Preventable Adverse Drug Reactions:  
A Focus on Drug Interactions

The first question healthcare providers should ask themselves is "why is it important to learn about ADRs?" The answer is because ADRs are one of the leading causes of morbidity and mortality in health care. The Institute of Medicine reported in January of 2000 that from 44,000 to 98,000 deaths occur annually from medical errors.1 Of this total, an estimated 7,000 deaths occur due to ADRs. To put this in perspective, consider that 6,000 Americans die each year from workplace injuries. 

However, other studies conducted on hospitalized patient populations have placed much higher estimates on the overall incidence of serious ADRs. These studies estimate that 6.7% of hospitalized patients have a serious adverse drug reaction with a fatality rate of 0.32%.2  If these estimates are correct, then there are more than 2,216,000 serious ADRs in hospitalized patients, causing over 106,000 deaths annually. If true, then ADRs are the 4th leading cause of death—ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents, and automobile deaths.

These statistics do not include the number of ADRs that occur in ambulatory settings. Also, it is estimated that over 350,000 ADRs occur in U.S. nursing homes each year.3 The exact number of ADRs is not certain and is limited by methodological considerations. However, whatever the true number is, ADRs represent a significant public health problem that is, for the most part, preventable.

1Committee on Quality of Health Care in America: Institute of Medicine. To err is human: building a safer health system. Washington, D.C.: National Academy Press; 2000. 2Lazarou J, Pomeranz B, Corey PN. Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA 1998;279:1200–1205. 3Gurwitz JH, Field TS, Avorn J, McCormick D, Jain S, Eckler M, et al. Incidence and preventability of adverse drug events in nursing homes. Am J Med 2000;

We can next ask ourselves, what are the health care costs associated with adverse drug reactions? Again, methodological constraints limit making completely accurate estimates, but one estimate of the cost of drug-related morbidity and mortality is $136 billion annually,1 which is more than the total cost of cardiovascular or diabetic care in the United States. In addition, one out of 5 injuries or deaths per year to hospitalized patients may be as a result of ADRs.2 Finally, a two-fold greater mean length of stay, cost and mortality has been reported for hospitalized patients experiencing an ADR compared to a control group of patients without an adverse drug reaction.3

1Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995;155(18):1949–1956. 2Leape LL, Brennan TA Laird N, Lawthers AG ,Localio AR, Barnes BA et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med 1991;324(6):377–384. 3Classen DC , Pestotnik SL, Evans RS, Lloyd JF, Burke JP. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA 1997;277(4):301–306.

Why are there so many ADRs? There are many reasons. Here are just a few.

First, more drugs—and many more combinations of drugs—are being used to treat patients than ever before. To exemplify this point, 64% of all patient visits to physicians result in prescriptions.

Secondly, 2.8 billion prescriptions were filled in the year 2000. That is about 10 prescriptions for every person in the United States.

Finally, the rate of ADRs increases exponentially after a patient is on 4 or more medications.

Efforts to reduce polypharmacy are important but for many patients, the number of medications cannot always be reduced without doing harm. That is why it is important to understand the basis for drug interactions. This will allow us to make the most appropriate choices in prescribing and avoiding preventable ADRs.

It is worth considering how well a drug’s safety is defined prior to its approval and marketing. This will indicate how confident practitioners can be that a new drug’s safety profile has been fully defined. 

Most new drugs are approved with an average of 1,500 patient exposures and usually for only relatively short periods of time. However, some drugs cause serious ADRs at very low frequencies and would require many more exposures to detect the reaction. For example, bromfenac (Duract) was a non-steroidal anti-inflammatory agent (NSAID) that was removed from the market in 1998, less than 1 year after it was introduced. Bromfenac caused serious hepatotoxicity in only 1 in 20,000 patients taking the drug for longer than 10 days.1 To reliably detect the toxic effects of a drug with a 1 in 20,000 adverse drug reaction frequency, the new drug application database would have to include 100,000 patient exposures. A drug that is tested in a few thousand people 11 may have an excellent safety profile in those few thousand patients. However, within a short time after entering the market, the drug may be administered to several million patients. That means that for drugs that cause rare toxicity, their toxicity can only be detected after, not before, marketing. 

If one case of hepatotoxicity is seen during pre-marketing testing, it can be difficult, if not impossible, to ascertain whether it was secondary to the drug or just the background rate of disease that is seen in the population. 

So, the safety profile for new drugs that come on the market is never totally defined because new drugs are studied only in relatively small and homogenous patient populations. The complete safety profile of a new drug will be defined only after it has been approved and is in use on the market.

1Friedman MA, Woodcock J, Lumpkin MM, Shuren JE, Hass AE, Thompson LJ. The safety of newly approved medicines: do recent market removals mean there is a problem? JAMA 1999; 281(18):1728–1734.

Health care providers have misconceptions about reporting ADRs.1–3 These misconceptions include the ideas that: 1) All serious ADRs are documented by the time a drug is marketed; 2) It is hard to determine if a drug is responsible for the ADR; 3) ADRs should only be reported if absolute certainty exists that the ADR is related to a particular drug; and, finally, 4) One case reported by an individual physician does not contribute to medical knowledge. Let’s look at each one of these points. 

1) As we have seen, rare ADRs are usually NOT documented by the time a drug is marketed. 

2) It can be hard to determine if an individual drug caused a reaction in a complicated patient receiving multiple medications. However, the temporal relationship of a reaction with regard to the administration of a new medication can be helpful. Also, biological plausibility (asking if the drug’s mechanism of action makes this possible or likely) can also be helpful. The bottom line is, even when in doubt about whether a drug caused the reaction, report it.

 3) A suspicion of an adverse drug reaction should be reported. A health care provider does not have to be absolutely certain that a drug caused a reaction. All reports contribute to the heightening of the awareness of FDA safety scientists as they monitor all of the evidence to evaluate the potential for drug-related toxicity. 

4) One individual report CAN make a difference. Many drug withdrawals began with one clinical report that initiated further investigation. In the example case in this module, a single report ultimately led to the removal of terfenadine from the market. This report potentially saved many lives and led to a better understanding of the mechanism involved in causing torsades de pointes. Almost all drugs are now evaluated prior to being released on the market for their potential to induce cardiac arrhythmias, also as a result of this single case report.

1Figueiras A, Tato F, Fontainas J, Gestal-Otero JJ. Influence of physicians’ attitudes on reporting adverse drug events: a case-control study. Med Care 1999;37(8):809-814. 2Eland IA, Belton KJ, van Grootheest AC, Meiners AP, Rawlins MD, Stricker BH. Attitudinal survey of voluntary reporting of adverse drug reactions. Br J Clin Pharmacol 1999;48(4):623–627.

This figure shows data from a national survey conducted in 1999 by the American Society of Health Systems Pharmacists (ASHP)1 that evaluated patient concerns about health systems. This was a random telephone survey of 1,008 adults. Although the respondents were very concerned about suffering from pain and the cost of filling prescriptions, they were most concerned about being given the wrong drug or that a drug interaction would occur. The public in general has a much greater level of concern about ADRs than most health care providers would suspect. These data demonstrate that drug interactions and reactions are not only a concern to health care providers but to patients as well.

1American Society of Health Systems Pharmacists. ASHP Patient Concerns National Survey Research Report. 1999. Bethesda, MD.

FDA WEB SITE Reactions/default.htm

Drug interaction web site