14.6 FDA Adverse Reaction Reporting Systems
Even if no medication errors occur, drug risks are still present. Though every US drug goes through a rigorous approval process, consumers need to remember that all drugs—prescription, OTC, and diet supplements—have some toxicity risks and a potential for adverse drug reactions. So the FDA established a nationwide post-marketing surveillance system to serve as a conduit for reporting serious adverse effects of certain medications. This FDA Adverse Event Reporting System (FAERS) is a centralized database that stores information from two separate federally sponsored reporting programs: MedWatch and the Vaccine Adverse Event Reporting System (VAERS). The VAERS database (discussed later) publishes a quarterly newsletter that can be accessed online at https://PharmPractice7e.ParadigmEducation.com/MedWatch.
MedWatch
MedWatch is a voluntary program (run in collaboration with the ISMP) that offers healthcare professionals and consumers an avenue to anonymously report a serious adverse event associated with any specific drug, biological device, or dietary supplement. From 1969 to 2012, the FDA received over nine million reports of medication problems of many types (reports from MedWatch began in 2000), with incidents rising each year. In 2014 (the latest posted FDA statistics), 1,289,133 reports were received. Reports may be filed online or by phone. Yet only those who actually recognize that their reaction was connected to a specific drug and are aware of the MedWatch program (listed in Medication Guides and on labels) and elect to report them online are tabulated. Clearly, these numbers are far lower than the actual incidents of ADRs per each medication. Even so, the FDA uses this information to track problems or issues that were not apparent when the medication was initially approved. In fact, the occurrence of some side effects may only be detected in a large population after the drug comes to market.
MedWatch gives consumers a way to make anonymous reports on adverse drug effects.
The recognition of a potential problem does not always mean that the product will be recalled to be removed from the market, as explained in Chapter 3. The FDA may respond in two other ways:
Issue safety alerts to healthcare professionals or consumers for drugs (including drug recalls), biologicals, dietary supplements, and counterfeit drugs
Request medication-labeling changes to the product package information (PI), including contraindications, warnings, boxed warnings, precautions, and adverse reactions
Safety alerts and labeling changes are published in a monthly MedWatch newsletter.
Risk Evaluation and Mitigation Strategies
As noted in earlier chapters, some drugs that are more dangerous require even more than a Medication Guide for communication before administration. As part of the risk evaluation and mitigation strategy (REMS) for certain drugs, community pharmacies (and prescribers) must register with the drug manufacturer (or official wholesaler) and receive drug-specific REMS training. The pharmacist must pledge to not only go over the Medication Guide with patients, but do other counseling and monitoring activities. REMS programs are designed to closely track patients on these high-risk drugs and make periodic assessment reports to the FDA on their status.
REMS are required and developed for new or existing drugs each year. Over 80 REMS drugs were posted in 2019 on the FDA’s website. You can become familiar with some of these drugs at https://PharmPractice7e.ParadigmEducation.com/REMS.
Some of the more common REMS drugs are discussed below.
Isotretinoin and the iPLEDGE Program
Isotretinoin (and isotroin, a derivative) is a common generic drug for intense acne and other skin problems that has a very high incidence of harm to the fetus, or teratogenicity. Common brands of this drug are Accutane and Claravis (see Table 14.14 for others). The iPLEDGE Program is a REMS that was designed for isotretinoin and related drugs to prevent fetal exposure and the resulting birth defects and to educate all patients (both female and male) on the drugs’ risks and how to use the medication safely.
Table 14.14 Isotretinoin and Isotroin Drugs in the iPledge Program
The generic drugs isotretinoin and isotroin come in the following brand names:
Pharmacists who dispense these drugs and patients who use them must agree to the terms of the iPledge Program as part of the REMS for these drugs. |
All prescribers, pharmacies, and drug wholesalers must be enrolled annually and certified to participate in this program; all patients must be registered and agree to meet all conditions required during treatment. Pharmacies may receive the drug only from a certified wholesaler and can only dispense written prescriptions authorized by a certified prescriber. An assigned Risk Management Association (RMA) number must be placed on each prescription, and prescribers must agree to provide contraception counseling to patients prior to and during treatment with this drug.
If patients are sexually active, prescribers must document the forms of contraception the patients are currently using. Women of childbearing potential must agree to monthly pregnancy tests, and they must have a negative result prior to prescribers issuing a new or refill prescription. If sexually active, they must commit to two forms of contraception while on the drug and for one month after drug discontinuation. In addition, they must agree to pick up the prescription within a specified period (usually within seven days) or the prescription is void.
The quantity is limited to a 30-day supply with no refills. All pregnancies while on this drug must be reported. Patients must also agree not to share their medication with anyone or donate blood while on the medication and for one month after drug discontinuation.
IN THE REAL WORLD
Accutane has caused huge controversy since it was first introduced to the market in 1982. After the patent ran out, other manufacturers followed with the generic drug isotretinoin. Dermatologists have praised it as a drug of choice for severe acne, yet some physicians compare the drug to thalidomide because of the extensive documentation on isotretinoin in connection to severe birth defects and miscarriages.
What is less discussed are the incidents in patients of both genders of inflammatory bowel diseases and severe depression, with some cases leading to suicide. The most frequent population for this acne drug is teens, an age group already at a higher risk of suicide. The Swiss drug manufacturer Roche has lost numerous lawsuits about these connections with Accutane and has paid a significant amount in damages.
Though the FDA has received case reports of increased suicide risk with isotretinoin, it has not deemed that there has been sufficient accumulated concrete evidence to make a definite causal relation sufficient to recall it. However, due to serious side effects, the FDA recommends that the drug be reserved for severe refractory cases of acne unresponsive to conventional therapies, stating:
“All patients treated with isotretinoin should be observed closely for symptoms of depression or suicidal thoughts, such as sad mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating, or for mood disturbance, psychosis, or aggression. . . . Patients taking isotretinoin may experience side effects including bad headaches, blurred vision, dizziness, nausea, vomiting, seizures, stroke, diarrhea, and muscle weakness. Additionally, serious mental health problems, such as depression and suicide, have been reported with isotretinoin use.”
Transmucosal Immediate-Release Fentanyl
The pain medication skin patches of transmucosal immediate-release fentanyl (TIRF) have a REMS program designed to mitigate the risk of misuse, abuse, addiction, overdose, or severe complications. The strategies seek to:
limit the medication only to appropriate opioid-dependent cancer patients tolerant of around-the-clock opioid therapy;
prevent inappropriate dosage conversion from similar narcotics;
promote safe storage to prevent accidental exposure in children;
educate prescribers, pharmacists, and patients on the safe and appropriate use of fentanyl.
As with isotretinoin, prescribers, pharmacies (both hospital and retail), and wholesalers must enroll and complete an education program to be certified to handle this medication (brand and generic). Renewal is every two years. Prescribers must agree to initiate therapy with the lowest dose, follow up on efficacy of dose titration, and document any signs of misuse or abuse. Pharmacies are also responsible for training all staff, including pharmacy technicians; hospital pharmacies can dispense TIRF to inpatients only.
Patients must review and study the Medication Guide, sign an agreement with the prescriber, and follow prescribed instructions exactly. There can be no medication transfer to others, and if, for any reason, the opioid therapy is discontinued, the TIRF therapy must also be stopped. Patients must also agree to safely store and discard the medication to prevent harm to children and pets.
Subutex and Suboxone
Sublingual (under the tongue) buprenorphine (Subutex, Suboxone) are used to treat opioid dependence. Certified physicians have DEA numbers that start with an “x,” indicating their ability to prescribe these medications. Subutex is commonly prescribed to initiate treatment and Suboxone to maintain it. The REMS goals are to prevent accidental overdose, misuse, and abuse, and to inform patients of serious risks. Prescribers must use low doses, conduct frequent follow-up visits to assess efficacy, and provide counseling and psychosocial support for the patient.
Pharmacists who are certified to dispense Subutex and Suboxone agree to counsel the patient on safe use, including potential drug interactions with alcohol, anxiety/sleep medications (such as benzodiazepines), and antidepressants. The pharmacist must also counsel patients on securely and safely storing their medication to deter theft or access by children.
Mycophenolate
Mycophenolate is an immunosuppresant medicine used to help prevent organ rejection in transplant patients and for autoimmune diseases. The REMS goals are to prevent miscarriage and birth defects when used in pregnancy. The prescriber, pharmacy, and patient all must participate in this REMS. Before starting mycophenolate, patients of childbearing potential require education on the risks of exposure during pregnancy. Pregnancy planning education must also occur. Women of childbearing potential must either abstain from intercourse or use acceptable contraception during their entire treatment course of mycophenolate, as well as six weeks after discontinuing therapy. Pregnancy testing must occur twice before starting mycophenolate (the second test occurs 8 to 10 days after the first). Repeat pregnancy tests must occur at all routine follow-up visits. Any pregnancies that occur while a patient is using mycophenolate should be reported.
Pharm Fact
A social controversy exists over whether or not the MMR (measles, mumps, rubella) vaccine or receiving numerous vaccines at very young ages can result in autism (a developmental disorder) or other health issues. Viewing the body of existing scientific study, the CDC stated in 2015 that there is insufficient scientific evidence to establish a relationship between autism and any particular childhood vaccination.
Vaccine Adverse Event Reporting System
A separate national reporting system, called the Vaccine Adverse Event Reporting System (VAERS), is run by the FDA and the Centers for Disease Control and Prevention (CDC) to collect and analyze information on adverse events that occur after immunizations. This is not a vaccine error-reporting system but rather a system for tracking dangers caused by the vaccines themselves. Since 1990, VAERS has received over 200,000 reports, most of which describe mild side effects, such as a fever. As with medications, hundreds of thousands of vaccine administrations often need to occur before being able to statistically detect a problem. In fact, it may take more than a million doses of a vaccine for a few adverse effects to occur and be investigated.
The FDA and the CDC use VAERS information to ensure the safest strategies of vaccine use and reduce the rare risks associated with vaccines. Healthcare personnel are mandated by the National Childhood Vaccine Injury Act of 1986 to report serious adverse reactions from vaccines. With pharmacists and their technicians becoming more involved in vaccine administration, it is important to report any adverse effects. Patients can report any problems with a vaccine as well. A VAERS report can be made via an 800 number (1-800-822-7967), by mail or fax on a downloaded form, or online at https://PharmPractice7e.ParadigmEducation.com/VAERS.