Where do you go when you want to know whether a symptom you are experiencing is related to your medicine? Many people type the name of their drug into a Google search. At the top of the list will be “side effects” and links to places like MedlinePlus, Mayo Clinic, WebMD, Cleveland Clinic or RxList. But where does the drug side effect information actually come from and is it reliable?
The Origins of Most Drug Information:
The source of virtually all drug information originates with the clinical trials conducted for FDA drug approval. The agency and the drug companies negotiate the final wording in the official prescribing information.
Amidst things like dosing instructions, warnings and precautions and drug interactions you will discover “ADVERSE REACTIONS.” Virtually all the databases you will find online create lists based on the side effects located in the official prescribing information.
Medical words such as “pruritis” will be converted to itching. “Dyspepsia” becomes heartburn. “Hepatotoxicity” turns into liver damage. You get the picture. The basic information is the same, but the words may be a bit more understandable in the databases that try to translate drug side effect information for the average person.
Finding the Official Prescribing Information:
The easiest way to find the key information about almost all drugs is by putting DailyMed into a search engine. Here is the URL.
And here is a description of “ABOUT DAILYMED”:
“The National Library of Medicine (NLM)’s DailyMed searchable database provides the most recent labeling submitted to the Food and Drug Administration (FDA) by companies and currently in use (i.e., “in use” labeling).”
Where Does the Drug Side Effect Information REALLY Come From and Is It Trustworthy?
Pharmaceutical manufacturers conduct randomized controlled trials (RCTs) to demonstrate that their new drugs are better than placebos. Without that, they don’t get to bring their medications to market.
RCTs are primarily designed to determine effectiveness. Please hit your internal pause button for just a sec. Reread that sentence. Drug companies care about drug effectiveness…a lot! If they can’t prove their “marvelous” new medicine is better than placebo, they are usually out of luck.
Sadly, the FDA sometimes bends its own rules a bit and approves a drug that barely demonstrates effectiveness. You can read about one such example at this link. In theory, though, the FDA is not supposed to approve any medication that does not work better than nothing (placebo).
Drug companies are also required to collect information about side effects. But that is where the system gets squirrelly!
Gathering Drug Side Effect Information:
There are numerous ways this kind of information is gathered. The specific choices a study sponsor makes can have an important impact on our understanding of the drug’s risks.
One of the first steps the researchers need to take in planning their trial is to decide who will be included (and, just as critical, who gets excluded). Until several decades ago, many trials didn’t include women. Scientists didn’t want to have to deal with potential variables such as menstrual cycles or pregnancy. At the same time, they just assumed that side effects would be the same—an assumption that hasn’t always been substantiated.
Study subjects may also be younger or healthier than the patients who will eventually be taking the medication. This simplifies the study, because the researchers don’t have to take multiple health conditions and additional medications into account. But it may also limit the usefulness of the side effect information gathered from the clinical trial. The real world is messy.
Another pitfall at the planning phase is how many people will be included. Clinical trials are expensive, so often they do not include enough subjects to be likely to reveal a rare or even uncommon reaction.
Finally, there is the actual process by which pharmaceutical companies collect drug side effect information. There is substantial variability in the way questions are asked about adverse drug reactions.
How Do Drug Companies Ask Questions?
If I were to ask you if you have experienced a headache recently, what would you say? A lot of people experience headaches on a regular basis. Once you stop to think about it, you might easily say yes. Ditto for indigestion or trouble sleeping or diarrhea. The very act of asking about a symptom can trigger a positive response.
If a researcher informs subjects in a clinical trial that the drug being tested is capable of causing headaches, indigestion, insomnia and diarrhea, the volunteers might very well be super vigilant for such complications. Even if they were to get the placebo, they would be primed to report one or more of those side effects.
When the data are analyzed, the company might report that the volunteers getting active drug complained of headaches 7% of the time. The participants in the placebo group noted headaches 6.8% of the time. The conclusion might be that there is no difference between the two groups and that the drug does not cause headaches.
Of course, that would be false; the placebo group was primed to report such an adverse reaction. To read more about this flaw in the system, check out this article. It discusses a landmark study by Dr. Jerry Avorn and colleagues involving antidepressant medications. It was published in Drug Safety in 2009.
Overlooking Adverse Drug Reactions!
There is another very serious flaw in the way pharmaceutical companies collect drug side effect information. If they do not “catch” an adverse reaction during the smallish preliminary phase 2 safety studies, they are not likely to look for an adverse reaction during the major clinical trials.
Unfortunately, prescribers don’t always recognize this shortcoming. We can’t tell you how often a reader has written to say that their physician dismissed a problem with the drug because he or she couldn’t find the side effect listed in the prescribing information. Yet adverse effects often crop up long after drug approval.
Prozac and Sexual Side Effects!
One example of this is the antidepressant fluoxetine (Prozac). When the FDA first approved this drug for depression, the prescribing information suggested that a relatively small number of people (3%) might have sexual difficulties while taking the drug.
Little by little, patients and their doctors began to realize that was a serious underestimate. As many as half of patients on fluoxetine in one study had reduced libido, erectile dysfunction or trouble achieving orgasm (Journal of Nervous and Mental Disease, April 2013). In other studies of healthy individuals, the rate rose as high as 80 percent (Journal of Clinical Medicine, Oct. 7, 2019).
This kind of adverse drug reaction is not one people are eager to discuss, so if the study supervisors waited for spontaneous reports, they could have missed the signal on what turned out to be a common rather than a rare side effect. Early clinical trials usually don’t catch suicidal thoughts and acts either. It seems counterintuitive that a drug for depression might trigger suicide.
Other Examples of Missed Drug Side Effect information:
Statins and Blood Sugar:
We cannot tell you how many times clinical trials completely missed catching serious drug side effects. Statin-type cholesterol-lowering drugs can raise blood sugar. People with diabetes may also have a harder time controlling their blood glucose when put on a statin.
Our readers told us about these complications in 2002, long before the FDA or the companies discovered them. You can read the sad saga at this link.
Zolpidem and GERD:
Our readers alerted us to heartburn associated with the sleeping pill zolpidem (Ambien). The official prescribing information lists “gastroesophageal reflux disease” (GERD) and abdominal discomfort at 1%. Judging from reports from our readers, though, the incidence could be significantly higher.
Cetirizine and Rebound Itching:
We had to arm wrestle the FDA to look into rebound itching when people stop the antihistamines cetirizine (Zyrtec) or levocetirizine (Xyzal). This complication was not discovered during clinical trials of these allergy meds. There is no warning on the OTC labels of these antihistamines. You can read about this problem here.
Fluoroquinolones (FQs) & Tendons & So Much More:
The tongue twister fluoroquinolones (FQs) may not be familiar to you. These are antibiotics such as ciprofloxacin (Cipro) or levofloxacin (Levaquin). They used to be prescribed regularly for sinusitis, cystitis, prostatitis, bronchitis and skin infections. They were perceived as highly effective and quite safe.
Long after these drugs were approved and prescribed promiscuously, it was discovered that they could cause devastating complications including:
“…disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system.”
In 2018 the FDA warned about new safety problems such as:
“…disturbances in attention, disorientation, agitation, nervousness, memory impairment and delirium. In addition, the FDA is concerned about the potential for hypoglycemic coma. This occurs when blood sugar levels drop precipitously. Hypoglycemic coma is a potentially life-threatening complication.”
We started asking the FDA about FQ dangers to the heart and the aorta in 2014. That’s because readers had alerted us to the risk of aortic aneurysms and other serious vascular complications. There was nothing in the prescribing information. It took the FDA until December 20, 2018 to warn that FQ antibiotics were linked to :
“ruptures or tears in the main artery of the body, called the aorta. These tears, called aortic dissections, or ruptures of an aortic aneurysm can lead to dangerous bleeding or even death.”
Can You Rely Upon Drug Side Effect Information?
I could go on and on citing example after example, but you should be fed up by now. The bottom line of this article is that you may not be able to rely on official prescribing information when assessing possible side effects of your medicine.
The FDA does not seem terribly concerned about the ways drug companies have been able to manipulate the collection of adverse drug reaction data. Norwegian researchers describe “biases in reporting of adverse effects in clinical trials” in Basic & Clinical Pharmacology & Toxicology, Dec. 2022.
The authors report that:
“The lack of common definitions and monitoring methods for adverse effects is likely to be valid across all medical areas and is potentially a large source of bias.
“Bias may be expected if study design is suboptimal, patient monitoring not clearly defined, outcomes diffuse, and reporting selective. For readers, absence of relevant data may be difficult to notice unless an article is subjected to close scrutiny.
“Our findings confirm the results of other researchers and show considerable pitfalls in identification and reporting of adverse effects in clinical trials. Some biases are caused by methods choices including study design and patient monitoring, and others are caused by use of thresholds, filters, and selective reporting.”
What Can You Do?
If you cannot rely on the FDA-approved information found in DailyMed, then you certainly cannot rely upon the drug side effect information found during an online search. Remember, everything traces back to the official prescribing information. If that is flawed, then all the databases are equally flawed.
What can you do? First, trust your body. If you suspect an adverse reaction to a medicine and it is not listed as a drug side effect, you may be right and the official prescribing information may be wrong.
Discuss your concerns with your doctor. If she dismisses the problem because it is not listed in her drug side effect information, point her to this article. It just might convince your doctor that her computerized drug database is not all it’s cracked up to be.
Please share your thoughts in the comment section below. If you have ever experienced a drug side effect that was not “officially” recognized, please relate your story.
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