May 10 2012
Consider this scenario: You’re in good health and take no prescription drugs. You use the following remedies occasionally:
- Excedrin for the rare migraine
- Arnica 30CH for bumps and bruises
- Echinacea capsules, when you feel a cold coming on
Today you look in your cupboard, and notice all three products expired last year. Would you still consider taking any of them? Why or why not?
Your answer is probably influenced by a number of factors, including perceptions of risk and benefit. I’ve encountered patients who believe that drugs are less active as they near the expiration date, and others who see expiry dates solely as marketing ploy from Big Pharma. Few understand how they’re calculated.
Over the past few months I’ve written several posts on different aspects of drug development and testing, including drug interactions, fillers and excipients in drug products, the equivalence testing of generic drugs, and the management of drug allergies. I’ve done this for two reasons. The first is to develop a SBM-oriented resource for common questions and misconceptions about the mechanics of modern medicines. The second, less obvious reason for these posts has been to illustrate the serious credibility gaps with CAM therapies. Largely because of a lax regulatory framework, the CAM industry has ballooned into a multi-billion dollar market without answering basic questions that should be asked of any supplement or drug, “alternative” or otherwise. What’s not well known to consumers, but is glaringly obvious to SBM advocates, is that CAM largely ignores issues of pharmacology: understanding how a chemical substance, once consumed, behaves in the body. It’s critical to scientific medicine, but an unnecessary step for CAM, where there’s no need to determine if a product has a beneficial biological effect before selling it. Fundamental tests in medicine, like the identification and isolation of an active ingredient, or understanding dose-effect relationships, are simply ignored. As David Gorski and Mark Crislip have pointed out over the past week, we have a reality bias at SBM. And this bias is equally jarring when it comes to considering expiry dates for products: real drugs, and also CAM.
Expiry dates are the source of a lot of questions to pharmacists. Not only is the pharmacy legally responsible for ensuring your prescription is filled with “in-date” stock, we’re regularly confronted with dealing with expired drugs. Because of expiry dates, an enormous quantity of drugs are manufactured and sold or dispensed, but never consumed. This creates a significant wastage issue: Last month, the U.S. Drug Enforcement Administration’s National Prescription Drug Take-Back Day collected 552,161 pounds (that’s 276 tons) of unwanted or expired drugs. Those are drugs that someone paid for, and are now being incinerated. If expiry dates are nonsense, extending them could have considerable economic and environmental benefits. So where does the expiry date come from? For drugs, they’re based on the chemical characteristics of the product itself.
Calculating the expiry date
At some point after major clinical trials are concluded, but before FDA approval, a series of quality standards are established for each new drug. These are the manufacturing and testing specifications, which includes upper and lower limits for the amount of the Active Pharmaceutical Ingredient (API) in each dose unit (e.g., 500mg per tablet). The final dosage form may be a mix of the API as well as fillers, binders, and other ingredients to ensure the API is delivered to the body in a reliable and predictable manner. But what certainty do we have that this new dosage form will maintain all of these properties over time? What happens after it sits on a shelf for two or three years, or more? Few companies have the patience to wait, so drug products are put through accelerated degradation testing, or “stress” testing, to estimate how quickly a drug will deteriorate. Depending on the dosage form, stress testing may include short-term exposure to extremes of heat, light, oxidation, and humidity. After exposure over different time periods, the quantity of the API, and the other product characteristics, will be assayed again. Not only does this help us understand how stable a drug is, it illustrates the degradation pathways – what chemical reactions that could be expected to occur over time. For liquid and injectable drugs, there will be additional tests for bacterial purity and chemical stability. All of these tests predict the overall stability of the dosage form – not just the amount of drug, but how that drug will be absorbed into the body. All of this is used to estimate what the expiry date should be: the date to which the manufacturer warrants the original product characteristics will be retained.
Expiry dates for drugs can vary dramatically. One of the shortest for a drug in common use is injectable epinephrine known as the “Epipen”, carried by those with severe allergies. Epinephrine for injection is notoriously unstable, and you’re lucky to find a product that expires longer than 18 months after you get it. Other drug products are highly sensitive to moisture, requiring dispensing in specialized containers with dessicants to trap moisture and enhance stability. Many liquid antibiotics have very poor stability, so they must be prepared in the pharmacy at the time of dispensing. Refrigeration is necessary for other drugs, ranging from vaccines to eyedrops, which keeps the dosage form stable.
It is important to keep in mind that the expiry date of a drug is based on testing of previously unopened products, stored in its original container, and maintained under typical conditions. Once you open a bottle, or transfer it to another container (like a prescription vial), the manufacturer’s expiry date is no longer reliable. That doesn’t mean a drug will become ineffective rapidly, but the stability could be compromised once it has been introduced to light, heat, and humidity. Humidity’s effects are frequently noticable with old bottles of Aspirin (acetylsalicylic acid) which breaks down via hydrolysis to salicylic acid and acetic acid giving old bottles a characteristic vinegar odour.
Are expired drugs still safe?
The first concern related to expired drugs is whether they are potentially harmful if consumed. Reassuringly, there is no published data to suggest harms from use of drug formulations after their expiry data. The example of degraded tetracycline causing kidney damage in cases dating back to the 1960′s, is drilled into every pharmacist’s brain. Reassuringly, this occurred with a version of the drug that is no longer available. While recognizing that case reports are an inaccurate and imprecise way of identifying harms, the lack of documented harms suggests that degradation of useful chemicals into toxic compounds is rare, if it occurs at all. Additionally, current requirements for stability testing of drugs should identify if expired products pose a safety risk – and there do not seem to be any other documented cases.
Are expired drugs still effective?
Again, the evidence is reassuring – with some caveats. The best way to verify long-term stability would be to stockpile supplies, let them sit for years, and even decades, and then test them. My American colleagues can thank their government for doing just such testing- the Department of Defense/FDA Shelf Life Extension Program has been in place for over 20 years. It tested 122 different products, stored unopened and in their original containers, and found that about 88% are stable for at least one year after expiry with an average of 5 years after the expiry date. However, this was under ideal conditions – not typical use consumer use, where bottles are usually partially consumed, and partially exposed to moisture and light. Stability isn’t always a given. Epipen’s active ingredient degrades consistently after the expiration. So I’d never suggest people carry an expired Epi-Pen – but I wouldn’t hesitate to recommend its use in life-threatening anaphylactic situations where no other alternatives existed. Similarly, you may be less concerned about drug potency if you’re taking something like Excedrin for a headache, versus medication to treat epilepsy, where small changes in the dose delivered could affect drug levels. Because of sterility concerns, you should throw out an eye drop that has been open for several months, even if the expiry date still says it’s OK to use – that expiry date was for unopened drug. And if you leave your prescriptions to cook on the dash of your car in the hot sun (I have encountered this) speak with a pharmacist who may be able to get drug-specific stability data.
Disposing of expired drugs
I was surprised to see that the FDA suggests some drugs can be safely disposed of by flushing down the toilet. I could not find similar guidance in Canada, where medication return programs are common and many pharmacies participate. Return program incinerate the drug, eliminating secondary environmental exposure. This method also minimizes the risk of diversion or accidental poisoning.
Revisiting our vignette
Excedrin is a combination of acetaminiophen (Tylenol), acetylsalicylic acid (Aspirin) and caffeine. Excedrin may be effective after expiration – but sniff for the vinegar odour, which indicates the ASA has deteriorated. Expired Excedrin is unlikely to be harmful, but has the potential for degradation over time.
Arnica 30CH is a homeopathic product. It has no active ingredients, and no meaningful therapeutic effects, so there’s nothing to “expire”. However, regulators like Health Canada insist that an expiry date must be assigned:
Expiry date: The earlier of:
the date, expressed at minimum as a year and month, up to and including which a NHP [Natural Health Product] maintains its purity and physical characteristics and its medicinal ingredients maintain their quantity per dosage unit and their potency; and
the date, expressed at minimum as a year and month, after which the manufacturer recommends that the NHP should not be used.
Given homeopathy, once diluted to typical concentrations, contains zero active ingredients, I’m curious why Health Canada allowed language like “medicinal ingredients” and “quantity per dosage unit” for establishing standards for what are quite literally sugar pills. The FDA, to its credit, recognizes that the non-ingredients of homeopathy can’t be measured and can’t expire:
1. Section 211.137 (Expiration dating) specifically exempts homeopathic drug products from expiration dating requirements.
There’s no good evidence to demonstrate echinacea is effective for preventing or treating colds. The active ingredients, if any exist, have not been identified and isolated. Capsules of echinacea usually contain pieces of the root or rhizome. Given the active ingredient isn’t known, there’s no way to test for its presence. And if you can’t verify the amount of active ingredient in each capsule, you can’t verify its stability over time. So for herbal products without standardized active ingredients, any expiry date is going to be arbitrary – unrelated to product quality or safety. Not surprisingly, the FDA does not require expiry dates to be placed on dietary supplements, an acknowledgement that you can’t verify what you haven’t found. In contrast to the FDA, Health Canada requires an expiry date to be assigned for herbal products.
There’s no single rule for expired drugs and supplements, owing to the variety of products, regulatory requirements, and other factors that can influence a product’s safety and efficacy. In general, expiry dates are conservative, and consumers can have confidence that drug labeling claims will be accurate up to, and in some cases well beyond, the labelled expiry date. The reality is that we don’t store drugs under ideal circumstances. So when absolute certainty is required, stick to drug products that are not expired. When absolutely necessary, expired drugs are probably safe, however, the potency may be compromised. And when you’re talking about supplements, herbals, and homeopathy, keep in mind that any expiry dates are usually arbitrary. And before you flush or toss those expired drugs, find ways to dispose of them in a way that minimizes the environmental impact and potential for harm.
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