Cisapride [Propulsid]*
Identifying Adverse Drug Reactions
It can be very difficult to determine whether a specific drug is responsible for an observed adverse event because other factors—especially the underlying illness and other drugs being taken—could be the actual cause. To help determine whether a particular drug is responsible, the following questions should be considered:
• Did symptoms appear shortly after the drug was first used?
• Did symptoms abate when the drug was discontinued?
• Did symptoms reappear when the drug was reinstituted?
• Is the illness itself sufficient to explain the event?
• Are other drugs in the regimen sufficient to explain the event?
If the answers reveal a temporal relationship between the presence of the drug and the adverse event, and if the event cannot be explained by the illness itself or by other drugs in the regimen, then there is a high probability that the drug under suspicion is indeed the culprit. Unfortunately, this process is limited. It can only identify adverse effects that occur while the drug is being used; it cannot identify adverse events that develop years after drug withdrawal. Nor can it identify effects that develop slowly over the course of prolonged drug use.
Adverse Reactions to New Drugs
Preclinical and clinical trials of new drugs cannot detect all of the ADRs that a drug may be able to cause. In fact, about 50% of all new drugs have serious ADRs that are not revealed during phase 1 and phase 3 trials.
Because newly released drugs may have as-yet unreported adverse effects, you should be alert for unusual responses when prescribing new drugs. If the patient develops new symptoms, it is wise to suspect that the drug may be responsible—even if the symptoms are not described in the literature. It is a good practice to initially check postmarket drug evaluations at www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm204091.htm to determine whether serious problems have been reported. If the drug is especially new, however, you may be the first provider to have observed the effect. If you suspect a drug of causing a previously unknown adverse effect, you should report the effect to MedWatch, the FDA Medical Products Reporting Program. You can file your report online at www.fda.gov/medwatch. Because voluntary reporting by health care professionals is an important mechanism for bringing ADRs to light, you should report all suspected ADRs, even if absolute proof of the drug’s complicity has not been established.
Ways to Minimize Adverse Drug Reactions
The responsibility for reducing ADRs lies with everyone associated with drug production and use. The pharmaceutical industry must strive to produce the safest medicines possible; the provider must select the least harmful medicine for a particular patient and provide clear instructions for its use; the nurse must evaluate patients for ADRs and educate patients in ways to avoid or minimize harm; and patients and their families must take medication only as directed, watch for signs that an ADR may be developing, and seek medical attention if one appears.
When patients are using drugs that are toxic to specific organs, function of the target organ should be monitored. The liver, kidneys, and bone marrow are important sites of drug toxicity. For drugs that are toxic to the liver, the patient should be monitored for signs and symptoms of liver damage (jaundice, dark urine, light-colored stools, nausea, vomiting, malaise, abdominal discomfort, loss of appetite), and periodic tests of liver function (e.g., aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) should be performed. For drugs that are toxic to the kidneys, the patient should undergo routine urinalysis and measurement of serum creatinine or creatinine clearance. For drugs that are toxic to bone marrow, periodic complete blood cell counts are required.
Adverse effects can be reduced by individualizing therapy. When choosing a drug for a particular patient, the provider must balance the drug’s risks and benefits. Drugs that are likely to harm a specific patient should be avoided unless the benefit of the drug exceeds the risk for injury.
Special Alerts and Management Guidelines
In an effort to decrease harm associated with drugs that cause serious adverse effects, the FDA requires special alerts and management guidelines. These may take the form of a Medication Guide for patients, a boxed warning to alert providers, or a Risk Evaluation and Mitigation Strategy (REMS), which can involve patients, providers, and pharmacists.
Medication Guides
Medication Guides, commonly called MedGuides, are FDA-approved documents created to educate patients about how to minimize harm from potentially dangerous drugs. In addition, a MedGuide is required when the FDA has determined that (1) patient adherence to directions for drug use is essential for efficacy or (2) patients need to know about potentially serious effects when deciding to use a drug.
All MedGuides use a standard format that provides information under the following main headings:
• What is the most important information I should know about (name of drug)?
• What is (name of drug)? Include a description of the drug and its indications.
• Who should not take (name of drug)?
• How should I take (name of drug)? Include importance of adherence to dosing instructions, special instructions about administration, what to do in case of overdose, and what to do if a dose is missed.
• What should I avoid while taking (name of drug)? Include activities (e.g., driving, sunbathing), other drugs, foods, pregnancy, and breastfeeding.
• What are the possible or reasonably likely side effects of (name of drug)?
• General information about the safe and effective use of prescription drugs.
Additional headings may be added by the manufacturer as appropriate, with the approval of the FDA. MedGuides for all drug products that require one are available online at www.fda.gov/Drugs/DrugSafety/UCM085729.The MedGuide should be provided whenever a prescription is filled, and even when drug samples are handed out.
Boxed Warnings
The boxed warning, also known as a black box warning, is the strongest safety warning a drug can carry and still remain on the market. Text for the warning is presented inside a box with a heavy black border. The FDA requires a boxed warning on drugs with serious or life-threatening risks. The purpose of the warning is to alert providers to (1) potentially severe side effects (e.g., life-threatening dysrhythmias, suicidality, major fetal harm) as well as (2) ways to prevent or reduce harm (e.g., avoiding a teratogenic drug during pregnancy). The boxed warning provides a concise summary of the adverse effects of concern. A boxed warning must appear prominently on the package insert, on the product label, and even in magazine advertising. Drugs that have a boxed warning must also have a MedGuide.
Risk Evaluation and Mitigation Strategies
A REMS is simply a plan to minimize drug-induced harm. For most drugs that have a REMS, a MedGuide is all that is needed. For a few drugs, however, the REMS may have additional components. For example, the REMS for the antiacne drug isotretinoin has provisions that pertain to the patient, provider, and pharmacist. This program, known as iPledge, is needed because isotretinoin can cause serious birth defects. The iPledge program was designed to ensure that patients who are pregnant, or may become pregnant, will not have access to the drug. Details of the iPledge program are presented in Chapter 85. All REMS that have received FDA approval can be found online at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.
