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.
Medication Errors
Medication errors are a major cause of morbidity and mortality. According to the Institute of Medicine (IOM), every year medication errors injure at least 1.5 million Americans and kill an estimated 7000. The financial costs are staggering: among hospitalized patients alone, treatment of drug-related injuries costs at least $3.5 billion a year.
What Is a Medication Error?
The National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) defines a medication error as “any preventable event that may cause or lead to inappropriate medication use or patient harm, while the medication is in the control of the healthcare professional, patient, or consumer. Such events may be related to professional practice, healthcare products, procedures, and systems, including prescribing; order communication; product labeling, packaging and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.” Note that, by this definition, medication errors can be made by many people—beginning with workers in the pharmaceutical industry, followed by people in the health care delivery system, and ending with patients and their family members. In this chapter, we focus on medication errors attributed to health care providers. These typically fall into one of the following categories:
Oversight
• Failure to keep an up-to-date medication list
Communication
• Inadequate or unclear instructions
• Failure to verify drugs that sound alike
• Inadequate patient education
TABLE 5.3
Examples of Drugs With Names That Sound Alike or Look Alike*
| Amicar | Omacar |
| Anaspaz | Antispas |
| Celebrex | Cerebyx |
| Clinoril | Clozaril |
| Cycloserine | Cyclosporine |
| Depo-Estradiol | Depo-Testadiol |
| Dioval | Diovan |
| Estratab | Estratest |
| Etidronate | Etretinate |
| Flomax | Volmax |
| Lamisil | Lamictal |
| Levoxine | Levoxyl |
| Lithobid | Lithostat |
| Lodine | Iodine |
| Naprelan | Naprosyn |
| Nasarel | Nizoral |
| Neoral | Neosar |
| Nicoderm | Nitroderm |
| Sarafem | Serophene |
| Serentil | Seroquel |
| Tamiflu | Theraflu |
| Tramadol | Toradol |
Ways to Reduce Medication Errors
Organizations throughout many countries are working to design and implement measures to reduce medication errors. Changes having the most dramatic effect have been those that focused on the IOM recommendations to (1) help and encourage patients and their families to be active, informed members of the healthcare team, and (2) give health care providers the tools and information needed to prescribe, dispense, and administer drugs as safely as possible.
Implementation of technology to reduce errors has had remarkable success, as well. For example, replacing handwritten medication orders with a computerized order entry system has reduced medication errors by 50%. Using bar-code systems that match the patient’s armband bar code to a drug bar code has decreased medication errors in some institutions by as much as 85%.
Targeted interventions to address provider-related errors can be employed to decrease medication errors by health care providers. These are provided in Table 5.4.
TABLE 5.4
Provider-Related Medication Errors and Interventions
| Errors | Interventions |
| PRESCRIBING PRACTICES | |
| Inappropriate drug selection |
Verify that the drug selected is the drug intended. (See Table 5.3 for a list of drugs that look or sound like other drugs.) Drug information changes frequently; make sure that drug references are authoritative and up to date. Verify allergies when ordering new medications. Display allergies prominently in the patient record. Check for interactions of new medications against all currently prescribed medications, over-the-counter medications, herbal remedies, nutritional supplements, and recreational drugs that the patient is taking. Authoritative drug interaction application software is recommended. Verify that patients can afford the medication; otherwise, this increases the likelihood of errors due to taking subtherapeutic doses, if filled at all. Consider individualized patient factors (e.g., age, pregnancy, comorbidities) when selecting the most appropriate drug. |
| Error in drug dosage |
Verify unit of measure (e.g., milligram versus microgram). Verify height and weight and verify unit of measure (e.g., kilograms versus pounds) for dosage calculations. Verify decimal placement; follow the ISMP recommendations in Table 5.5. |
| Lack of clear labeling instructions |
Incorporate ISMP-recommended substitutions for any error-prone abbreviations. (See Table 5.5.) Write precise and detailed instructions. Avoid “Take as directed” and similar nonspecific labeling. Request large font labeling for patients who have difficulty reading small print. |
| Illegible writing | |
| OVERSIGHT | |
| Failure to keep an up-to-date medication list | |
| Failure to continue/discontinue medications | |
| Absence of medication reconciliation |
Medication reconciliation should occur any time there is a transfer of patients to another provider or to another facility. (See Box 5.1.) Develop interprofessional relationships to facilitate communication regarding reconciliation needs. |
| COMMUNICATION | |
| Inadequate or unclear instructions | |
| Inadequate patient education |
Develop strong collaborative partnerships with patients (or their caretakers) and consider their perspectives and preferences when making treatment decisions. Verify patient understanding of teaching by repeating instructions or demonstrating procedures. Provide handouts to reinforce teaching. These should be written at the 5th grade level or, at most, the 8th grade level. |
Incorporating medication reconciliation (Box 5.1) has resulted in decreasing medication errors by 70% and reducing ADRs by 15%.
Many medication errors result from using error-prone abbreviations, symbols, and dose designations. To address this concern, the Institute for Safe Medical Practices (ISMP) and the FDA together compiled a list of error-prone abbreviations, symbols, and dose designations (Table 5.5) and have recommended against their use. This list includes eight entries (at the top of Table 5.5) that have been banned by The Joint Commission (TJC). These banned abbreviations can no longer be used by hospitals and other organizations that require TJC accreditation. The full list is available online at www.ismp.org/tools/errorproneabbreviations.pdf.
TABLE 5.5
Abbreviations, Symbols, and Dose Designations That Can Promote Medication Errors
| Abbreviations, Symbols, or Dose Designations | Intended Meaning | Potential Misinterpretation | Preferred Alternative |
| ABBREVIATIONS AND NOTATIONS FOR WHICH THE ALTERNATIVE MUST BE USED (TJC MANDATED) | |||
| U or u | Unit | Misread as 0 or 4 (e.g., 4U seen as 40; 4u seen as 44); mistaken to mean “cc” so dose given in volume instead of units (e.g., 4u mistaken to mean 4 cc) | Write “unit” |
| IU | International unit | Misread as IV (intravenous) or “10” | Write “international unit” |
| q.d./Q.D. | Every day | Misread as q.i.d. (four times a day) | Write “daily” |
| q.o.d./Q.O.D. | Every other day | Misread as q.d. (daily) or q.i.d. (four times a day) | Write “every other day” |
| MS or MSO4 | Morphine sulfate | Mistaken as magnesium sulfate | Write “morphine sulfate” |
| MgSO4 | Magnesium sulfate | Mistaken as morphine sulfate | Write “magnesium sulfate” |
| Trailing zero after final decimal point (e.g., 1.0 mg) | 1 mg | Mistaken as 10 mg if the decimal point is missed | Never write a zero by itself after a decimal point |
| Leading decimal point not preceded by a zero (e.g., .5 mg) | 0.5 mg | Mistaken as 5 mg if the decimal point is missed | Write “0” before a leading decimal point |
| SOME ABBREVIATIONS AND NOTATIONS FOR WHICH THE ALTERNATIVE IS RECOMMENDED (BUT NOT YET TJC MANDATED) | |||
| µg | Microgram | Mistaken as “mg” | Write “mcg” |
| cc | Cubic centimeters | Mistaken as “u” (units) | Write “mL” |
| IN | Intranasal | Mistaken as “IM” or “IV” | Write “intranasal” or “NAS” |
| H.S.; hs | Half-strength; at bedtime | Mistaken as opposite of what was intended | Write “half-strength” or “at bedtime” |
| qhs | At bedtime | Mistaken as qhr (every hour) | Write “at bedtime” |
| q1d | Daily | Mistaken as q.i.d. (four times daily) | Write “daily” |
| q6PM, etc. | Nightly at 6 PM | Mistaken as every 6 hours | Write “nightly at 6 PM” |
| T.I.W. | Three times a week | Mistaken as three times a day or twice weekly | Write “three times weekly” |
| SC, SQ, sub q | Subcutaneous | SC mistaken as “SL” (sublingual); SQ mistaken as “5 every”; the “q” in “sub q” mistaken as “every” (e.g., a heparin dose ordered “sub q 2 hours before surgery” mistaken as “every 2 hours before surgery”) | Write “subQ,” “sub-Q,” “subcut,” or “subcutaneously”; write “every” |
| D/C | Discharge or discontinue | Premature discontinuation of medications if D/C (intended to mean “discharge”) has been interpreted as “discontinued” when followed by a list of discharge medications | Write “discharge” or “discontinue” |
| AD, AS, AU | Right ear, left ear, each ear | Mistaken as OD, OS, OU (right eye, left eye, each eye) | Write “right ear,” “left ear,” or “each ear” |
| OD, OS, OU | Right eye, left eye, each eye | Mistaken as AD, AS, AU (right ear, left ear, each ear) | Write “right eye,” “left eye,” or “each eye” |
| Per os | By mouth, orally | The “os” can be mistaken as “left eye” (OS = oculus sinister) | Write “PO,” “by mouth,” or “orally” |
| > or < | Greater than or less than | Mistaken for the opposite | Write “greater than” or “less than” |
| AZT | Zidovudine [Retrovir] | Mistaken as azathioprine or aztreonam | Write complete drug name |
| CPZ | Prochlorperazine [Compazine] | Mistaken as chlorpromazine | Write complete drug name |
| ARA A | Vidarabine | Mistaken as cytarabine (ARAC) | Write complete drug name |
| HCT | Hydrocortisone | Mistaken as hydrochlorothiazide | Write complete drug name |
| HCTZ | Hydrochlorothiazide | Mistaken as hydrocortisone | Write complete drug name |
A wealth of information is available on reducing medication errors. See Table 5.6 for some good places to start.
TABLE 5.6
Resources on Decreasing Medication Errors
| Resource | Location |
| Agency for Healthcare Research and Quality’s Patient Safety Network | www.psnet.ahrq.gov |
| Institute for Safe Medication Practices | www.ismp.org |
|
Institute for Healthcare Improvement Medication Reconciliation Information and Tools |
http://www.ihi.org/topics/adesmedicationreconciliation/Pages/default.aspx |
| National Coordinating Council for Medication Error Reporting and Prevention | www.nccmerp.org |
| Institute of Medicine: Reducing Medication Errors (“The IOM Report”) | www.nap.edu/catalog.php?record_id511623 |
| The Joint Commission: Resources Related to Medication Errors | www.jointcommission.org/topics/default.aspx?k=660 |
| U.S. Food and Drug Administration: Medication Errors Related to Drugs | www.fda.gov/Drugs/DrugSafety/MedicationErrors/default.htm |
How to Report a Medication Error
You can report a medication error through the MER Program, a nationwide system run by the ISMP. All reporting is confidential and can be done by phone or through the Internet. Details on submitting a report are available at www.ismp.org/orderForms/reporterrortoISMP.asp. The MER Program encourages participation by all health care providers, including pharmacists, nurses, physicians, and students. The objective is not to establish blame, but instead to improve patient safety by increasing our knowledge of medication errors. All information gathered by the MER Program is forwarded to the FDA, the ISMP, and the product manufacturer.
