What Constitutes an Adverse Drug Event?

"Adverse drug event" is a broad term that encompasses a variety of incidents with problematic outcomes that occur within the context of drug therapy. Simply put, an ADE is any unfavorable event associated with the use of a medication. One of the most commonly accepted definitions is based on the International Conference on Harmonization Guidelines^[13]: "any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment." The definition continues: "any unfavorable or unintended sign, symptom, or disease temporally associated with the use of any dose of a medicinal product, whether or not considered related to the medicinal product."

Although the definition of an ADE may seem broad, it is designed to be very inclusive. Physicians, pharmacists, nurses, and consumers often mistakenly believe that an ADE must have a definite temporal relationship with a drug therapy, or that a drug must be the sole cause of the event; this is not true, and this misunderstanding may partially explain why many ADEs are not recognized or reported. Causality and probability that an event is related to drug therapy will be discussed further.

There are 5 different categories of ADEs:

1. Adverse drug reactions
2. Medication errors
3. Therapeutic failures
4. Adverse drug withdrawal events
5. Overdoses

Adverse Drug Reactions

Causality comes into play within the first category, adverse drug reactions (ADRs). In these cases, there is a defined temporal relationship between the adverse event and the administration of the drug. A commonly cited definition of an ADR is delineated by the World Health Organization (WHO) as "any response to a drug that is noxious and unintended, and that occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease."^[10]

ADRs generally are assigned to 1 of 2 subgroups. Events that fall within the first subgroup are known as type A reactions: an "A"ugmentation of a drug's primary or secondary pharmacologic effect. A simple example of a type A reaction is coagulopathy with warfarin. The primary therapeutic effect is to interfere with the hepatic synthesis of vitamin K-dependent coagulation factors, but when there is too much inhibition, unwanted hypoprothrombinemia and bleeding episodes may result.

Drugs also may exhibit adverse reactions due to a secondary pharmacologic effect. For example, this is sometimes seen with fluoroquinolones. Their primary pharmacologic effect is to inhibit certain bacterial enzymes, exerting their antimicrobial activity. However, fluoroquinolones can also inhibit gamma-amino butyric acid (GABA), an inhibitory central nervous system neurotransmitter; inhibition of this neurotransmitter is believed to be the mechanism of fluoroquinolone-induced seizures, which represent a rare adverse reaction to this class of drugs.

The other general subgroup of ADRs encompasses type B reactions, which are considered "B"izarre, or idiosyncratic, in nature. Such reactions are not related to a drug's primary or even secondary pharmacologic effect. The best examples in this group are allergic reactions such as rashes, hives, and systemic anaphylaxis.

Table 1 offers a comparison of the 2 types of ADRs.

Table 1. Descriptions of Adverse Drug Reactions (ADRs)

Medication Errors

Medication errors represent another classification of ADEs. Medication errors are defined as "unintended acts (either of commission or omission) resulting in actual or potential harm to a patient, or an act that does not achieve its intended outcome when dealing with drug therapy."^[14] Medication errors of commission are generally blatant even though usually unintended; for example, a patient who is supposed to receive the drug Lamictal (lamotrigine) for seizure control instead receives the drug Lamisil (terbinafine) for onychomycosis. This type of error often occurs when different drug names look or sound alike.

Another type of medication error of commission is that which results from unclear or misinterpreted handwriting. An example is the patient who is supposed to receive 1 mg of a drug but instead receives 10 mg when the order for 1.0 mg is misinterpreted as 10 mg, because the decimal point was either overlooked or poorly written. Whether such an error results in patient harm may depend on when it is discovered during the medication-use process system. (When such errors are corrected before any patient harm occurs, they are often described as "near misses.")

Medication errors of omission are those that occur when a clinician fails to detect an important factor in a patient's drug therapy regimen, such as a clinically significant drug interaction, allergy history, or disease state contraindication. Errors of omission also may occur when important drug information is not adequately conveyed to prescribers or patients. All of these omitting factors have the potential to result in patient harm.

Consider, for example, the case of a pharmacist who dispenses the fertility drug clomiphene citrate to a young woman; within the next 3 months, the pharmacist dispenses to this same patient the drug misoprostol to prevent gastrointestinal distress caused by a nonsteroidal anti-inflammatory drug (NSAID) that she is taking. The error here is that misoprostol is labeled by the US Food and Drug Administration (FDA) as a category X pregnancy risk drug, which is contraindicated for women who are pregnant and or who are planning to become pregnant. A woman who is taking clomiphene citrate is clearly trying to get pregnant, and the misoprostol could cause a spontaneous abortion or could result in congenital defects in the baby, representing a most egregious error. In this scenario, the errors of omission are the pharmacist's failure to conduct a full prospective drug-utilization review and the failure to communicate warnings associated with the drug's labeling to the patient.

Therapeutic Failures and Adverse Drug Withdrawal Events

The third and fourth types of ADEs occur when drug therapy is "not given" or "not optimally given." In a therapeutic failure, suboptimal amounts of a medication are given to a patient, and the patient's condition fails to stabilize or symptoms become even worse as a result. For example, certain antibiotics bind to the minerals found in some other drugs, and if taken together, the amount of antibiotic available for absorption will be lowered. This may result in a treatment failure.

Sometimes a patient may not fully understand the importance of the drug regimen and may not take the drug as prescribed or may discontinue therapy altogether; this often occurs in patients with chronic disease states. Medication nonadherence is a major factor in therapeutic failures.

In contrast, an adverse drug withdrawal event (ADWE) occurs when a patient on long-term drug therapy experiences a withdrawal syndrome after discontinuing taking the drug, especially when this is an abrupt change. Examples of ADWEs include rebound hypertension in patients on long-term clonidine use, as well as agitation and/or seizures in patients abruptly discontinuing long-term benzodiazepine therapy.

Drug Overdoses

The final class of ADEs includes drug overdoses, whether intentional or accidental. These events differ from adverse reactions in that the doses are not "those that are normally used to treat disease." Accidental overdoses occur most commonly in 2 patient populations at opposite ends of the age spectrum: the very young and the very old. In these instances, the root causes generally are medication compliance problems and patient or caregiver knowledge deficits about the drugs involved.