Adverse drug events, (ADEs) often referred to as side effects, are a long-standing and serious medical problem. Adverse drug events are not the result of medical errors, they only occur within the FDA-approved dosage and labeling recommendations and represent an unexpected side effect to the medication. The FDA has acknowledged that adverse drug events associated with the following types of medications may be directly linked to patient’s genetic characteristics: anti-platelet agents (e.g. Plavix®), anti-depressants (e.g. Celexa®, Prozac®), anti-seizure medications (e.g. Dilantin®, Tegretol®).
Things you need to know about adverse drug events
According to the FDA ADEs are the fourth greatest killer in the US, with more than 100,000 deaths per year; 2.2 million serious adverse reactions occur per year. From January 2008 to June 2015, the FDA issued 111 black box warnings to drugs on the US market.
Of these warnings:
- Thirty-two (29%) were new
- Thirty-five (32%) were major updates
- Forty-four (40%) were minor updates
The top three treatment categories receiving new black box warnings were drugs for neurological conditions (including Psychiatric conditions and Epilepsy), cardiovascular conditions, and infection.
Based on 2013-2014 surveillance data, an estimated 4 emergency department (ED) visits for ADEs occurred per 1000 individuals annually and that 27.3% of these ED visits resulted in hospitalization.
Among children 5 years old or younger, antibiotics were most commonly implicated.
Among older children and adolescents, between the ages of 6 to 19, antibiotics followed by anti-psychotics were most commonly implicated.
Among Adults 65 or older: anticoagulants, diabetes agents and opioid analgesics were implicated in nearly 60% of ED visits for ADEs.
The potential of pharmacogenetic testing and Clinical Decision Support Tools (CDST) to reduce ADEs and improve healthcare
More than 90% of Americans have gene-based variations that can be tested for and that increase the risk of an ADE. The wide use of the YouScript CDST has the potential to 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 ADE 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.
Hospitalized psychiatric patients who are poor metabolizers cost $4,000–6,000 more in medical care Currently, available tests help predict a patient’s response to many prescriptions, 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.
The Financial Consequence of Adverse Drug Events
The financial impact of ADEs is complex. In the U.S. alone it was estimated to cost up to $30.1 billion annually when including costs for increased hospitalization, prolongation of hospital stay and additional clinical investigations for more serious cases.
Important Studies Related to Adverse Drug Events
- 41,000 hospitalizations and 3,300 deaths per year from NSAID-induced ulcers. (Amer J Med. 1998; 104(3A):23S-29S. 41S-42S) View Study >
- 16,000 car accidents each year can be attributed to psychoactive drug use in the elderly. (Amer J Epidemiology 136(7):Oct 1992:873-883). View Study >
- Significant increased risk of motor vehicle accidents noted in patients taking antidepressants and benzodiazepines within one month of accident. (Br J Clin Pharmacol 2013 Apr; 75(4):1125-1133). View Study >
- 32,000 hip fractures per year leading to 1,500 deaths secondary to psychotropic drug use in the elderly. (NEJM 1987; 316:363-369). View Study >
- Drug-induced Parkinson’s disease (PD) is the second most common etiology of PD in the elderly and is caused most often by atypical antipsychotics, gastrointestinal prokinetic agents, calcium channel blockers and antiepileptic drugs. (J Clin Neurol. 2012 Mar:8(1):15-21). View Study >
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, particularly for smaller firms. None of the $7.67 billion in user fees collected from 1993 to 2016 can be used for drug safety or post-marketing surveys, which includes investigating and addressing adverse drug events.
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 have taken at least 1 prescription drug in the last month, nearly 70% have taken 3 or more and 40% have taken 5 or more in the last 30 days. (National Center of Health Statistics, U.S. 2017; table 79).
- 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, the only psychiatric drugs approved by the FDA for use by children and teenagers are:
- clomipramine (Anafranil® - OCD),
- duloxetine (Cymbalta® - anxiety),
- escitalopram (Lexapro® - depression),
- fluoxetine (Prozac® - depression, OCD),
- fluvoxamine (Luvox® - OCD),
- olanzapine/fluoxetine (Symbyax® - bipolar depression)
- and sertraline (Zoloft® - OCD)
Additional FDA Warnings for adolescents:
The FDA recently issued a warning that codeine use children that are CYP2D6 ultra-rapid metabolizers after pediatric surgery may lead to rare, but life-threatening adverse events or death.
The FDA 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).