Tylenol has been in the news lately, and while there isn’t any new science to discuss, it’s worthy of some attention, as it illustrates how safety data is used to constantly evaluate the risks and benefits of a drug.
In the case of Tylenol (aka acetaminophen or paracetamol or APAP), the issue is liver toxicity. While acetaminophen is exceptionally safe when used at appropriate doses, at excessive doses, it is highly toxic to the liver. Take enough, and you’ll almost certainly die of liver failure. Acetaminophen poisonings, whether intentional or not, are a considerable public health issue. In the USA, it results in 56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year.  Overdoses are treatable if identified early, and liver damage can be avoided or minimized in mose cases.  But due to its widespread use, acetaminophen is responsible for more overdoses, and overdose deaths, than any other drug.  So the FDA’s discussion was one of risk versus benefit: How much harm do we accept with a drug, before we decide its risks outweigh its benefits to society? And given the overwhelming majority of use cause no health problems, is there anything that can be done to reduce the risk of overdoses?
On June 29 and 30, the FDA held a series of hearings to address this problem. But the issue isn’t just plain Tylenol. Acetaminophen is in hundreds of prescription and non-prescription products, and is used at all stages in life, starting with infant versions. 28 billion doses of acetaminophen were consumed in the USA in 2005.  Acetaminophen is the usual drug of choice for conditions like arthrtis and headache. And hydrocodone-acetaminophen combination drugs (i.e., Vicodin) have been the most frequently prescribed drug for over 10 years. 
How can a safe drug also be toxic? It’s all in the science of metabolism.
Once swallowed, acetaminophen is quickly absorbed from the gastrointestinal tract into your bloodstream but about 25% of the drug is immediately eliminated by the liver.  The liver converts this foreign substance into something that is easy to eliminate through the kidneys and into the urine – and that’s where the risk of toxicity comes from.
There are a number of different enzymes in the liver that act on acetaminophen.  The main metabolic pathways, sulfation and glucuronidatation, transform acetaminophen into harmless products that are easily and quickly eliminated in the urine. In overdosage situations, these pathways become clogged, saturated, and eventually exhausted. Other metabolic pathways kick in. Unfortunately, these other pathways create toxic versions of acetaminophen that attach to, and destroy, liver cells. So at normal doses, acetaminophen causes no toxicity. At high doses, liver injury is almost a certainty. This chart illustrates the science of metabolism and toxicity: Blue is good, and red is bad.
What leads to poisonings?
While many acetaminophen overdoses are intentional poisonings, a significant (and increasing) number of cases are unintentional.  In adults, the maximum recommended dose within a 24 hour period is 4000mg. That’s eight extra-strength (500 mg) Tylenol tablets, or twelve regular-strength (325 mg) tablets. This dosage is generally safe in adults regardless of other illnesses or medical conditions. A single dose of 7,500mg can cause liver injury, and consumption of 10,000 to 15,000 mg can be fatal.  It’s important to note that 4000mg is the maximum daily dose from all sources – and that’s where many accidental poisonings come from. Combining cough and cold products, or taking too many painkillers, bumping your total daily dose slightly over 4000mg in 24 hours is unlikely to cause any harm. But take enough, or do this consistently (say in the case of someone taking excessive doses of Vicodin or Percocet) and it’s easily to picture a situation where liver toxicity can result. Taking 5,000 to 8,000mg per day, regularly, can lead to liver problems.  Chronic consumption of acetaminophen is a problem that pharmacists encounter often – I’ve personally met patients taking well over a dozen Percocet per day, for weeks or months. They are surprised when I tell them my concern isn’t the dose of the narcotic, but rather the huge amount of acetaminophen they’re consuming daily, doing almost certain damage to their liver.
Another form of accidental poisoning is due to inappropriate dosing, particularly in children. Acetaminophen is dosed by weight, and there are two different concentrations of liquid available – infant drops, and and a syrup for older children. When you’re a sleep deprived parent, trying to give your a teething infant a dose of Tylenol or Tempra in the middle of the night, without turning on too many lights, it’s easy to get the dose wrong. Fortunately, the risk to a child from a single modest overdose (e.g., a double dose) is negligible. But the dosing calculations can be confusing and it’s not surprising that this is the source of a lot of reported poisonings.
The awareness of the risks of acetaminophen overdose may not be well understood by the public, according to the FDA.  Given that it’s been around for decades, is essentially free of side-effects, and available in huge quantities, consumers may not understand the significant risks of excessive doses.
What did the FDA discuss?
Here is a summary of the some of the advice the expert panel gave the FDA, and my comments. This is an expert panel, and the FDA can accept or reject the advice given. But traditionally, advice of this type is usually accepted.
Should the maximum daily dose (4000mg) (all sources) be lowered?
The committee voted in favour of this motion, 21-16. (yes vs. no) The reason for reducing the maximum daily dose would be to reduce the likelihood that patients would repeatedly take more than a safe dose. There is debate around the 4000mg maximum dose, and data was submitted to support the maintenance of a 4000 mg maximum. 
Should the maximum adult single dose (currently 1000mg) be lowered to 650mg (two regular strength tablets)?
The committee voted in favour of this motion, 24-13. This question is similar to the last question. By reducing the maximum recommended single dose, the likelihood of taking an excessive daily dose is lessened.
Should the current maximum OTC dosage (1000mg) be changed to prescription only?
The committee voted in favour of this motion, 26-11. What this essentially means is that the 500mg (“extra strength”) tablets would disappear from store shelves, and become available by prescription only. This would be a situation similar to other painkillers: lower doses of drugs like ibuprofen (Advil) and naproxen (Aleve) are available without prescriptions, and higher doses require a prescription. Of course, a determined patient could take a dose that’s beyond the maximum recommended, but we would expect this to be less likely to occur. There may not be much difference in efficacy, in any case.
Should pack size limits be implemented for non-prescription acetaminophen?
The committee did not support this motion, voting 17:20. One strategy used to reduce the risk of intentional and unintentional acetaminophen overdoses is to make it available for sale in smaller package size: In England, plain acetaminophen is available only in small pack sizes: 32 tablets per package in pharmacies, and 16 tablets when purchased from other settings. Quite a contrast from the 200-count (and up) bottles you can find on pharmacy shelves in North America. The data on whether this reduces overdoses does not seem conclusive – and it appears that was not convincing to the expert committee.
Should combination over-the-counter products be eliminated?
This motion was firmly rejected, 13:24. This would eliminate a huge number of non-prescription cough and cold products from the market, including products like Tylenol Cold, Tylenol Sinus, and NyQuill. The risk with these products is that consumers may not realize they contain acetaminophen, and take another product as well, possibly consuming an excessive dose. However, the benefit to combination drugs is that they simplify the dosage calculations – you only have to take a single dose, rather than two or even three different cough and cold products. It’s likely we can expect new labelling with large-print warnings about the acetaminophen content.
Do you recommend only one concentration of acetaminophen liquid be marketed?
This motion was weakly supported by the committee, 19:18. The advantage of the concentrated infant liquid is that only a small volume needs to be administered, and it can be easily measured with an oral syringe. Older children can swallow larger volumes and so their medication is measured with a small cup. The challenge, as I’ve already noted, is for parents to keep the dosing instructions clear. Based on the vote, it appears that there is support for both arguments.
Do you recommend eliminating combination prescription products?
This motion was supported by the commitee: 20-17. Drug abuse/misuse issues related to combination narcotic/acetaminophen products are well known. By eliminating these products, patients will need to take other combination products. The elimination of these products will dramatically change prescribing patterns, and may seem catastrophic to some patients: Combination products like Percocet, Vicodin, and Tylenol #3 are among the most-prescribed (and dispensed) drugs in the world. They’re inexpensive (as generic versions exist) and used for a huge variety of conditions. And single-ingredient (“straight”) narcotics often have much more stringent prescribing requirements. For example, in Ontario, pharmacists can accept verbal (telephone) prescriptions from physicians for combination narcotics, but cannot do so for straight narcotics.
Do you recommend (a) “unit-of-use” packaging for prescription combination narcotics (if still marketed) and (b) boxed warnings for these products?
Both motions were supported by the committee: 27-10 and 36-1. Unit of use packages are pre-packaged versions of prescription drugs that are not broken down by the pharmacist – a label is simply stuck on the box. It ensures that package inserts (and product warnings) reach the patient. The boxed warning was strongly supported by the committee. Unit-of-use packages have a significant downside: packaging waste. Given that painkillers are given out in varying quantities, patients could potentially receive dozens of small boxes with identical inserts, all of which would be discarded by the patient.
Safety profiles of drugs evolve over time. Acetaminophen is a remarkably safe and effective drug that is also associated with significant medical problems in a small minority of patients. Over the past several years, the FDA has taken some steps to reduce the incidence of acetaminophen poisonings. Poisonings continue to be a significant public health issue. But is acetaminophen safe? When used at the appropriate dose, yes. If you’re following the directions correctly, there’s little reason to be concerned. Adults need to ensure that their total daily intake (from all sources) does not exceed 4000mg. If you are in doubt about whether a product contains acetaminophen, ask your pharmacist.
In light of the panel’s recommendations, watch for changes on your pharmacy’s shelves in the future – your favourite “extra strength” product may soon disappear. And be prepared to say goodbye to Percocet, Vicodin and Tylenol #3.
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