Terra Sigillata

Perhaps you’ve stumbled on this post late at night while tending to a child suffering from a cold.

Well, I’ve been reading a fair bit lately about the 18-19 October meeting of the FDA’s joint meeting of their Nonprescription Drug and Pediatric Advisory Committees, trying to make sense about calls to restrict or prohibit the use of cough and cold medicines in children under age 6. There is so much material on the subject that I have hesitated to post on the issue until I received the following e-mail from an old friend, fellow scientist and parent, North of 49:

Okay, so I’m writing to you to in order to prod you to open up a discussion on Terra Sig about the FDA recommendation that cough and cold medicines not be administered to kids. As a pharmacologist, what are your thoughts on this? What about as a parent?

According to the FDA’s own report, only 11 [efficacy] studies (in humans) have been done on these compounds, and even they admit that many of these were scientifically flawed. Yet, the FDA panel voted (13-9) to recommend stopping the use of cough and cold meds for kids [aged 2 to 5 yrs]. My feeling is that this is likely because of the deaths that have resulted from their improper use – A quick check, however, reveals that since 1969, 123 kids have died. This sounds like a lot, but when you calculate the number of doses that must have been given in the 38 yr time period, and the fact that (according to the FDA) a number of deaths were the result of parental error (either overdose of using multiple meds with similar active ingredients), it seems to me (as a humble physiologist) that your chances of being struck by lightning are higher if the meds are used properly – In fact, your chance of being struck (and killed) by lightning are approximately 20-fold higher – In the USA every year, 73 people die after being struck by lightning!!! (source)

Damn you Mother Nature!! Perhaps the FDA will recommend that we never go outside.

Also, the odds of death by a spoonful of medicine don’t even come close to the matching the odds of what we would (rationally) consider highly, highly improbable events:

Odds of fatally slipping in bath or shower: 2,232 to 1
Odds of getting away with murder: 2 to 1
Odds of dating a supermodel: 88,000 to 1
Odds of being on plane with a drunken pilot: 117 to 1
Chance that Earth will experience a catastrophic collision with an asteroid in the next 100 years: 1 in 5,000
(source)

Please guide us in this important discussion, o wise one.


Long story made short, I share the sentiments of North of 49. The benefit of decongestants for our PharmKid have far, far outweighed any risks – and the risks are indeed negligible.

Here is a brief description of the purpose of the 18-19 October meeting of the FDA Nonprescription Drug Advisory Committee:

…the Agency has received a Citizen Petition requesting that action be taken to re-label cold and cough products to say that they have not been found to be safe or effective in children under the age of 6 for treatment of cough and colds, and that the products should not be used for treatment of cough and colds in children under 6 years of age. The Committee is being asked to evaluate the data that will be presented in regards to the efficacy and safety of these products.

I took a look at the 356-page(!!!) “briefing document” for the meeting and found that most of the adverse events and deaths were due to inappropriate/over-dosing. (Click the following link only if you want to download the full 356-page PDF document.). Inappropriate dosing can result from the lack of a standardized measuring cup or syringe or, as most parents find, kids spit out the medicine and then you have to guess how much got in and how much more to give.

As noted by North of 49, the FDA has compiled between 1969 and Fall, 2006, 54 pediatric deaths associated with the use of decongestants (e.g. pseudoephedrine, phenylephrine) and 69 deaths from antihistamines (e.g., diphenhydramine, bromphemiramine, carbinoximine). The “Citizen Petitioner” is a group of Baltimore area academic pediatricians (from Johns Hopkins and Univ of Maryland) and Baltimore City Health Department officials led by Commissioner of Health, Joshua M. Sharfstein, MD.

Beyond these drug-associated fatalities, the petitioners also point out that published studies have not shown any efficacy of antitussives, antihistamines, or decongestants against cough and cold symptoms in young kids – that is the main crux of their argument: these agents are potentially unsafe and there is no need to use them anyway because they lack clinical efficacy.

One FDA review of this limited literature (only 11 studies) points out that the most common endpoint measured was cough frequency (where the data was indeed unimpressive) and that it is much more difficult to for little kids to define relief from congestion and inflammation with decongestants and antihistamines.

So, are these drugs ineffective or does pediatric study design simply make it difficult to demonstrate efficacy?

While we scientists are not ones to make conclusions based on anecdote, I can tell you that our daughter responds beautifully to decongestants especially when she has sinus or ear problems, improving her quality of life as much as it does ours! However, I am especially careful about reading too much into my own experiences because I have cautioned users of herbal and other alternative medicines not to rely on anecdotes as proof of efficacy.

Of course, I cannot imagine the pain of those parents who have lost children due to adverse effects of these drugs. My intention is not to minimize the gravity of these losses. But the point by North of 49 about relative risk made is well-taken. The FDA report indicates that in 2006 alone, 3.9 million prescription cough and cold remedies were sold for use in children 0-6 years old; the databases were unable to give information about total OTC use of these products. However, in the overall (adult + pediatric) US cough and cold market, prescriptions accounted for only 19% of these products. So, there could be another 20.5 million boxes/bottles (3.9/0.19) of products sold per year. Let’s round that off to a combined 25 million units of Rx and OTC cough and cold products per year. (Gardiner Harris at the New York Times came up with a value of 95 million boxes/year representing 3.8 billion doses but I am unable to confirm a source for that number.).

Using a conservative average of 10 million units being sold per year between 1969 and 2006 – that’s a total of 123 reported deaths over the use of 370 million boxes of cough/cold remedies, or 1 death per 3 million boxes.

To put these 123 deaths in perspective, 4767 US teenagers died in motor vehicle accidents in 2004 alone (CDC), or the equivalent of 123 deaths every 38 days, not 37 years. Safety of anything is never absolute, especially across a diverse population of 300+ million US citizens. The goal of drug safety officials or motor vehicle regulators is to minimize risk of injuries or death from use of a product. For example, we do not outlaw automobiles – we try instead to make them safer with seat belts, airbags, child safety and booster seats, etc. (all of which present their own, much smaller risks).

Therefore, the discussion I might expect from readers is whether the lack of documented “clinical efficacy” of children’s cold medicines truly reflects real-life efficacy as observed by parents. Again, this gets into the dodgy issue of having two standards for medicine: we live and die by RCTs for adult medicines but should we make an exception for observational, anecdotal endpoints in pediatric medicine because we parents think we see that the cold medicines are helping our kids? I’d greatly appreciate any input from pediatric clinical trialists on this issue.

But as a parent willing to accept the risks for my perception that my child benefits from OTC cough and cold medicine, I’ll be ticked off if the FDA removes all products intended to treat kids between 2 and 5. A patient representative quoted in a 19 October New York Times article remarked on a new concern that might then emerge: that parents would then try to give their kids reduced doses of adult cough and cold meds using pill cutters and such – a formula, I think, for far more dosing errors. (As North of 49 points out more eloquently, “I too am concerned that parents (if deprived of child-strength formulas) will attempt to harness the full power of their mathematical acumen towards doing dilutions of adult remedies.”).

Linda A. Suydam, D.P.A., president of the trade group, Consumer Healthcare Products Association (CHPA), noted that current government regulations still classify these cough and cold remedies as safe and effective, a pronouncement passed in the 1960s by the Drug Efficacy Study of the National Academies of Science. The deliberations of this panel, convened by FDA in April 1966, was charged with reviewing drugs that had been marketed between 1938 and 1962 for their safety and efficacy without having to conduct the prospective clinical trials required for drugs introduced after 1962.

The industry has already issued a voluntary recall of cold remedies for infants under age 2 as dosing guidelines are not clear for little ones whose drug metabolizing enzyme systems are still developing. The label directions of “ask your doctor” for dosing infants under age 2 were deemed uninformative for most parents and CHPA supported withdrawal of this use for these remedies.

However, restrictions on availability of cough and cold remedies to children aged 2 to 5 seems ill-advised. The CHPA maintains on their website, OTCsafety.org, some general information on cough and cold remedies use in kids, including tips to parents on how to dose children properly. CHPA also intends to support clinical trials of some cold remedies to test their efficacy and pharmacokinetics to investigate whether toxic levels can be achieved with normal dosing guidelines.

Disclosure: Neither Abel Pharmboy or North of 49 derive any research support or other financial compensation from manufacturers of cough and cold remedies.

Comments

  1. #1 decrepitoldfool
    October 29, 2007

    My first thought was that a lot of parents would try to figure out how to dose their kids with adult meds. The idea of banning seems to ignore that real-world probability. Besides, when my kids were little we found that the OTC meds did help, no question about it. No, they didn’t kill cold germs but they let everyone, most of all the suffering child, get a little much-needed sleep and we all, most of all again the child, felt better in the morning.

  2. #2 Joseph j7uy5
    October 29, 2007

    I do have the impression that the FDA is being unduly restrictive. The cynical side of me wonders if the absence of non-prescription products in this area will open up a market for prescription products. The noncynical part of me says I should not think that way.

    On a more practical note, I think that the labels for these products are indeed confusing for people. Most people have no idea that, when they are looking at a mind-boggling array of boxes, there are really only a few active ingredients represented. I would prefer that the most prominent part of the label include the generic names for the product, with the flashy logos and brand names being smaller. I also would prefer that OTC products contain only one active ingredient.

  3. #3 davidp
    October 30, 2007

    The cough remedies do not help coughs. That is grounds for removal from the market. The anti-congestants’ effectiveness is much harder to measure.

    They do seem to help breathing and infant breast-feeding, but I don’t know of good trial results for this.
    They have been shown not to prevent progression to inner ear infections.

    A digression: I was impressed by the placebo effectiveness when I unintentionally gave an anti-congestant instead of a painkiller at 3am. It worked beautifully – baby soothed and back to sleep promptly, but that was for a child conditioned by previous experience of effective analgesia.

  4. #4 Mager
    October 30, 2007

    You talk much about (the really low) risk – but we should focus on PROVEN benefits. If there are not benefits, ANY risk is unaccepable! Unfortunately, after tens of years of use, we don’t have a proof of benefit -> so, let’s dump these dangerous placebos!

  5. #5 Fillippelli the Cook
    October 30, 2007

    I agree that it would be foolish to remove products from the market that work. I also agree that the cough remedies we have tried do not work, while the decongestants seem to offer some relief, at least some times. Based on my experience as a parent scrambling around in the middle of the night, half asleep, to find the decongestant and deliver it to a groggy, miserable kid, I’m surprised that there have not been more deaths from overdosing. I would be willing to wager that a lot of kids have gotten sick, just not been killed, as a result of cold medicine overdosing.

  6. #6 DuWayne
    November 1, 2007

    You talk much about (the really low) risk – but we should focus on PROVEN benefits. If there are not benefits, ANY risk is unaccepable! Unfortunately, after tens of years of use, we don’t have a proof of benefit -> so, let’s dump these dangerous placebos!

    Hmmm. Instead of dumping them, what about forcing some legitimate studies instead? It seems to me that the problem is lack of empirical evidence, rather than lack of effectiveness. Considering the very low risk involved, I would be content to see some studies, rather than just dumping them. Especially given the propensity of people to attempt to figure out the proper dose from the adult strength drug, which would be far more dangerous.

  7. #7 Abel Pharmboy
    November 2, 2007

    Here’s something I missed from the Wall Street Journal’s resident family doc, Benjamin Brewer, MD:

    The runny nose started in the morning. By bedtime, a cold had settled in my 3-year-old son’s chest, and a deep, hacking cough could be heard throughout the house.

    At 1 a.m., my wife gave me the look that said: “You’re a doctor; do something.”

    After the recommendations against over-the-counter cold medicines came out, we heeded them for less than 24 hours in our house. Once my sick son took the medicine, his sniffles and coughing abated a bit. His symptoms returned later that day, after we discontinued the treatment. Our experience showed that whatever mild benefits these medications offer, they don’t last long.

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