90% in another medication that contained that drug
(Table). 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 Measured
macy in their original, unopened containers. All had ex-
With Active Declared
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
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.
CONTEST RULES All in a Day Hopes and Dreams Part Two (“Contest”) from 3:00 p.m. on Friday, November 29, 2013 EST to 11:59 a.m. on Thursday, December 5, 2013 EST (“Contest Period”) Canadian Broadcasting Corporation (“CBC”) and Shepherds of Good Hope (“Sponsor”) 1. HOW TO ENTER No purchase required . To enter the Contest, go to the Shepherds of Good Hop
CONSUMER PRICES INDEX: REPRESENTATIVE ITEMS IN 2009 01.1 Food 01.1.1 Bread and Cereals Large white loaves - sliced and unsliced Large wholemeal loaf Bread rolls Pitta bread Flour Rice Pasta Breakfast cereals Various selected biscuits Corn based snacks Doughnuts Sponge cakes Crackers Pack of individually wrapped cakes Frozen pizzas Fruit pies Dehydrated noodles / pasta Chocolate wafers Rump