Risk evaluation and mitigation strategies


From Rx-wiki

On September 27, 2007, President George W. Bush signed into law the Food and Drug Administration Amendments Act of 2007 (FDAAA), further amending the Food, Drug, and Cosmetic Act. The FDAAA authorizes the Food and Drug Administration (FDA) to require risk evaluation and mitigation strategies (REMS) on medications if necessary to minimize the risks associated with some drugs.

The FDA has a responsibility to ensure that the benefits of a medication outweigh the potential risks of that medication. To determine this, the FDA looks at the seriousness of the disease or condition to be treated, size of the patient population, expected benefit of the drug, expected duration of treatment, and seriousness of the known or potential adverse events.

If a medication's benefits outweigh the risks associated with it, the FDA approves it. Sometimes though, the medication therapy itself still carries a lot of risks with it. In that situation, the FDA may require REMS. These risk minimization strategies go beyond FDA professional labeling. FDA can require a REMS before a drug is approved if they have determined that a REMS is necessary to ensure the benefits of the drug outweigh its risks. Also, FDA can require a REMS post-approval if they become aware of new safety information and make the determination that a REMS is necessary, again, to ensure that the benefits of the drug outweigh its risks.

Elements of risk evaluation and mitigation strategies

REMS may contain any of the following elements:

  • Medication Guide – Document written for patients highlighting important safety information about the drug; this document must be distributed by the pharmacist to every patient receiving the drug.
  • Communication Plan – Plan to educate healthcare professionals on the safe and appropriate use of the drug and consists of tools and materials that will be disseminated to the appropriate stakeholders.
  • Elements to Assure Safe Use (EASU) – These are strictly controlled systems or requirements put into place to enforce the appropriate use of a drug. Examples of EASUs include physician certification requirements in order to prescribe the drug, patient enrollment in a central registry, distribution of the drug restricted to certain specialty pharmacies, etc.
  • Implementation Plan – A description of how certain EASUs will be implemented.
  • Timetable for Submission of Assessments – The frequency of assessment of the REMS performance with regard to meeting the goal(s) and objective(s). FDA requires that assessments be conducted at 18 months, 3 years, and 7 years post-launch, at a minimum. Results of these evaluations must be reported to the FDA and will determine whether additional actions or modifications to the REMS program are required.

Restricted drug programs

There are a number of medications with restrictions due to patient safety concerns. The FDA primarily manages these medications through their Risk Evaluation and Mitigation Strategy (REMS) initiative. The FDA may require manufacturers of drugs with safety concerns to submit a REMS program at the time a new drug is approved. These programs may contain any combination of 5 criteria (Medication Guide, Communication Plan, Elements to Assure Safe Use, Implementation System, and Timetable for Submission of Assessments). Restricted access programs are considered Elements to Assure Safe Use. A current list of medications with REMS programs can be found at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

Some of the medications with the most significant restrictions include thalidomide, clozapine, buprenorphine, and isotretinoin. These programs are intended to make sure that the patients are using the medications appropriately and to monitor them for undesirable side effects.


Thalidomide was first developed in Germany as a sleep aid and shortly after entering the European market, the manufacturer decided it was also good for treating morning sickness. Unfortunately, the drug caused severe and life-threatening birth defects in 40% of infants. In 1998 thalidomide was approved for limited distribution in the United States for treating multiple myeloma. It is also used to treat erythema nodosum leprosum.

Thalidomide is only available through the THALOMID REMS program. Prescribers must be certified with program, patients must comply with the strict guidelines of the program, and pharmacies must be certified with the program. Pharmacies must only dispense to patients that are authorized to receive the drug and comply with the requirements.


Clozapine is an atypical antipsychotic medication used in the treatment of schizophrenia, and is also sometimes used off-label for the treatment of bipolar disorder. Clozapine carries many warnings, including warnings for agranulocytosis, CNS depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension (with or without syncope) and seizures.

With these severe side effects in mind each of the manufacturers are required to enroll patients taking their medication into a national registry where they will monitor a patient's white blood cell count (WBC) and their absolute neutrophil count (ANC). If the numbers fall below a particular level their therapy may need to be halted and the national registry has a responsibility to report the information to the nonrechallengeable database, that way if a physician goes to place the patient on the medication again the various manufacturers will know they are not allowed as they always need to check new orders for a patient against the nonrechallengeable database. Once listed in the nonrechallengeable database they may never use clozapine again.


The Drug Addiction Treatment Act of 2000 (DATA 2000) permits physicians who meet certain qualifications to treat opioid addiction with Schedule III, IV, and V narcotic medications that have been specifically approved by the Food and Drug Administration for that indication. Such medications may be prescribed and dispensed by waived physicians in treatment settings other than the traditional Opioid Treatment Program (methadone clinic) setting.

Since there is only one narcotic medication approved by the FDA for the treatment of opioid addiction within the Schedules given, DATA 2000 basically refers to the use of buprenorphine for the treatment of opioid addiction. Methadone is a Schedule II narcotic approved for the same purpose within the highly regulated methadone clinic setting.

Under the Act, physicians may apply for a waiver to prescribe buprenorphine for the treatment of opioid addiction or dependence. Requirements include a current State medical license, a valid DEA registration number, specialty or subspecialty certification in addiction from the American Board of Medical Specialties, American Society of Addiction Medicine, or American Osteopathic Association. Exceptions were also created for physicians who participated in the initial studies of buprenorphine and for State certification of addiction specialists. However, the Act is intended to bring the treatment of addiction back to the primary care provider. Thus most waivers are obtained after taking an 8 hour course from one of the five medical organizations designated in the Act and otherwise approved by the Secretary of the Department of Health and Human Services. When a physician qualifies for the waiver, he is given a second DEA number that begins with an 'X'. This new DEA number is only to be used when prescribing buprenorphine for the purpose of treating addictions. Once a physician obtains the waiver, he or she may treat up to 30 patients for narcotic addiction with buprenorphine. Recent changes to DATA 2000 have increased the patient limit to 100 for physicians that have had their waiver for a year or more and request the higher limit in writing.


Isotretinoin is indicated for severe nodular acne unresponsive to conventional therapy in patients 12 years of age and older. Isotretinoin is a teratogen and is highly likely to cause birth defects if taken by women during pregnancy or even a short time before conception. A few of the more common birth defects this drug can cause are hearing and visual impairment, missing or malformed earlobes, facial dysmorphism, and mental retardation.

Due to the teratogenicity of this product, isotretinoin is only available through a restricted program under REMS called iPLEDGE. Prescribers, patients, pharmacies, and distributors must enroll in the iPLEDGE program (https://www.ipledgeprogram.com).

Phentermine and topiramate

Phentermine and topiramate (available under the brand name Qsymia) is intended to be used in combination with calorie reduction and increased physical activity to assist in chronic weight management. The combination product of phentermine and topiramate is a teratogen and is highly likely to result in either cleft palate and/or cleft lip.

Due to the teratogenic concerns associated with this product, women of childbearing age should take a pregnancy test prior to starting this therapy and they should consistently use effective contraception while taking this medication. Pharmacies must be certified by VIVUS (the manufacturer for Qsymia) to dispense the medication and as part of the mandatory REMS on this product pharmacies must handout the FDA approved Qsymia brochure that details concerns over the products teratogenicity and offers guidance on effective birth control options.

See also

Medication errors
Five rights
Drug recalls
Vaccine Adverse Event Reporting System
Tallman lettering
High-alert medications
Barcoding technologies
Medication safety


  1. FDA, Guidance for Industry Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf
  2. FDA, Approved Risk Evaluation and Mitigation Strategies (REMS), http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm
  3. Medscape, Risk Evaluation and Mitigation Strategies: An Introduction for Physicians, Nurses, and Pharmacists, Claudia B. Karwoski, PharmD; Marcie A. Bough, PharmD; Todd M. Colonna, MD; Lisa A. Gorski, RN, MS, May 15, 2012, http://www.medscape.org/viewarticle/762673_transcript
  4. ParagonRx, Risk Evaluation and Mitigation Strategies (REMS) - A Brief History. September 2009, http://www.paragonrx.com/rems-hub/rems-history/
  5. FDA, Postmarket Drug Safety Information for Patients and Providers, http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm
  6. Wikipedia, Drug Addiction Treatment Act, http://en.wikipedia.org/wiki/Drug_Addiction_Treatment_Act
  7. iPledge program, https://www.ipledgeprogram.com
  8. Vivus, Risk of Birth Defects with Qsymia, https://qsymia.com/wp-content/wbuploads/pdf/risk-of-birth-defects.pdf