90% in another medication that contained that drug RESEARCH LETTER
Comment. The US Food and Drug Administration (FDA)
permits “reasonable variation,” such that most medica-tions marketed in the United States contain 90% to 110% Stability of Active Ingredients
of the amount of the active ingredient claimed on the la- in Long-Expired Prescription Medications
bel.5 Drug expiration dates typically range from 12 to 60months after their production.4 However, FDA regula- D ebateexistsregardingtherelativepotencyof tionsdonotrequiredeterminationofhowlongmedica-
medications beyond their labeled expiration tions remain potent after that, allowing manufacturers dates. Expired medications have not necessar- to arbitrarily establish expiration dates without deter- ily lost potency, since the expiration date is only an as- mining actual long-term drug stability.
surance that the labeled potency will last at least until The Shelf-Life Extension Program (SLEP) checks that time.1 Clinical situations may arise in which ex- long-term stability of federal drug stockpiles. Eighty- pired drugs might be considered owing to lack of viable eight percent of 122 different drugs stored under ideal alternatives2 or financial concerns.3 Ongoing studies show environmental conditions had their expiration dates that many medications retain their potency years after extended more than 1 year, with an average extension their initially labeled expiration dates.4 We sought to char- of 66 months and a maximum extension of 278 acterize the potency of some prescription medications thathad expired decades ago.
Table. Declared and Measured Amounts in Drugs
Methods. Eight long-expired medications with 15 dif-
ferent active ingredients were discovered in a retail phar-
Drug Trade Name
macy in their original, unopened containers. All had ex- With Active
pired 28 to 40 years prior to analysis. Three tablets or Ingredients
Amount, mg
Mean (SD), mg
capsules of each medication were analyzed, with each sample tested 3 times for each labeled active ingredient.
No analytical standard for homatropine could be found, Tablets or capsule contents were dissolved and soni- cated in methanol, reconstituted in analysis buffer (10% methanol) and analyzed with Liquid Chromatograph (Agi- lent Technologies) Time-of-Flight Mass Spectrometer (Agilent) using electrospray ionization in negative and positive polarities. Chromatography was run with gra- dient elution using Eclipse Plus C18 column (Agilent).
Data analysis was performed using Mass Hunter Quali- tative and Quantitative Analysis (Agilent). Quantifica- tion was performed by isotope dilution method with a Results. Twelve of the 14 drug compounds tested (86%)
were present in concentrations at least 90% of the la- beled amounts, the generally recognized minimum ac- ceptable potency. Three of these compounds were present at greater than 110% of the labeled content. Two com- pounds (aspirin and amphetamine) were present in amounts of less than 90% of labeled content. One com- pound (phenacetin) was present at greater than 90% of labeled amounts from 1 medication tested, but less than 2012 American Medical Association. All rights reserved.
months.4 In our data set, 12 of 14 medications retained ascribed expiration dates. Given the potential cost- full potency for at least 336 months, and 8 of these for savings, we suggest the current practices of drug expi- at least 480 months. Given our inability to confirm ideal storage conditions for our samples, our resultssupport the effectiveness of broadly extending expira- tion dates for many drugs, the efficacy of which has been demonstrated by SLEP in a more controlled The 3 drugs found with less than 90% of their la- beled potency were amphetamine and aspirin in both Published Online: October 8, 2012. doi:10.1001
samples tested and phenacetin in 1 of 2 samples tested.
Aspirin is known to degrade in vitro,6 but there are no Author Affiliations: California Poison Control System,
such published data regarding amphetamine. For phen- San Diego Division, University of California San Fran- acetin, the difference in recovery between the 2 samples cisco School of Pharmacy, San Diego (Dr Cantrell); De- could be due to differences in packaging or storage of the partment of Emergency Medicine, University of Califor- containers. Aside from aspirin, all drugs in Fiorinal (butal- nia, Irvine Medical Center, Orange (Dr Suchard); and bital, aspirin, caffeine, and codeine phosphate) had al- Department of Laboratory Medicine, San Francisco Gen- most 100% of labeled concentrations, while those of Co- eral Hospital/University of California San Francisco, San dempiral No. 3 (phenacetin with codeine phosphate) were all less than 95%. Since the codeine measured in Codem- Correspondence: Dr Cantrell, California Poison Con-
piral No. 3 was also lower than that of Fiorinal (90% vs trol System, San Diego Division, University of Califor- 99%), this suggests that Codempiral’s packaging was less nia San Francisco School of Pharmacy, 200 W Arbor Dr, intact, allowing moisture to penetrate, which can pro- San Diego, CA 92103-8925 ([email protected]).
mote hydrolysis. Because phenacetin has an amide func- Author Contributions: Study concept and design: Cantrell,
tional group, it is more prone to this type of degradation Suchard, Wu, and Gerona. Acquisition of data: Gerona.
Analysis and interpretation of data: Cantrell, Wu, and Three drugs were unexpectedly found in our samples Gerona. Drafting of the manuscript: Cantrell, Suchard, Wu, at potencies greater than 110% of the labeled amounts.
and Gerona. Critical revision of the manuscript for impor- Some samples may have been produced prior to 1963, tant intellectual content: Cantrell, Suchard, Wu, and when FDA-mandated quality control measures were in- Gerona. Statistical analysis: Gerona. Obtained funding: Wu.
stituted (Paula R. Katz, Regulatory Counsel, FDA, Cen- Administrative, technical, and material support: Cantrell ter for Drug Evaluation and Research, Division of Manu- and Wu. Study supervision: Cantrell and Wu.
facturing and Product Quality, Guidance and Policy; Financial Disclosure: None reported.
e-mail communication, May 23, 2011); however, exact Previous Presentation: This study was an oral presen-
dating of all our samples was not possible. Alternately, tation at the 2011 North American Congress of Clinical these drugs could have come from lots untested by the Toxicology; September 23, 2011; Washington, DC.
manufacturer, or the accuracy between analytical meth-ods used in this study compared with those used de- 1. Title 21 CFR 211.166(a) and (b). Current good manufacturing practice in manufacturing for finished pharmaceuticals and expiration dating (2012).
2. Sandford-Smith J. Outdated drugs may be useful. BMJ. 2003;326(7379):51.
The most important implication of our study in- 3. Consumer Reports. Risky prescription drug practices are on the rise in a grim volves the potential cost savings resulting from lengthier economy. http://news.consumerreports.org/health/2011/09/risky product expiration dating. Each dollar spent on SLEP to -prescription-drug-practices-are-on-the-rise-in-a-grim-economy.html. AccessedOctober 11, 2011.
demonstrate longer than labeled drug stability results in 4. Courtney B, Easton J, Inglesby TV, SooHoo C. Maximizing state and local medi- $13 to $94 saved on reacquisition costs.4 Given that cal countermeasure stockpile investments through the Shelf-Life ExtensionProgram. Biosecur Bioterror. 2009;7(1):101-107.
Americans currently spend more than $300 billion an- 5. US Food and Drug Administration. Questions and answers on levothyroxine nually on prescription medications,7 extending drug ex- sodium products. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrug piration dates could yield enormous health care expen- SafetyInformationforPatientsandProviders/ucm161266.htm?utm_source=fdaSearch&utm_medium=website&utm_term=. Accessed April 18, 2012.
6. Martin BK. The formulation of aspirin. Adv Pharm Sci. 1971;3:107-171.
In conclusion, this study provides additional evi- 7. The White House. We can’t wait: Obama administration takes action to re- dence that many prescription pharmaceuticals retain their duce prescription drug shortages, fight price gouging. http://www.whitehouse.gov/the-press-office/2011/10/31/we-can-t-wait-obama-administration full potency for decades beyond their manufacturer- -takes-action-reduce-prescription-drug. Accessed January 18, 2012.
2012 American Medical Association. All rights reserved.

Source: http://files.javier-montero-perez.webnode.es/200000008-c8eb1c9e63/Farmacos_expirados.pdf

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