P T Chapter 40 Adverse Drug Reaction Reporting Lee B. Murdaugh, RPh, PhD The Conditions of Participation standards of the Centers for Medicare & Medicaid Services (CMS) and the standards of accrediting organizations such as The Joint Commission, the Healthcare Facilities Accredi- tation Program (HFAP), and the National Integrated Accreditation for Healthcare Organizations (NIAHOSM) require hospitals to identify and report adverse drug reactions (ADRs). These ADRs must be reported to LEARNING OBJECTIVES patients’ attending physicians and the hospital’s quality assessment and performance improvement program. Additionally, hospitals are expected to report serious • Define an adverse drug reaction. ADRs (as defined by the Food and Drug Administration • Discuss the detection of adverse [FDA]) to the FDA’s MedWatch program and ADRs to vaccines to the FDA’s Vaccine Adverse Events Reporting drug reactions. System (VAERS). • Discuss the assessment of adverse drug reactions. Defining Adverse Drug Reactions To recognize and assess ADRs, there must be a defini- tion of what constitutes an ADR. Examples of commonly used definitions are discussed in the following text. The FDA defines a serious adverse reaction as one in which “the patient outcome is death, life threat- ening (real risk of dying), hospitalization (initial or prolonged), disability (significant, persistent, or perma- nent), congenital anomaly, or required intervention to prevent permanent impairment or damage.”1 The American Society of Health-System Pharma- cists (ASHP) defines a ADR as “any unexpected, unin- tended, undesired, or excessive response to a drug that • requires discontinuing the drug (therapeutic or diagnostic) • requires changing the drug therapy • requires modifying the dose (except for minor dosage adjustments) • necessitates admission to a hospital 546 Competence Assessment Tools for Health-System Pharmacies • prolongs stay in a healthcare facility routine observation and assessment. Inclusion of an • necessitates supportive treatment individual sign or symptom will depend on the defini- tion of an ADR at the specific institution. • significantly complicates diagnosis • negatively affects prognosis or Surveillance Systems • results in temporary or permanent harm, disability, There are three types of surveillance systems that may 2 or death.” be used to detect ADRs: The ASHP definition includes allergic reactions (an 1. Prospective immunologic hypersensitivity response to a drug) and 2. Concurrent idiosyncratic reactions (an abnormal response to a drug 3. Retrospective that is specific to an individual). ASHP excludes the following from this definition: Identifying which methods to use will depend on the unique characteristics of a facility. However, ADRs are • Drug withdrawal more likely to be detected when a combination of • Drug-abuse syndromes surveillance systems are used. It should be noted that • Accidental poisonings the success of any surveillance system depends on • Drug overdose complications the willing participation of healthcare professionals in reporting ADRs. • Side effects PROSPECTIVE SURVEILLANCE SYSTEM A side effect is defined as an “expected, well-known reaction resulting in little or no change in patient Prospective surveillance occurs prior to initiation of management” that occurs with a “predictable medication therapy and can be accomplished in two frequency and whose intensity and occurrence are ways: related to the size of the dose.”2 1. Monitoring of patients who are at a high risk for experiencing ADRs The World Health Organization (WHO) defines an —Risk factors for ADRs include the following: ADR as “any response to a drug, which is noxious and unintended, and which occurs at doses used in man • Polypharmacy for prophylaxis, diagnosis, or therapy or for modifica- • Extremes of age (e.g., neonatal, pediatric, and tion of physiologic function.”3 The definition excludes geriatric patients) cases attributed to drug abuse or overdose (intended • Presence of concurrent disease states (e.g., or unintended). impaired renal or hepatic function) Karch and Lasagna define an ADR as “any response • Severity of illness to a drug that is noxious and unintended and that • History of allergy/previous ADR occurs at doses used in humans for prophylaxis, • Pharmacodynamic/pharmacokinetic changes diagnosis, or therapy, excluding failure to accomplish the intended purpose.”4 In addition to the exclusions 2. Monitoring of patients who are receiving medica- of the WHO definition, this definition also excludes tions known to have a high potential for causing therapeutic failures. ADRs—The drug classes most frequently impli- cated in ADRs include the following: Review appropriate policies and procedures to identify the definition used by your organization. • Anticoagulants (e.g., heparin and warfarin) • Antimicrobials (e.g., penicillins, cephalospo- Detection of Adverse Drug Events rins, sulfa antibiotics, and aminoglycosides) • Antineoplastics Signs and Symptoms • Cardiac agents (e.g., antiarrhythmics, digoxin, Signs and symptoms of ADRs are many and varied and diuretics, and antihypertensives) may be similar to signs and symptoms of disease states • Central nervous system (CNS) agents (e.g., or medical conditions. Table 40-1 contains some of analgesics, anticonvulsants, and sedatives/ the common signs and symptoms of ADRs (grouped hypnotics) by body systems) that may be seen in patients during • Diagnostic agents (e.g., contrast media) Adverse Drug Reaction Reporting 547 TABLE 40-1. Signs and Symptoms of ADRs by Body System Body System Examples Body System Examples Cardiovascular • Arrhythmias Hematological • Bleeding • Angina • Increased eosinophils • Hypertension • Increased PT and PTT • Hypotension • Decreased WBC, RBC, HCT, and • Bradycardia platelets • Tachycardia Hepatic • Hepatitis Dermatological • Rash • Jaundice • Itching • Increased AST, ALT, and LDH • Erythema Musculoskeletal • Arthritis • Hives • Joint pain • Phlebitis • Myalgia • Bruising Neurological • Headache • Petechiae • Tremor • Ecchymosis • Seizures • Drowsiness/somnolence Endocrine/metabolic • Hyperglycemia • Vertigo • Hypoglycemia • Altered vision • Sexual dysfunction • Movement disorders (e.g., • Hypothyroidism dyskinesia, akathisia, tardive ENT/oral • Altered taste dyskinesia) • Stomatitis • Depression • Thrush • Confusion • Tinnitus • Agitation • Hearing loss • Psychosis Reproductive • Fetal hemorrhage • Hallucinations • Fetal respiratory depression Renal • Bladder spasms • Teratogenesis • Oliguria Electrolyte • Hyperkalemia • Increased BUN or creatinine homeostasis • Hypokalemia • Renal failure • Hypernatremia Respiratory • Wheezing • Hypocalcemia • Increased or decreased respirations Gastrointestinal • Diarrhea • Constipation ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; ENT = ear, nose, throat; • Nausea/vomiting HCT = hematocrit; LDH = lactate dehydrogenase; • Hemorrhage PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; WBC = white blood cell. Generalized • Anaphylaxis • Fever • Skin reaction • Angioedema 548 Competence Assessment Tools for Health-System Pharmacies • Antidiabetic agents (including insulin) • Flumazenil • Sodium polystyrene • Corticosteroids sulfonate (SPS) The major advantage of prospective surveillance • Protamine • Antidiarrheals is that it is the most sensitive and specific method for (e.g., loperamide, detecting ADRs.5 However, it has a significant disad- colestipol) vantage in that it is very labor intensive and involves • Nitroglycerin • Antiemetics continuous monitoring. Prospective surveillance (e.g., hydroxyzine, systems are best accomplished through the use of prochlorperazine) decentralized pharmacists and/or utilization review • Physostigmine • Glucocorticosteroids personnel. (e.g., methylprednisolone) CONCURRENT SURVEILLANCE SYSTEM Alerting orders also include nonroutine orders for Concurrent surveillance involves the identification of laboratory tests, such as the following: ADRs close to the time they occur. There are several methods that can be used to detect ADRs concurrently: • BUN • Clostridium difficile • Spontaneous reporting of ADRs by primary care • AST, ALT • Guaiac test practitioners (such as physicians and nurses) during • PT, PTT, platelet • Serum creatinine the course of their work using telephone hotlines, count ADR alert cards, report forms, etc. • Drug serum • Urine protein, cells, • Analysis of medication usage evaluation (MUE) concentration casts studies • Reporting of suspected ADRs by hospital utilization Usually, a combination of orders gives the phar- review/quality assurance personnel from their macist the best clue that an ADR may have occurred. concurrent review of patient charts Table 40-2 includes examples of combination alerting orders and the corresponding possible ADR. • Monitoring of orders and patient charts by phar- macy personnel for clues (often called triggers) Concurrent surveillance has the advantage of that an ADR has occurred allowing a more thorough investigation because the patient, nurse, and physician are available for inter- Triggers include the following: views and are likely to recollect events more accurately. ͷ Abnormal test results such as serum drug Also, this method allows interventions and manage- concentrations above therapeutic levels and ment of the ADR to take place in a timely manner. laboratory test results outside a particular range or threshold (e.g., platelet count less RETROSPECTIVE SURVEILLANCE SYSTEM