Do Drug Expiration Dates Really Matter?

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I have been sick with the flu for almost an entire week now, and let me tell you, if you ever want a great abdominal workout just get the flu and cough up a lung for a week straight. I’m going to have a 6-pack by the time I am fully recovered! If you would literally do anything else then get the flu like a normal person, just get your flu shot. It’s much more fun than this ‘workout’ I promise. But in all seriousness, when I first got sick I did what everybody does, and looked at my medicine cabinet. I had a whole collection of pills and potions, half of which were expired. Has this ever happened to you? You are terribly sick and only have expired drugs, and debate if it’s worth going to the store to get new ones or just risk using the expired meds you already have? You’re not alone. As much as I would love to say the good pharmacist in me never let any expired drugs into my house I am still human. And this got me to wondering do drug expiration dates really matter?

I want to preface this article with a gentle reminder that while I am a pharmacist, I am not YOUR pharmacist. Medical advice over the internet is never a substitute for discussing your individual health needs with a physician or pharmacist face to face. It is never recommended to take expired meds, however I am fully aware that the temptation is there and I want to do my best to present the facts to you so that you and your medical team can make the best decision for you. This article is written more scientifically than most of our posts as it is my hope that you will print this out and take it to your pharmacist or physician to discuss with them, and use the resources listed to check the claims I make and come to your own conclusions. With that being said, let’s find out if drug expiration dates really matter.

Why Drug Expiration Dates Matter

Under section 501(a)(2)(B) of the federal Food, Drug and Cosmetic Act (FDCA), manufacturers of prescription drug products establish controls for the manufacture, processing, packing, and holding of drug products to ensure their safety. Requirements for these controls are known as current good manufacturing practices (CGMPs), and include the requirement of an expiration date as of 1979. Current requirements include medications to be within 90%-110% of their stated potency.1 The FDA defines an expiration date as “the date placed on the container/label of a drug product designating the time during which a batch of the product is expected to remain within the approved shelf life specifications if stored under defined conditions, and after which it may not be used.”

The expiration date is determined by a review of documentation submitted to the FDA in a New Drug Application (NDA). This includes a stability assessment of the new drug substance and product (dosage form). The stability assessment follows procedures agreed upon by the United States, European Union, and Japan established at the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). How the stability assessments are conducted varies based on the substance and its dosage form, however stress tests are performed evaluating the effects of elevated temperature and humidity, oxidation and photolysis, and hydrolysis over a wide range of pH values.1Expiration dates for prescription drugs (and over the counter drugs) that are subject to premarket approval requirements are based on the amount of real time data available at the time of FDA approval of the NDA.

However, the expiration date may be extended as long as adequate data is provided to the FDA. This is rarely done however, as there is traditionally no incentive to extending expiration dates and extension is strictly voluntary. According to PhRMA, the initial expiration dating for prescription drug products is usually between 18 and 24 months, and expiration dates can range from 12 to 60 months. As of 2006 no drug has an expiration date longer than 60 months. As a general rule, solid dosage forms tend to have longer expiration dates than liquid ones.2

Many studies have proven stability of medications beyond their expiration date. Reducing waste is a key way to reduce healthcare costs and extending expiration dates is one tool through which this can be accomplished. In 1986, the FDA and the Department of Defense (DoD) singed an interagency agreement to “conduct a comprehensive, scientifically sound testing and evaluation program that will determine whether there is justification for extending the shelf life of stored medical items owned by components of DoD or their authorized program partners.”3This created the Shelf Life Extension Program (SLEP) providing the FDA with the largest data source of expired medications to date. From this study, Robbe et al published in 2006 that 122 medications have been tested and 88% were extended past their original expiration date for an average of 66 months.4

Some manufacturers have extended expiration dates during times of drug shortages. In June, 2017 the FDA posted extended expiration dates for batches of injectable atropine, dextrose, epinephrine, and sodium bicarbonate manufactured by Pfizer. This resulted in one hospital, Newton-Wellesley, saving $7,500 in drugs that were in short supply.2

It is important to note that once the manufacturers container is opened and a drug product is transferred to another container for dispensing and repackaging the expiration date no longer applies. The United States Pharmacopeia (USP) and the American Pharmacists Association (APhA) provide guidance to pharmacists on placing a “beyond use date” on the label of the new container.2

The AMA has resolutions drafted by its house of delegates stating that the AMA “Urges the pharmaceutical industry, in collaboration with purchasers, the FDA, and the United States Pharmacopeia (USP), to determine whether lengthening of expiration dates will provide clinical and/or economic benefits or risks for patients and, if this is the case, to conduct longer stability testing on their drug products.”2They have written many letters and provided many public comments on this topic.T

The SLEP Study

The SLEP study contains the most comprehensive database of long-term stability data in existence. This study published its research on 122 medications (3005 lots) in 2006.5Of the 3005 lots tested, 2650 were extended past their original expiration date. 1237 lots were found to be still viable at 70 months past their expiration date, and were abated before failure and were not studied past this time. Of the 479 lots that eventually failed no lots failed prior to one year past their expiration date, and 312 lots were extended beyond 4 years.

The DoD maintains a stockpile of medications worth around $13.6 billion as of 2016.6Based on the SLEP program and their research the DoD has been able to extend the expiration dates of medications saving $2.1 billion in 2016.6The cost of running the SLEP program in 2016 was $3.1 million resulting in a return on investment of $677 per dollar spent on this program. It is important to note that while many states and hospitals also maintain stockpiles of medications the data used from this study are proprietary to federal agencies such as the DoD, the Center for Disease Control’s Strategic National Stockpile (SNS), and the Veterans Administration (VA).3Non-federal or civilian agencies (including state stockpiles) may not avail themselves of this program.

The medications included in the SLEP study are medications that have been selected specifically for their likelihood of being stable past their expiration dates and have been properly stored under conditions consistent with CGMPs and thus cannot be generalizable to medications that have not been stored under these conditions.3There is much interest in states access to SLEP study data. Kozak et all studied patient attitudes towards unused and expired medication (UEM) in Indiana, and discovered that 40% of patients were unaware of a medication take-back location in their community, and while 77% were willing to drive to a take-back location to return UEM, only 15% had utilized take-back locations.7 Kuspis et all surveyed patients and pharmacies, and out of the 500 people surveyed only 1.4% returned medications to a pharmacy, and out of 100 pharmacies only 5% had consistent recommendations for their customers on drug disposal.8

The SLEP study has evaluated over 500 medications however most of this data is unpublished. Even with the data being unpublished the FDA has used the data to improve manufacturing practices.2,3,9 One study conducted by the Office of Regulatory Affairs (ORA) field laboratory evaluated Mark 1 Nerve Agent Antidote Kits containing atropine sulfate. Five out of every six atropine autoinjectors failed the stability testing due to brown particulate matter or cloudy brown solution.3Further testing revealed that the discoloration was a result of leaching iron from the stopper. The FDA can now use this data to advise the use of non-iron containing stoppers as a potential method of increasing the shelf life of these autoinjectors.

Other Studies

Research on medication stability past it’s expiration date has also been done in the civilian sector. Cantrell et al evaluated 31 expired EpiPens and 9 EpiPen Jrs all of which were 1 to 50 months past their expiration date.10 19 of the EpiPens (65%) and 5 of the Epipen Jrs (56%) contained at least 90% of their stated amount of epinephrine and all of them contained at least 80% their stated amount of epinephrine. This study asked for consumers to donate their autoinjectors. By using donated auto injectors they were able to get a more realistic view, as these medications were commonly stored in cars, humid bathrooms, or other less than optimal settings,

Teder et al evaluated expired and non-expired nifedipine formulations from Estonia and Russia and used IR spectroscopy, HPLC analysis, and evaluation of dissolution rates to compare the drugs to current European Pharmacopeia Standards.11 All tested products had at least 80% nifedipine and did not exceed tolerance limits for impurities. Expired nifedipine formulations did however release faster than their non-expired counterparts.

Binkhathlan et al evaluated tacrolimus extracted from expired Prograf®capsules and established through multiple tests including gas chromatography-mass spectrometry (GC-MS), X-ray diffraction (XRD), and differential scanning that extracted/purified tacrolimus retains its purity and immunosuppressive action.12

Tetracyclines, and their safety past expiration dates, have been highly debated. One report in 1963 by Frimpter et all discovered three cases of Fanconi Syndrome and postulated that the either the tetracycline degradation product epi-anhydrotetracycline or anhydrotetracycline was responsible.13However the SLEP study encountered no toxicity with tetracycline and found batches effective more that two years past their expiration dates.9

Tricyclic antidepressants (TCAs) are one of the few medications that have not been studied past their expiration date. This is potentially due to newer drugs like SSRIs and SNRIs being more common in practice as they have safer toxicity profiles.14According to a review of antidepressant overdose cases gathered from calls to Poison Control Centers, tricyclic antidepressants account for the second highest mortality index of all anti-depressants (40.7 per 10,000 exposures).15Only combination products such as olanzapine/fluoxetine and perphenazine/amitryptyline has a higher mortality index (45.7 per 10,000 exposures). It is worth nothing that the perphenazine/amitriptyline combination product has the highest mortality rate out of the combination products listed (74.1 out of 10,000), and that out of the individual products the TCAs had the highest specifically Amoxapine (124.2 out of 10,000) and Desipramine (141 out of 10,000). This toxicity is due to the cardiac effects of tricyclic antidepressants including dysrhythmias, EKG changes such as prolongation of conduction time, prolonged PR intervals and increased corrected pre-ejection period interval.14

Conclusion

Overall, there is much evidence for the safety and efficacy of medications past their stated expiration date. Many factors are involved in the lack of testing for extension of expiration dates. These include a lack of incentives, the high cost of testing, and the high burden of proof required to be submitted to the FDA. Much can be done to change this, however pharmaceutical companies fiercely fight to keep expiration dates within the traditional two to three year window. Drug manufacturers use patient safety as a defense, due to creation of new marketing materials in that time-frame. They claim patients may get confused between the old and new labeling.

Solid dosage forms tend to be more stable than liquid ones, and many medications, both solid and liquid, have been studied 70 months past their stated expiration dates in the SLEP study. The SLEP study has lead to massive cost savings in the DoD, SNS, and VA systems. This information is proprietary however, and while there is much interest in extending this information to the private sector and states, they argue that such programs would not result in equitable cost savings due to the unique set-up of entities involved in SLEP.

The SLEP study has also provided the FDA with information that can be used in guiding manufacturing pharmaceutical products to improve stability, such as using non-iron containing stoppers. Tetracyclines and tricyclic antidepressants are just a few examples of the need for more research into the safety and efficacy of medication past their expiration dates, as evidence to their harm is inconclusive.

Many medications have been tested past their expiration date, however the FDA, USP, and APhA currently all advise against the use of medications past their expiration date. The AMA also advises against the use of medications past their expiration date, however the have urged the FDA, USP and the pharmaceutical industry to continue to explore the safety, efficacy, risk, and economic benefits of extending expiration dates.

So with all this being said, do drug expiration dates really matter? The answer is honestly, it depends on the drug. There are a few drugs that can become toxic when taken past their expiration dates, however most drugs simply lose potency This means they may not be as effective as usual but will still be marginally effective and may still provide some benefit. I hope this helps! Let us know if you like these types of articles and we will be happy to provide more!

References:

1.     Commissioner, O. of the. (n.d.). MCM Legal, Regulatory and Policy Framework – Expiration Dating Extension [WebContent]. Retrieved October 20, 2017, from https://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMLegalRegulatoryandPolicyFramework/ucm411446.htm

2.     (ProPublica), M. A. (n.d.-a). AMA report_CSA Rep 1 (Pharmaceutical Expiration Dates) a 01 FINAL… Retrieved October 20, 2017, from https://www.documentcloud.org/documents/3671873-CSA-Rep-1-Pharmaceutical-Expiration-Dates-a-01.html

3.     Khan, S. R., Kona, R., Faustino, P. J., Gupta, A., Taylor, J. S., Porter, D. A., & Khan, M. (2014). United States Food and Drug Administration and Department of Defense shelf-life extension program of pharmaceutical products: progress and promise. Journal of Pharmaceutical Sciences, 103(5), 1331–1336. https://doi.org/10.1002/jps.23925

4.     Lyon, R. C., Taylor, J. S., Porter, D. A., Prasanna, H. R., & Hussain, A. S. (2006). Stability profiles of drug products extended beyond labeled expiration dates. Journal of Pharmaceutical Sciences, 95(7), 1549–1560. https://doi.org/10.1002/jps.20636

5.     (ProPublica), M. A. (n.d.). Stability Profiles of Expired Drugs. Retrieved October 20, 2017, from https://www.documentcloud.org/documents/3525372-Stability-Profiles-of-Expired-Drugs.html

6.     (ProPublica), M. A. (n.d.-c). Expired drugs research letter. Retrieved October 20, 2017, from https://www.documentcloud.org/documents/3516397-Expired-drugs-research-letter.html

7.     Kozak, M. A., Melton, J. R., Gernant, S. A., & Snyder, M. E. (2016). A needs assessment of unused and expired medication disposal practices: A study from the Medication Safety Research Network of Indiana. Research in Social & Administrative Pharmacy: RSAP, 12(2), 336–340. https://doi.org/10.1016/j.sapharm.2015.05.013

8.     Kuspis, D. A., & Krenzelok, E. P. (1996). What happens to expired medications? A survey of community medication disposal. Veterinary and Human Toxicology, 38(1), 48–49.

9.     Cohen, L. P. (2000). Drugs frequently potent past expiration. Wall Street Journal.

10.  (ProPublica), M. A. (n.d.-b). Epinephrine Concentrations in EpiPens. Retrieved October 20, 2017, from https://www.documentcloud.org/documents/3696595-Epinephrine-Concentrations-in-EpiPens.html

11.   Teder, K., Pepeloshev, A., Matto, V., & Meos, A. (2013). Pharmacopoieal quality of non-expired and expired nifedipine formulations from Estonian and Russian Federation medicinal products market. Acta Poloniae Pharmaceutica, 70(3), 539–546.

12.  Binkhathlan, Z., Badran, M. M., Alomrani, A., Aljuffali, I. A., Alghonaim, M., Al-Muhsen, S., … Alshamsan, A. (2016). Reutilization of Tacrolimus Extracted from Expired Prograf® Capsules: Physical, Chemical, and Pharmacological Assessment. AAPS PharmSciTech, 17(4), 978–987. https://doi.org/10.1208/s12249-015-0433-7

13.  Frimpter GW, Timpanelli AE, Eisenmenger WJ, Stein HS, Ehrlich LI. Reversible “Fanconi Syndrome” Caused by Degraded Tetracycline. JAMA. 1963;184(2):111–113. doi:10.1001/jama.1963.03700150065010

14.  Khalid, M. M., & Waseem, M. (2017). Toxicity, Tricyclic Antidepressant. In StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK430931/

15.  Nelson, J. C., & Spyker, D. A. (2017). Morbidity and Mortality Associated With Medications Used in the Treatment of Depression: An Analysis of Cases Reported to U.S. Poison Control Centers, 2000-2014. The American Journal of Psychiatry, 174(5), 438–450. https://doi.org/10.1176/appi.ajp.2016.16050523

 

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Welcome To Poise and Potions!
Where Art and Medicine Dance
We hope to be your go-to blog for all things art, medicine, and everything in between