The most common adverse drug reactions are the effects from the drug itself - a virtual double-edged sword!

Billions of people use medications each day. In the U.S. alone, an estimated 3 billion prescriptions are issued each year. As a result, the pharmaceutical industry has become one of the most profitable businesses worldwide. Drugs are meant to treat, provide relief from or cure an ailment. But, taking drugs comes with a price - adverse drug reactions - and we are not even talking about the cost of medications, which can be exorbitant.

Adverse drug reactions (ADRs) may be due to all types of drugs, prescription as well as nonprescription, with the latter known as over-the-counter (OTC) drugs. A recent study by researchers at the Children's Hospital Boston reported that more than half a million children in the U.S. suffer from medication side effects (also called adverse drug reactions) every year.¹

Of those affected, the majority are under the age of 5 and 5% of cases led to hospitalization. In the general population, U.S. surveillance data show that more 700,000 adverse drug reactions are reported in the U.S. every year. 16.7% of cases required hospitalization and accounted for 2.5% of emergency room cases. And we are not even talking about the cases that go unreported.²

The most common ADRs are the effects from the drug itself - a virtual double-edged sword!

Whereas allergic reactions, medication mix ups, drug-drug interactions, and accidental overdose all play a role in ADRs the drug itself is usually the culprit. A classic example is the wonder drug aspirin which has been in existence for more than 100 years. Aside from being an analgesic and antipyretic agent, it is also used in the treatment and prevention of cardiovascular disorders and potentially has anti-cancer properties. Yet, it has one major side effect that is potentially dangerous – gastrointestinal bleeding.

And who would have thought that plain old cough syrup could be dangerous. Evidence has been piling up that OTC Cough and Cold Medications (CCMs) are not as harmless as originally thought. Next to painkillers and vitamin supplements, perhaps the most commonly bought OTC drugs are CCMs for children.³

Between February 1999 and June 2005, the Philadelphia Medical Examiner’s Office reported 15 cases of deaths among children 16 months and younger which could be related to the use of OTC CCMs.  The following drugs were detected postmortem; pseudoepinephrine, dextromethorphan, acetaminophen, brompheniramine, carbinoxamine, chlorpheniramine, ethanol and doxylamine - not surprisely all found in the usual child cough and cold medications.⁴

As a result, the U.S. FDA Nonprescription Drugs Advisory Committee convened to discuss the safety of OTC CCM drugs especially for children under the age of 2. New FDA OTC products recommendations came out in January 2008 and were updated in October 2008.⁵

And in 2008, researchers investigated the link between sudden infant death (SIDS) and the use of cough and cold medications. The study results support “the recommendation that such medications should not be given to infants and that these medications may play a role in unexpected infant deaths. Postmortem toxicology studies and interviews of caregivers should be conducted to determine whether OTC CCMs were given to the infant before death”.⁶

Sadly, long term ADRs can be worse than the disease itself!

Unfortunately, despite exhaustive research and approval, drugs can cause irreparable harm before being pulled from the marketplace. Although Vioxx and Avandia are highlighted, there have been many prescription drugs that have removed and without a doubt, more will follow.

The drug rofecoxib (Vioxx) was a popular prescription drug to treat chronic pain due to arthritis. However, after just over 5 years in the market, it was withdrawn due to increased risk of heart attack and stroke among long-term users. Several cases of cardiac events, some fatal, have been documented to be linked to rofecoxib.

The anti-diabetic drug rosaglitazone (Avandia) has a controversial reputation regarding cardiac safety. It has been linked to increased risk for cardiac events. In 2007, the U.S. FDA issued a safety alert on Avandia and required its manufacturer GlaxoSmithKline to include a black box warning about the risks on the drug’s labels.⁷

And  despite the continued controversy surrounding its use, a FDA advisory panel in July 2010 voted 20-10 to keep the drug in the marketplace but subject to certain restrictions.

Perhaps there is no drug safety controversy bigger than that one surrounding vaccines, especially childhood vaccines. 

It remains to be seen whether the controversy over the adjuvants in the seasonal flu and the H1N1 vaccines will surpass the notoriety of the childhood vaccination controversy which continues to rage! Over the years, more and more parents refuse to have their children immunized due to growing concerns about the side effects of vaccines. Many claim that vaccines can cause autism and the ingredient responsible is said to be thimerosal, which is a mercury-containing preservative for the vaccine. 

In 1999, the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) asked that thimerosal be removed from vaccines. During the last 10 years, thimerosal has been excluded from childhood vaccines but it remains in most other vaccines including most of the flu vaccines including the recent adjuvant added H1N1 flu vaccine.⁸

The vaccine LYMErex against Lyme disease was approved by the U.S. FDA in 1998. Barely a year later, a class action suit was filed against its manufacturer SmithKline Beecham claiming that the shot triggers a degenerative autoimmune disorder whose symptoms are more severe than those of Lyme disease. The U.S. FDA conducted an investigation and failed to find evidence to support the litigants’ claims. However, LYMErex’s reputation was damaged beyond repair. In 2002, the manufacturer withdrew the vaccine from the market as it was no longer economically feasible to continue its production due to insufficient demand.

And recent evidence also suggests that the Gulf War Syndrome with its severe neurologic complications is most likely related to an adjuvant or a combination of adjuvants used in the mass vaccinations of the GI's prior to engaging in the Persian Gulf War of 1991.⁹

Besides, despite the inherent risk of ADRs prescription drug abuse is on the rise.

A recent Canadian study ranks prescription drug abuse only second to marijuana as the most prevalent illegal drug problem according to the U.S. Office of National Drug Control Policy. Michael Jackson and Heath Ledger are two of the many celebrities who became victims of prescription drug abuse and misuse. It could be sleeping pills, pain killers, or antidepressants or simply for recreation to get high.^10-12

The 3 classes of prescription drugs most commonly abused are:

• opioids such as codeine, oxycodone, and morphine
• central nervous system (CNS) depressants such as barbiturates and benzodiazepines
• stimulants such as dextroamphetamine and methylphenidate

Teenagers and young adults are among the most common prescription drug abusers. Statistics showed that 2.1 million American teenagers (12 to 17 years of age) abused prescription drugs in 2006.

So who's minding the 'Drug' Store?  

In developed countries, there is nothing more strictly regulated than drug safety. The basic principle of drug development is “First do no harm”. Drugs are rigorously tested before they can be approved for marketing. It is not enough that a drug is effective. Safety should come first.

The FDA oversees the approval of drugs for marketing in the U.S. It also regulates the so-called product labeling which gives information on dosage and mode of administrations as well as side effects of the drugs, the so-called almost irreadable package inserts! Similar drug regulatory bodies exist in most countries. In addition, unexpected adverse events due to drug use must be reported to health authorities.

However, every now and then, and unfortunately, the propensity is for more now, than then, serious drug reactions occur in relation to drugs already in the market. And most adverse reactions remain unreported and in fact a great percentage of ER visits continue to be related to drug side effects and drug-drug interactions, and in some cases, too many prescription drugs.

How can this happen despite the strict drug regulations?

Children are different than adults
Dosages for pediatric patients are usually calculated by simply considering them as “mini-adults”, e.g. dosages are calculated based on body weight. Recent studies revealed that children may actually react differently to certain drugs compared to adults and these can cause reactions that are sometimes unexpected.  A recent study, for example, show that commonly used cough drugs that contain codeine and corticosteroids have different effects and reactions in adult and pediatric patients. In 2008, some countries are now requiring drug companies to actually test drugs on children before they can be approved for pediatric use. However, testing drugs on children remains a very sensitive topic.¹³

Long-term side effects remain a sore spot
Some side effects may take years to emerge. In the case of the arthritis drug Vioxx, drug problems only arose after years of long-term use, long after the drug has been approved for marketing. Similarily for the mass vaccinations during the Persian Gulf War.

Genetic variances
In some cases, drugs may react differently in certain people with rare genetic variants, and can lead to side effects that might not be observable during controlled clinical trials. For example, the statin drugs simvastatin and pravastatin may produce side effects in people who carry reduced-function single nucleotide polymorphism (SNP) of the SLCO1B1 gene. The side effects, however, are described as mild.^14,15

Cover ups
Despite strict regulation and watchdog groups, pharmaceutical companies sometimes commit mistakes from inadvertent errors to downright negligence. There have been cases of unethical behavior and cover ups among drug makers. Again, citing the case of Vioxx, there have been questions as to whether its manufacturer Merck correctly reported its side effects. More recently, Pfizer subsidiary Pharmacia & Upjohn Co was fined $1.3 billion for fraudulent marketing of the arthritis drug valdecoxib Bextra despite safety issues. Bextra was withdrawn from the U.S. market in 2005 due to increased risks for heart attacks.¹⁶

To help keep you and your family safe, check out the following resources.

Consumer Reports Best Buy Drugs - Free Guidance for Consumers on Prescription Medicines.

Right Diagnosis - Good resource for adverse drug reactions.

The Consumer Healthcare Products Association (CHPA) , the 128-year-old-trade association representing U.S. manufacturers and distributors is a good resource for OTCs and nutritional supplements.

OTCsafety.org - Last year, CHPA started the public service campaign “Treat with Care” to educate parents on how to use OTC CCMs for children safely.¹⁷

FDA Drug Safety and Availability - Information for consumers and health professionals on new drug warnings and other safety information, drug label changes, and shortages of medically necessary drug products. Website also includes the FDA Drug Safety Newsletter and Drug Safety Podcasts.

MedWatch - The FDA Safety Information and Adverse Event Reporting Program.¹⁸

YellowCardUK - The Yellow Card Scheme is run by the Medicines and Healthcare Products Regulatory Agency and the Commission on Human Medicines (CHM), and is used to collect information from both health professionals and the general public on suspected side effects or ADRs to a medicine.

MedEffect e-Notice is a free service that stays on top of  advisories, warnings and recalls for health products that Canadians use every day, such as pain relievers, cold medicines, prescription drugs and natural health products.

The Bottom Line

The take home message is - you cannot rely solely on the regulatory drug approval agencies, the adverse drug reactions reporting bodies, watchdog groups or even the above resources. Always pay attention to the drug inserts, if you can read them, and not just the TV commercials.

Now, more than ever, it's up to you to mind the 'Drug' store!

Published August 3, 2010, updated June 16, 2012

References

1. Bourgeois FT, Pediatric adverse drug events in the outpatient setting: an 11-year national analysis, Pediatrics. 2009 Oct;124(4):e744-50. Epub 2009 Sep 28
2. Budnitz DS et al, National surveillance of emergency department visits for outpatient adverse drug events, JAMA. 2006 Oct 18;296(15):1858-66
3. Vassilev ZP et al Adverse reactions to over-the-counter cough and cold products among children: the cases managed out of hospitals, J Clin Pharm Ther. 2009 Jun;34(3):313-8
4. Wingert WE et al, Possible role of pseudoephedrine and other over-the-counter cold medications in the deaths of very young children, Forensic Sci. 2007 Mar;52(2):487-90
5. OTC Cough and Cold Products: Not For Infants and Children Under 2 Years of Age, FDA January 17, 2008
6. Rimsza ME, Unexpected infant deaths associated with use of cough and cold medications, Pediatrics 2008;122;e318-e322
7. FDA Issues Safety Alert on Avandia, FDA 4/14/2009
8. Offit PA, Thimerosal and Vaccines — A Cautionary Tale, NEJM 357:1278-1279
9. Roslin A, What’s in your H1N1 flu vaccine? Straight.com November 19, 2009
10. Good Medicine, Bad Behavior: Drug Diversion in America, Goodmedicinebadbehaviour.org
11. Dhalla I, Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone, CMAJ December 8, 2009 vol. 181 no. 12
12. Prescription Drug Abuse Prevention, Office of National Drug Control Policy
13. Chang AB, Cough: are children really different to adults Cough 2005 Sep 20;1:7
14. Voora D et al, The SLCO1B1*5 genetic variant is associated with statin-induced side effects, J Am Coll Cardiol 2009; 54: 1609-1616
15. O'Riordan M, Genetic variant again linked with statin side effects, Heartwire October 12, 2009
16. US court imposes penalties on Pfizer unit in Bextra case, Reuters 16 Oct 2009
17. OTC safety, Consumer Healthcare Products Association
18. FDA Unveils Safe Use Initiative that Targets Preventable Harm from Medication Use, FDA 4 Nov 2009