Adverse Drug Events

Adverse drug events, (ADEs) often called side effects, are a long-standing and largely neglected major medical problem. These are not medical errors and occur within the FDA-approved dosage and labeling recommendations. The recently reported genetically-based problems with Plavix and codeine reported by the FDA are the tip of the iceberg.

Incidence of adverse drug events (ADEs)

  • ADEs are the fourth to sixth greatest killer in the US, with more than 100,000 deaths per year; 2.2 million serious adverse reactions occur per year, according to a 1998 Journal of the American Medical Association report. (JAMA 279:1200 1998) This study is a meta-analysis of 39 research reports published from 1966 to 1996.
  • 21.3% of the 548 most recently FDA approved medications were subsequently withdrawn from the market or given a black box warning. JAMA 287:2215 2002
  • The GAO reports that 51% of new drugs have serious, undetected adverse effects at the time of approval.
  • Of the best selling prescription drugs, 148 can cause depression, 133 hallucinations or psychoses, 105 constipation, 76 dementia, 27 insomnia and 36 parkinsonism. “Worst Pills Best Pills: A Consumer’s Guide to Avoiding Drug-Induced Death or Illness,” third edition, 1999.

Financial Consequences

  • $289 billion in added health care costs per year (Thinking Outside the Pillbox, A System-wide Approach to Improving Patient)
    Medication Adherence for Chronic Disease
  • A NEHI Research Brief – August 2009HMOs spend more treating ADRs than on drugs.
  • ADEs are the cost leader for malpractice payouts.
  • Up to one-third of drug prescriptions are not needed and therefore wasted.

The potential of pharmacogenetic testing and Clinical Decision Support Tools (CDST) to reduce ADEs and save money

  • More than 75% of Americans have gene-based variations that can be tested for and that increase the risk of an ADR.
  • The wide use of the YouScript CDST has the potential to save tens of thousands of lives, prevent hundreds of thousands of serious events that initiate or extend hospital stays, and save hundreds of millions of dollars in healthcare costs. Fifty-nine percent of drugs most commonly cited in ADR studies are processed by enzymes with genes known to have poor metabolizer variants. This is compared to 7% of a random selection of the top selling drugs. (JAMA 286:2270 2001).
  • Currently available tests help predict a patient’s response to many prescription, over-the-counter (OTC), and herbal medicines—including those used to treat depression, anxiety, seizures and psychoses; blood pressure, anticoagulation and other heart medicines; anti-diabetic agents, and many pain relievers.
  • Many known drug-to-drug interactions are based on a knowledge of the drug metabolizing systems that have a high level of genetic variation. When those variations are present in individuals taking more than one drug, the chance of having an adverse drug reaction is greatly increased.
  • Hospitalized psychiatric patients who are poor metabolizers cost $4,000–6,000 more in medical care compared to patients with an average metabolizer genotype. All antidepressants and antipsychotic medicines are processed by enzymes with a high incidence of poor metabolizers. Journal of Clinical Psychopharmacology 20:246 2000

Some examples of studies pointing out the results of adverse drug events

  • 41,000 hospitalizations per year for NSAID-induced ulcers. Health Affairs 1990
  • 16,000 car crashes per year from anti-psychotics. American Journal Epidemiology 1992
  • 32,000 hip fractures per year leading to 1,500 deaths. NEJM 1987:A.J.Epi 1991
  • Drug-induced Parkinson’s has developed in 63,000 patients. CMAJ 1982

Why adverse drug events are a growing problem

The 1992 Prescription Drug User Fee Act requires drug companies to pay “user fees” to fund the FDA in order to accelerate the drug approval process. None of the $825 million in user fees collected from 1993 to 2001 can be used for drug safety or post-marketing surveys.


Percentage of new drugs first introduced in the US:
1980: 3%1998: 60%
Drug approval time:
1993: 27 months2001: 14 months
Percentage of drugs recalled:
1993 – 1996: 1.56%1997 – 2001: 5.35%
According to the FDA, Vioxx may have contributed to almost 28,000 heart attacks in the U.S. between 1999 and 2003.

Adverse drug events in the elderly

Elderly patients have a decreased capacity to detoxify the drugs they are taking. Drug-to-drug interactions are also an important contributor to adverse drug reactions. This makes the aging population vulnerable because of the large number of drugs they are taking.

  • 90% of all persons 65 or older are taking at least one medication per week, 40% use five or more and 12% ten or more.
  • A recent one-year study of 30,000 Medicare outpatients showed that in a single year there were 1,523 identified adverse drug events, 421 of which were preventable. 578 of these events were serious, life threatening, or fatal. The most serious events were also the most preventable. JAMA 289:1107 2003

Adverse drug events in children and adolescents

Few drugs are tested in children prior to release. Many are used off-label in pediatric populations. For example, only Prozac (fluoxetine) has been approved for use in children, yet many others are prescribed off-label.

  • The FDA recently issued a warning that codeine use children that are CYP2D6 ultra-rapid emtabolizers after pediatric surgery may lead to rare, but life-threatening adverse events or death.
  • The FDA recently released an analysis of previous studies showing that suicidality doubled in children taking antidepressants compared to a placebo, resulting in a black box warning being added to antidepressants’ required labeling. NEJM 351:16 2004
  • While the rate of adverse drug reactions in children is lower than in adults, children with severe medical conditions are the most affected. Drug Safety 27:819 2004
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