure that the hospital is in compliance with the ESA APPRISE Oncology Program.
3. For a health care system to be in compliance with the ESA APPRISE Oncology Program, ESAs must only be dispensed under safe-use conditions.

Therefore, certified hospitals and certified health care providers must agree only to dispense ESAs before each course of ESA therapy if patients and their health care providers have had a risk-benefit discussion and signed the acknowledgment form.

As illustrated by the ESA APPRISE Oncology Program, REMS with ETASUs can require a significant amount of time by those involved. As a result, several professional societies have expressed concerns regarding REMS (specifically ETASUs) in association meetings, workshops, and white papers.^7-9

The Academy of Managed Care Pharmacy (AMCP) published a statement in 2013 in response to FDA notice known as Standardizing and Evaluating REMS.²⁶ The statement encouraged FDA to refine the existing REMS process by reexamining each drug safety program regularly and eliminating REMS that are no longer necessary. AMCP cited the increasing complexity of drugs and expectation that biosimilars would enter the market. Biosimilars and other proteins in various phases of clinical development probably will require additional pharmacovigilance by physicians, pharmacists, and nurses due to an overall lack of experience with these agents. This emphasizes the importance of standardizing and/or eliminating undue administrative burdens to the health care system. However, some health care practitioners argue that REMS will become even more important moving forward because of limited data and lack of clinical experience with these agents.

Execution of REMS often results in administrative responsibilities beyond the usual dispensing process and patient care services provided by pharmacists. In addition to standardizing and refining existing and future REMS, AMCP has asked FDA to consider a compensation mechanism for pharmacists and pharmacies that handle REMS.²⁶ Currently, pharmacists and pharmacies are uncompensated for these additional dispensing and counseling efforts. AMCP's primary concern, which also has been expressed by the American Pharmacists Association and the American Society of Health-Systems Pharmacists, is that current REMS programs negatively affect the limited time pharmacists have available to care for and ensure the safety of their patients.²⁷

In 2012, the first shared system REMS (i.e., a single REMS program that includes multiple agents) was established for extended-release and long-acting opioids. Previous REMS programs involved single agents only, including agents within the same drug class. Single-agent REMS programs, developed by individual drug manufacturers, often have unique requirements and this can confuse practitioners and create unnecessary burdens on health systems and pharmacies. The shared system REMS aims to alleviate interruptions in pharmacy work flow, considering that pharmacists are responsible only for familiarizing themselves with a single REMS, not multiple programs within a given drug class. FDA has approved 6 currently shared system REMS programs (Table 4).

Table 4. Shared System Risk Evaluation and Mitigation Strategies
REMS Program	REMS Requirements
Buprenorphine transmucosal products for opioid dependence	MedGuide, ETASU implementation system
Extended-release and long-acting opioid analgesics	MedGuide, ETASU
Isotretinoin iPLEDGE	MedGuide, ETASU implementation system
Mycophenolate	MedGuide, ETASU
Rosiglitazone	ETASU
Transmucosal immediate-release fentanyl products	MedGuide, ETASU Implementation system
Source: Reference 19
Abbreviations: ETASU, element to assure safe use; MedGuide, medication guide; REMS, risk evaluation and mitigation strategy.

REMS programs may be an impediment to practitioners and may affect managed care organizations for 3 reasons.²⁸ First, managed care organizations and hospitals often have established prior authorization procedures, step-therapy protocols, and drug utilization criteria to ensure the safe and cost-effective use of drugs. Adding REMS programs to these existing practices can affect formulary placement of medications, add criteria to the drug approval process, and limit the indications for which a medication can be prescribed. Ensuring that the appropriate documentation is obtained and evaluated may increase administrative burden on the managed care organization.

Second, drug manufacturers may request patient-specific data, such as laboratory values, from managed care organizations to meet REMS program assessment criteria. This raises questions about patient confidentiality as required by the Health Information Portability and Accountability Act.

Third, drug manufacturers often prefer to distribute specialty pharmaceuticals through certified pharmacies that market themselves as experts in handling specialty drugs to reduce risks to patients.¹³ In such cases, this requirement becomes part of an ETASU protocol. It can markedly affect patient access to select drugs and increase the economic burden on the managed care organization. When a manufacturer distributes a drug through a few mail order, specialty, or outpatient pharmacies, the pharmacies may not participate in the managed care organization network; the managed care organization may be required to enter into separate contracts with other pharmacies, creating the additional responsibility of managing single product contracts.²⁸

These situations may necessitate additional patient and provider education to prevent access issues for patients who need specialty drugs or biologic agents, and this raises operational questions for managed care organizations.

ROLE OF THE PHARMACIST

Pharmacists must remain up to date with REMS developments because of ongoing discussions that occur between the pharmaceutical industry, managed care organizations, health care practitioners, and FDA to improve and adequately assess REMS. Moreover, pharmacists will continue to play an important role in REMS management and evaluation because risk containment, patient counseling, and drug safety are the cornerstones of pharmacy practice. Pharmacists can assist patients during the administrative process of REMS in several key areas. These include communicating specific requirements to patients and caregivers, such as the need to plan laboratory monitoring; distributing patient education materials when appropriate; assisting patients and caregivers with a plan of action in case a serious adverse event may occur; and validating that patients and prescribers are enrolled in a REMS database before dispensing a drug product.

REFERENCES

1. Nearly 7 in 10 Americans take prescription drugs, Mayo Clinic, Olmsted Medical Center find. Mayo Clinic News Network website. http://newsnetwork.mayoclinic.org/discussion/nearly-7-in-10-americans-take-prescription-drugs-mayo-clinic-olmsted-medical-center-find. Accessed June 25, 2015.
2. Vioxx (rofecoxib) questions and answers. US Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106290.htm. Accessed June 1, 2015.
3. The Institute of Medicine. The Future of Drug Safety: Action Steps for Congress–Report Brief. National Academy of the Sciences; 2006. http://www.iom.edu/~/media/Files/Report%20Files/2006/The-Future-of-Drug-Safety/futureofdrugsafety_reportbrief.pdf. Accessed May 10, 2015.
4. Food and Drug Administration Amendments Act (FDAAA) of 2007. US Food and Drug Administration website. http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/foodanddrugadministrationamendmentsactof2007/default.htm. Accessed July 1, 2015.
5. Rodriguez-Monguio R, Spielberger K, Seoane-Vazquez E. Examination of risk evaluation and mitigation strategies and drug safety in the US. Res Social Adm Pharm. 2014;10(1):232-238.
6. US Department of Health and Human Services, Office of Inspector General (OIG). FDA Lacks Comprehensive Data to Determine Whether Risk Evaluation and Mitigation Strategies Improve Drug Safety. Rockville, MD: US Dept of Health and Human Services, Office of Inspector General; 2013. OEI-04-11-00510. https://oig.hhs.gov/oei/reports/oei-04-11-00510.pdf. Accessed May 16, 2015.
7. American Pharmacists Association (APhA), Bough M. APhA 2011 REMS white paper: summary of the REMS stakeholder meeting on improving design and implementation. J Am Pharm Assoc. 2011;51:340-358.
8. Frame JN, Jacobson JO, Vogel WH, et al. Assessment of risk evaluation and mitigation strategies in oncology: summary of the oncology risk evaluation and mitigation strategies workshop. J Oncol Pract. 2013;9(2):e24-e39.
9. Standardizing and Evaluating Risk Evaluation and Mitigation Strategies; Notice of Public Meeting; Request for Comments. Bethesda, MD: American Society of Health-Systems Pharmacists; 2013. http://www.ashp.org/DocLibrary/Advocacy/ASHP-Comments-FDA-2013-N-0502-16-SEP-2013.pdf. Accessed July 2, 2015.
10. Risk evaluation and mitigation strategies: discussion guide. American Society of Health- Systems Pharmacists website. http://www.ashp.org/DocLibrary/Policy/REMS/REMS-Discussion-Guide.aspx. Accessed June 3, 2015.
11. US Department of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications. Rockville, MD: US Dept of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research; 2009. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation /Guidances/UCM184128.pdf. Accessed June 8, 2015.
12. US Food and Drug Administration. Guidance for Industry: Development and Use of Risk Minimization Action Plans. Rockville, MD: US Dept Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research; 2005.
13. Kirschenbaum BE. Specialty pharmacies and other restricted drug distribution systems: financial and safety considerations for patients and health-system pharmacists. Am J Health Sys Pharm. 2009;66(24 Suppl 7):S13-S20.
14. US Food and Drug Administration. Symlin (pramlintide acetate). Risk Evaluation and Mitigation Strategy (REMS). AstraZeneca; 2014. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM404706.pdf. Accessed July 2, 2015.
15. FDA Amendments Act of 2007: Impact of risk evaluation and mitigation strategies on health systems pharmacy. ASHP Advantage E-Newsletter, 2010. American Society of Health-System Pharmacists website. http://www.ashpadvantage.com/fdaaa/fdaaa-spring-newsletter.pdf. Accessed July 2, 2015.
16. American Pharmacists Association (APhA), Bough M. APhA 2011 REMS white paper: summary of the REMS stakeholder meeting on improving program design and implementation. J Am Pharm Assoc. 2011;51(3):340-358.
17. US Food and Drug Administration. Avandia (rosiglitazone). Risk Evaluation and Mitigation Strategies (REMS) Document. Single, Shared System for Rosiglitazone-containing Medicines; 2014. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/UCM337552.pdf. Accessed July 2, 2015.
18. US Department of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance: Medication Guides – Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS). Rockville, MD: US Dept of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research; 2011. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM244570.pdf. Accessed June 2, 2015.
19. Approved risk evaluation and mitigation strategies. US Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation forPatientsandProviders/ucm 111350.htm. Accessed June 2, 2015.
20. Hansberry DR, Agarwal N, Gonzales SF, Baker SR. Are we effectively informing patients? A quantitative analysis of on-line patient education resources from the American Society of Neuroradiology. AJNR Am J Neuroradiol. 2014;35(7):1270-1275.
21. US Food and Drug Administration. Gilenya (fingolimod). Risk Evaluation and Mitigation Strategy (REMS). Novartis; 2013. http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm227965.pdf. Accessed June 3, 2015.
22. Thompson CA. Dear healthcare professional letters may not be effective REMS communication tool. American Society of Health-Systems Pharmacists website. http://www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=4006. Accessed June 1, 2015.
23. U.S. Food and Drug Administration. Tikosyn (dofetilide). Risk Evaluation and Mitigation Strategy (REMS). Pfizer; 2011. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/UCM266277.pdf. Accessed June 8, 2015.
24. Reeves DJ, Quebe AK, Patel R. The ESA APPRISE Oncology Program: a history of REMS requirements, a review of the data, and an approach to compliance in the hospital. P T. 2011;36(7):423-433.
25. U.S. Food and Drug Administration. Epogen/Procrit (epoetin alfa). Risk Evaluation and Mitigation Strategy (REMS). Amgen; 2010. http://www.fda.gov/downloads/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/UCM200105.pdf. Accessed June 1, 2015.
26. Statement in Response to Food and Drug Administration Notice Standardizing and Evaluating Risk Evaluation and Mitigation Strategies Docket Number FDA–2013–N–0502. Academy of Managed Care Pharmacy website. http://www.amcp.org/WorkArea/DownloadAsset.aspx?id=16994. Published July 25, 2013. Accessed July 1, 2015.
27. Barlas S. Pharmacists, deluged with requirements, pressure FDA to standardize REMS programs. PT. 2014;39(1):12-13.
28. Academy of Managed Care Pharmacy Special Projects Committee. Implications of risk evaluation and mitigation strategy (REMS) programs for managed care pharmacy. J Manag Care Pharm. 2012;18(3):268-275.

Back to Top