Scenario: You’re out in the field when an NCO approaches you about spraining his ankle during one of the last movements through some rough terrain. “It’s not that bad,” he tells you, “I just want some ibuprofen for the pain. Can you help me out?” You reach into your bag and pull out your favorite go-to pain medication: 800mg ibuprofen. As your about to pour some out into his outstretched hand, you pause.
On the side of the bottle is clearly printed “EXP: 08/27/2016”.
It’s January 7th, 2018.
That ibuprofen is about over a year past expiration.
“It’s just a date,” the NCO tells you, still holding his hand out. “I mean, it can’t hurt me that much, right?”
You agree, and hand him some tabs.
BUT, do you actually know whether or not the expired medication you just dished out will even work? Or, could it actually hurt him?
Fortunately, there actually is some research regarding this common dilemma to answer these questions, and NGCM is here to help distill, translate, and inform.
Expiration Dates and “Shelf Life”
According to the Code of Federal Regulations (CFR) regarding the “Current Good Manufacturing Practice for Finished Pharmaceuticals” (CFR 21, Chapter I, Subpart G, § 137) medication expiration dates exist to “assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use.” Prior literature has interpreted this regulation to mean that expiration dates are “an assurance that the labeled potency will last at least until that time” (although “potency” is not in the codes cited when we verified them at the time of publishing this article, but the terminology is similar).
In order for a drug to be efficacious (effective), we want to make sure that its potency/concentration/strength is enough to do its intended job (analgesia, fight infection, etc). The expiration date, in theory, is supposed to guarantee us how long a medication will technically be good for.
The shelf life, or time until expiration, is usually 12-60 months after production, but there is no FDA regulation specifically aligning a decline in potency levels with a specific date, meaning that pharmaceutical companies can (and do) arbitrarily establish expiration dates without any actual determination of stability beyond that date. This is good to know when you are a big-name pharmaceutical company looking to ensure you can turn out the newest product. You don’t want to have to wait 36 months before you can alter and re-market a current medication, so you say “testing said that it was fine at 18 months, so let’s just stop there as the expiration date.” Expert opinions support this scenario. FDA pharmacists have stated that expiration dates are generally based on marketing, rather than science and that they “typically have no bearing on whether a drug is usable for longer” than the date on the bottle.
The Shelf Life Extension Program: The Military’s Answer to Expiration Dates
Given short expiration timelines, it is easy to imagine how strict regulations on storage and shelf life would force the Department of Defense (DOD) to constantly turn over and destroy huge stores of unused medications. Approximately 25 years ago, however, a little-known initiative was started, and although it is not a secret, the Shelf Life Extension Program (SLEP) has certainly not made headline news. It is rather easy to find if you use an internet search (or simply click here to directly reach their official website).
The SLEP program operation is summarized here:
“Pharmaceutical drug products sealed in original container closures are stored under controlled conditions by the military services. Certain lots of drug product that are approaching their labeled expiration date are selected by the [Defense Medical Standardization Board] for participation in the SLEP program. Representative sealed containers of drug product from a given lot are submitted to the FDA SLEP coordinator… for testing by the FDA field labs… The FDA SLEP chemist evaluates the test results, approves or rejects the extension of the shelf life for that lot…” .
Now, we added a lot of emphasis at the end of that quote because it is an important point to stress. While the SLEP has provided some significant data, the approval for continued use of expired medications gives an expiration date extension for that lot only and does not apply broadly to other medications if it is outside of that lot that was tested, even if it is the same exact type of medication. Not much literature has been openly published directly from the SLEP crew, but they did publish some data a few years ago on the actual shelf life and stability of medications beyond their stated expiration date. But again, SLEP testing and approval are for the tested lot only, and cannot be broadly applied to all medications (including that bottle of half-used Motrin in your aid bag).
It is impressive, however, just how long some of these medications have been retained and deemed acceptable for continued use in the SLEP lots, despite being far past their expiration date. In all, of the 122 drug products that range from simple analgesics to antibiotics to intravenous fluids, 88% of lots have been extended beyond their stated expiration date. Below, we grouped together some common medications according to their uses and compiled their average lot extension times.
|Medication Type||Medication Generic Name||Average Extension Time in Months (Range)|
|Morphine sulfate (injectable)||89 (35-119)|
|Fentanyl citrate (injectable)||84 (70-96)|
|Ketamine HCl (injectable)||64 (42-87)|
|Naproxen (tablets)||52 (46-62)|
|Amoxicillin sodium (tablets)||23 (22-23)|
|Ciprofloxacin (tablets)||55 (12-142)|
|Doxycycline hyclate (capsules)||50 (37-66)|
|Cephalexin (capsules)||57 (28-135)|
|Ceftriaxone (powder)||60 (44-69)|
|Sodium Chloride||50 (12-113)|
|Dextrose (5%)||65 (13-128)|
|Lactated Ringer’s||53 (20-87)|
The conclusion, per the authors: “The SLEP data supports the assertion that many drug products can be extended past the original expiration date, but this additional stability period is highly variable. Due to the lot-to-lot variability, the stability and quality of extended drug products can only be assured by periodic testing and systematic evaluation of each lot. The results of this stability program can only be related to products that have been carefully stored in their original sealed container closures.” [emphasis added]
So, clearly, some medications have been proven to far exceed their expiration date and retain their potency/efficacy.
But, can’t you argue that this proves your 800mg ibuprofens are still good?
What does this generally mean for the use of the medications in your aid bag or aid station?
The Expiration Date and Redistribution of Medications
We discussed some broad FDA and USP guidelines and regulations above, but let’s bring it back to a more line medic-style focus.
How often have you been in the field, deployment, etc., with a bottle of 500 tabs, and you divvy them up into little baggies to hand out pill counts of 20, 30, or 40?
Well, do you know how this redistribution affects the expiration date?
The FDA released guidance that shortens the expiration date of these repackaged containers to either:
- the manufacturer’s printed expiration date (no change),
- 6 months from the date of repackaging, or
- 25% of the time remaining until the expiration date on the container of the original manufacturer’s product,
whichever time period is shorter.
So, here’s a helpful infographic summarizing these recommendations with an example:
Much shorter than you probably thought, right? However, it is important to note that there are several FDA-mandated “conditions” that come with its recommendations, two of the most relevant of which are below, with commentary:
- “the unit-dose container complies with Class A or Class B standards as described in USP General Chapter 671”. This chapter provides a “series of test methods specific to the functionality and performance of containers and package systems” to include: light transmission, container permeation testing, and barrier protection. Do you think that your old, clear, zip-lock-style plastic baggies that have been in your kits for who-knows-how-long add up to these standards?
- “the drug product’s original container has not been opened previously and the entire contents are repackaged in one operation.” Does this sound like that giant, 500-count bottle of Ibuprofen that you have been divvying out to your guys and gals throughout multiple field problems over the past year?
Most likely, the answer to both questions above is probably “no”. This means you are technically giving likely expired meds without any true FDA backing as to their efficacy and/or safety.
Mind blown, right?
But, hey, let’s work our way around that thought-provoking obstacle, and try to pretend that we are all not sitting here rethinking about how we have been repackaging and dishing out many of our commonly carried medications.
What about the stability and usability of meds that you haven’t opened yet? Ones that have just been sitting in your cage, connex, office, or aid bag, sealed in their original container, and have yet to be popped open and divvied up for use by your medics and troops?
Remember, that SLEP data cited above was only good to support the use of “that lot” stored under controlled conditions in accordance with manufacturer guidance.
Let’s Go Back to Shelf Life
The International Conference on Harmonization (ICH), often cited when discussing medication stability, defines shelf life as “the time period which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under conditions defined on the container label.” Similarly, an expiration date is defined based on a medication that is stored under “ideal manufacturer-suggested conditions of temperature, humidity, light exposure, and packaging integrity.”
First, think about whether or not you have actually been storing the medication under the conditions defined on the label (i.e. not in a blazing hot or freezing cold connex). While we will discuss below some of the published literature showing that going outside of these label specifications may not destabilize the medication to the point of making it unusable, it is important to note that medication shelf life and efficacy technically cannot be validated unless it has been stored appropriately according to its tested manufacturer standards.
The concern regarding temperature and climate controls with medication storage is a breakdown and/or decomposition of the drug and its active components or functional abilities. Extreme temperatures can cause significant degradation of medications by chemical reactions such as oxygenation (air) and hydrolysis (moisture).
However, recent literature from austere medicine supports the continuing use of medication that has been temporarily stored in extreme conditions outside of manufacturing recommendations as long as two conditions are met:
- The drug is not exposed to a maximum temperature constituting excessive heat for a period longer than 24 hours
- The mean kinetic temperature (MKT), or average temperature, for the drug remains at or below the maximum temperature of its ideal range
So, are your medications still ‘good-to-go’, despite being packed and shipped in connex containers, stored in trucks and aid bags?
Consider the following recommended storage temperatures for medications you likely carry or have access to in a field environment. (Note: In this analysis, “room temperature” was defined as 25°C/77°F) :
- Acetaminophen: “excessive heat” (>40°C [104°F]) should be avoid
- Albuterol inhaler: store at 15-25°C (59-77°F); to avoid bursting, do not exceed 49°C (120°F)
- Ciprofloxacin tablets: store tablets below 30°C (86°F)
- Doxycycline: store at room temperature
- Ibuprofen: store tablets at room temperature
- Morphine: store injection solution at room temperature. Brief excursions are permitted up to 30°C (86°F). Do not freeze
- Nitroglycerin: store capsules at room temperature; sprays may have brief excursions to room temperature
- Trimethoprim/Sulfamethoxazole (Septra DS, Bactrim): Store tablets at room temperature
Now, consider the following data:
- When 1:10,000 concentrations of epinephrine (the concentration used for an IV push in cardiac arrest) were exposed to 7 days of constant exposure at 65°C (149°F), there was “complete destruction” of the medication, essentially rendering it unusable. However, there was no evidence of an effect on the 1:1,000 concentration (for intramuscular use in anaphylaxis).
- A study of multiple pre-hospital medications in extreme temperatures found that when epinephrine, atropine, and lidocaine solutions were exposed to an MKT of 29°C (84°F) and showed no degradation for 45 days. However, the authors could only conclude that these drugs could tolerate spikes up to 52°C (125°F) for a cumulative time of up to 13 hours without degradation.
- A study of 0.3mg of 1mg/mL (1:1,000 concentration) epinephrine in clear syringes showed no breakdown based on light exposure; however, low humidity (15%) accelerated decompensation significantly. Epinephrine syringes in low humidity decompensated to less than 90% potency within 60 days, then dropped to 60%, 50%, and 39% potency by the end of 90, 120, and 150 days, respectively. (Do you know what the humidity is when you’re not in a clinic?). The authors’ conclusion? “In hot climates, if an unsealed syringe prefilled with an epinephrine dose is provided for the first-aid treatment of anaphylaxis, it should be replaced every few months on a regular basis with a new syringe containing a fresh dose of epinephrine.”
“But some of those study conditions were pretty extreme,” you might say.
“I know that my aid bag doesn’t get that hot,” you might also say.
But, do you actually know what your storage temperatures and environments have been?
Do you actually know what your storage temperatures and environments are right now?
The following is some data looking at medication storage conditions:
- In a study of personal emergency bags, internal bag temperatures of up to 80.2°C (176.36°F) were recorded.
- A study of internal temperatures within nylon aid bags stored inside EMS helicopters in Texas found that when compared to USP recommendations for room temperatures of 15-30°C (59-86°F), the aid bags failed to comply with USP temperature recommendations on an average of 49% of winter days, 62% of winter nights, 56% of summer days, and 27% of summer nights.
- A study of medication transportation on ships found large temperature ranges of -20°C (-4°F) to 40°C (104°F).
- A study of temperatures during transportation of medication on commercial aviation flights across climates found temperature ranges of -3.5°C (25.7°F) to 42.4°C (108.32°F).
Do these temperatures seem to be aligned with those found in the studies of aid bags and transports listed above?
Do they adequately reflect the conditions of your aid bag and transports? Are you sure?
Finally, a small but important note on initial drug concentrations:
The literature we found often cited (such as here and here) that the US Food and Drug Administration (FDA) allows for ‘reasonable variation’ with medications so that most contain 90-110% of the amount of active ingredient listed on their label. This 90-110% potency is cited as the benchmark when establishing the expiration date of a drug, also known as its shelf life. However, of note, when we went looking for the links cited in the papers above, it turns out that this quote is a little misleading, as it was a Q&A page about a specific medication, levothyroxine, used in hypothyroidism, and it’s from October of 2007. It was not some broad FDA regulation stated in a federal code. The exact quote provided here is “currently, these products are required to meet a USP-authorized potency specification of 90-110 percent, which is typical for most drug products” [emphasis added]. What we found in searching for “reasonable variations” on the FDA website was, per the “Guide to Inspections of Oral Solid Dosage Forms Pre/Post Approval Issues for Development and Validation”, dated from January 1994, in section V.B.4., explicitly states that “Since most USP assay limits are 90 to 110%, it would seem reasonable that each unit manufactured comply with these specifications. It should be pointed out that 85 to 115% limits are established by the USP for variability…”
What does this mean? YOU DON’T ACTUALLY KNOW if that 800mg Ibuprofen is initially in concentrations of 680mg (85%), 720mg (90%), 800mg (100%), 880mg (110%), or even up to 920mg (115%). And, if you haven’t been storing it correctly, well then you really don’t know.
If You DO Use Expired Meds, What Happens?
So, now let’s return to the original scenario: the NCO asking to use your expired Ibuprofen. What happens if you do accidentally give expired medications?
Is the NCO above going to suddenly have a gastric ulcer or anaphylactic reaction?
Fortunately, limited data we uncovered supports that the answer is “probably not”.
Will the expired Ibuprofen, possibly improperly stored, be as effective as properly-stored, fresh out-of-the-pharmacy Ibuprofen?
The limited data we uncovered above supports that the answer is “maybe, maybe not” (primarily since it was not stored and tested with the SLEP lots).
We did find an old case report of an adverse reaction related using an expired medication, where a case of “renal tubular damage” (kidney injury) is believed to be caused by an expired prescription of the antibiotic tetracycline, from a 1963 article in JAMA. It was believed that this was caused by a chemical transformation of the active ingredient. In our searches, there have been no case reports of adverse outcomes from the usage of expired Ibuprofen, as well as many of the medications listed in the SLEP inventories above.
However, let’s step away from NSAIDs, and instead suppose that the medication in question was antibiotics for an infection. What data is there to determine how the expiration date affects the efficacy of antibiotics? Medical literature has looked at the use of expired antibiotics, primarily to help highlight poor ethical practices of donor nations and private companies “dumping” expired medications disguised as “donations” to poorer countries needing healthcare aid. We found a study published in the Pan African Medical Journal in 2014 that looked at the in vitro (out-of-body, i.e. in a petri dish) effect of expired pediatric antibiotics on infantile diarrheagenic bacteria samples. Although this study did demonstrate increased rates of resistance by cultured bacteria to the expired antibiotics, including some strains that were up to 100% resistant to the expired antibiotics compared to antibiotics that were not expired, it was significantly limited by the fact that pediatric preparations are liquid, and therefore more susceptible to degrade given the limited lifespan of their preservatives (compared to the protective coating of found on most tablets and pills). Therefore, the applicability of this data to a larger population is difficult.
Similarly, few studies have taken expired adult antibiotics in pill or tablet form to look at their efficacy. One study, although not published in any peer-reviewed journals, found that there was no decrease in the dissolution rate, or breakdown, of expired tablets and capsules, compared to non-expired controls. However, this study was limited by the fact that dissolution was observed in vitro (in this case, in a test tube), and, more importantly, that the medications were stored at a controlled room temperature of 20+2°C (68-71.6°F) throughout 10+ years of storage after their expiration.
Conclusions on the Use of Expired Medications
There is a generally consistent, albeit cautious, speculation that most drugs maintained outside of perfectly-controlled climates can still be used far beyond their expiration date. In addition to the fact that drug makers have readily acknowledged the commercial dimension to expiration dates, multiple FDA officials have acknowledged that most drugs are “probably as durable” as those maintained via the SLEP. Exceptions include nitroglycerin, insulin, and liquid antibiotics, but most remaining medications have been theorized to maintain potency even 10 years after the expiration date, but again, there is little peer-reviewed published data outside of the SLEP to support this statement for many medications. The official FDA position remains that “using expired medical products is risky and possibly harmful to your health… if your medicine has expired, do not use it.”
It is also important to acknowledge that the original scenario of a medic carrying expired medications could be avoided altogether with a strong emphasis on simple pre-combat checks and pre-combat inspections (PCC’s & PCI’s) including medication verifications.
Given the severe temperature variability that most military medics and providers encounter, and the fact that we here at NGCM believe most of us do not perfectly monitor temperature and other environmental parameters when storing and transporting medications, we want to stress that medication storage practices are something that should be more closely reviewed and monitored at all levels, from medical supply and transportation down to the individual line medic. In addition, there is little analytical support for the use of medications beyond the expiration date at the line medic level, and we are not supporting the regular use of expired medications. Ensure you are always checking and rechecking your labels as part of PCCs and PCIs, and maintain always maintain a keen awareness of environmental exposures when outside of a controlled setting.
We want to stress that this is an informative article, used to show that certain medications, when stored properly and in their proper containers, can be stable for periods of time far beyond their stated expiration date. Please do not cite this as a reason to give expired medication. We are not translating this data to be used with our own meds, so please do not do it with yours.
Standard Disclaimer: The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Army, the Department of Defense, or the US Government.
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