Is This Medication Still Good?

I was asked by a patient today with a bag of medication, “Are these still good?”.  Here is some guidance on this subject from The Medical Letter, a nonprofit publication to which I subscribe.

Healthcare providers are often asked if drugs can be used past their expiration date. Because of legal restrictions and liability concerns, manufacturers do not sanction such use and usually do not comment on the safety or effectiveness of their products beyond the date on the label. Since our last article on this subject,1 more data have become available.

SAFETY — There are no published reports of human toxicity due to ingestion, injection, or topical application of a currently available drug formulation after its expiration date. Renal tubular damage has been reported with use of degraded tetracycline in a formulation that is no longer manufactured.2

THE EXPIRATION DATE — The manufacturer’s expiration date is based on the stability of the drug in the original sealed container. The date does not necessarily mean that the drug was found to be unstable after a longer period; it only means that real-time data or extrapolations from accelerated degradation studies indicate that the drug is expected to be stable on that date if stored in the closed container under recommended conditions. Most drug products have a labeled shelf life of 1-5 years, but in some cases (e.g., ophthalmic products), the expiration date on the original container no longer applies once it is opened.

STABILITY — Data from the US Department of Defense/FDA Shelf Life Extension Program, which tests the stability of drug products past their expiration date, have shown that 2650 of 3005 lots (88%) of 122 different products stored in their unopened original containers were able to have their shelf lives extended by an average of 66 months past the labeled expiration date.3 Potassium iodide, which has been extensively stockpiled for use in a radiation emergency, has shown no significant degradation over many years.4 A 2020 report from the US Department of Health and Human Services advised that it would be reasonable if necessary to use the antiviral products Tamiflu (oseltamivir; 75-mg capsules) and Relenza (zanamivir inhalation powder) for up to 15 and 10 years, respectively, after their date of manufacture if the products were stored under labeled conditions.5

HEAT, HUMIDITY, AND LONG-TERM STORAGE — Storage in high heat and/or humidity can accelerate the degradation of some drug formulations, but in one study, captopril tablets, theophylline tablets, and cefoxitin sodium powder for injection, stored at 40°C and 75% relative humidity, remained stable for 1.5-9 years beyond their expiration dates.6 In another study, theophylline tablets retained 90% of their labeled content 30 years past their expiration date.7 A study of 8 products that had been stored in their unopened original containers for 28-40 years past their expiration dates found that 12 of 14 active ingredients had retained ≥90% of their original potency; aspirin retained <5% of its potency, and amphetamine <60%.8

LIQUID FORMULATIONS — Solutions and suspensions are generally less stable than solid dosage forms, but in one report, 4 outdated samples of atropine solution (three up to 12 years past expiration and one >50 years past the expiration date) were all found to contain significant amounts of the drug.9 Drugs in solution that have become cloudy or discolored or show signs of precipitation should not be used. Suspensions are particularly susceptible to freezing. Limiting factors with ophthalmic drugs include evaporation of the solvent and a decreasing ability of preservatives to inhibit microbial growth.10

EPINEPHRINE — Epinephrine solutions, which can reverse the life-threatening effects of allergic reactions, may lose potency after the expiration date. In a study of 34 auto-injectors that had expired within the previous 90 months, the decrease in epinephrine content was inversely proportional to the number of months past the expiration date.11 Multiple studies of epinephrine auto-injectors (including EpiPen, EpiPen Jr, Auvi-Q, and the generic for Adrenaclick) have found pens up to 6 years past their expiration dates to contain ≥80% of the labeled dose,12-14 but these studies were not designed to detect the potential conversion of epinephrine from the active L-enantiomer to the inactive D-enantiomer.15,16 One study of >100 pens that were 1-11 years past their expiration date and had been exposed to wide temperature ranges while stored in EMS vehicles found that only 12.6-31.3% of the labeled dose remained.17

NALOXONE — Available as injectable solutions and nasal sprays for reversal of opioid overdose, naloxone is now widely distributed to first responders and family members of opioid users, who may retain these products beyond their expiration date. In a 2019 study of naloxone samples collected from EMS or law enforcement training supplies and returns that had expired between 1990 and 2018, most samples were found to contain more than 90% of their labeled content.18

CONCLUSION — When no suitable alternative is available, outdated drugs may be effective. How much potency they retain varies with the drug, the formulation, the lot, the preservatives (if any), and the storage conditions, especially heat and humidity. Many solid dosage formulations stored under reasonable conditions in their original unopened containers retain ≥90% of their potency for at least 5 years after the expiration date on the label, and sometimes much longer. Solutions and suspensions are generally less stable. There are no published reports of toxicity from degradation products of currently available drugs.

REFERENCES

1. Drugs past their expiration date. Med Lett Drugs Ther 2015; 57:164.
2. GW Frimpter et al. Reversible “Faconi syndrome” caused by degraded tetracycline. JAMA 1963; 184:111.
3. RC Lyon et al. Stability profiles of drug products extended beyond labeled expiration dates. J Pharm Sci 2006; 95:1549.
4. US Department of Health and Human Services. Guidance for federal agencies and state and local governments: potassium iodide tablets shelf life extension. March 2004. Available at: www.fda.gov/media/72521/download. Accessed July 16, 2020.
5. US Department of Health and Human Services. State antiviral drug stockpile HHS update: February 11, 2020. Available at: www.fda.gov/media/135460/download. Accessed July 16, 2020.
6. G Stark et al. A study of the stability of some commercial solid dosage forms beyond their expiration dates. Pharm J 1997; 258:637.
7. R Regenthal et al. The pharmacologic stability of 35-year old theophylline. Hum Exp Toxicol 2002; 21:343.
8. L Cantrell et al. Stability of active ingredients in long-expired prescription medications. Arch Intern Med 2012; 172:1685.
9. JG Schier et al. Preparing for chemical terrorism: stability of injectable atropine sulfate. Acad Emerg Med 2004; 11:329.
10. GD Novack. Can I use those eyedrops after the expiration date? Ocul Surf 2015; 13:169.
11. FE Simons et al. Outdated EpiPen and EpiPen Jr autoinjectors: past their prime? J Allergy Clin Immunol 2000; 105:1025.
12. O Rachid et al. Epinephrine doses contained in outdated epinephrine auto-injectors collected in a Florida allergy practice. Ann Allergy Asthma Immunol 2015; 114:354.
13. FL Cantrell et al. Epinephrine concentrations in EpiPens after the expiration date. Ann Intern Med 2017; 166:918.
14. L Kassel et al. Epinephrine drug degradation in autoinjector products. J Allergy Clin Immunol Pract 2019; 7:2491.
15. J Lan et al. Evaluation of epinephrine’s expiration date: a US Food and Drug Administration’s perspective. J Allergy Clin Immunol Pract 2019; 7:2948.
16. L Hollein and U Holzgrabe. Ficts and facts of epinephrine and norepinephrine stability in injectable solutions. Int J Pharm 2012; 434:468.
17. A Stonemen et al. Stability of epinephrine in expired EpiPen products from EMS ambulances. AAPS 2014; W5370.
18. S Pruyn et al. Quality assessment of expired naloxone products from first-responders’ supplies. Prehosp Emerg Care 2019; 23:647.

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