COMMENTARY
`
`From The University of Texas
`Dell Medical School, Austin
`(D.G.D.); Tufts University
`School of Medicine, Boston,
`MA (D.W.B.); and Pharmacy,
`Northwest Hills Surgical
`Hospital, Austin, TX (D.R.C.).
`
`Extending Shelf Life Just Makes Sense
`Dayna G. Diven, MD; Diana W. Bartenstein, AB; and Daniel R. Carroll, PharmD
`
`S ince 1979,
`
`the US Food and Drug
`Administration (FDA) has
`required
`pharmaceutical companies to provide
`rigorous proof that their medication is stable
`over the course of months when submitting a
`New Drug Application or an Abbreviated
`Drug Application.1,2 A medication’s shelf
`life, or expiration date, is the time frame in
`which a medication has been proven safe
`and effective despite exposure to various
`environmental factors including temperature,
`humidity, and light.2 Although expiration
`dates guarantee a certain length of stability,
`the FDA has no requirement for long-term
`testing. Many medications may have much
`longer shelf lives than labeled.
`The best evidence indicating that medi-
`cations can last
`longer than their labeled
`expiration date comes from the Shelf Life
`Extension Program (SLEP). Rather
`than
`disposing of billions of dollars of the mili-
`tary’s stockpiled medications that were set
`to expire in the 1980s,
`the FDA tested
`various batches of the medications in their
`supplies to provide extensions in shelf life.3
`In their studies of 122 different medication
`products, nearly 90% met the requirements
`for an extension. Table 1 includes medica-
`tions for which all lots tested by SLEP when
`approaching their expiration dates met the
`criteria for initial shelf life extension, and
`Table 2 lists medications for which less than
`50% of lots tested were initially extended.
`Whereas the shelf life of most medications
`in the United States is 1 to 5 years, the average
`additional extension length by SLEP was 5.5
`years, and some lots were extended by more
`than 20 years.4
`Cantrell et al,5 in another study, tested
`medications that had expired 28 to 40 years
`earlier that were discovered unopened and
`in their original containers at a retail phar-
`macy. Twelve of the 14 active ingredients
`were present in at least 90% of the labeled
`amount, meeting our standard of acceptable
`minimum potency. Given these data, it seems
`
`that many labeled expiration dates do not
`reflect true longevity.
`Despite extensive federal data on the
`long-term quality of many medications, shelf
`life extensions that occur in our national
`stockpiles do not transfer to state or local
`supplies,
`let alone hospitals, pharmacies,
`and those of individual patients, although
`more accurate expiration dates could reduce
`costs.6 As an example, Tufts Medical Center in
`Boston, Massachusetts, disposes of approxi-
`mately $200,000 worth of expired medications
`per year (written personal communication,
`Department of Pharmacy at Tufts Medical
`Center, January 8, 2015).
`life
`shelf
`for
`The current
`standards
`troublesome
`assignment
`are
`especially
`when populations that are unable to afford
`medications are considered. Infrastructural
`obstacles can delay health care distribution
`in developing countries,7 but medications
`cannot be donated internationally if
`they
`do not meet the donor country’s standards.8
`A donated drug that reaches a developing
`country past its stated expiration date must
`be discarded, although SLEP evidence sug-
`gests longer-term stability. Furthermore,
`it
`is illegal to dispense expired medication to
`any American regardless of whether they
`can obtain it otherwise.9
`Longer shelf lives could also play a role in
`decreasing medication shortages. Many medi-
`cation shortages occur for an unknown reason
`and without warning.10 If we had evidence that
`medications were stable for longer periods,
`pharmacy operation managers might have
`more flexibility to avoid shortages and paying
`the higher prices that are often associated
`with medications in short supply.11 Of the 15
`medications that SLEP determined to be top
`performers in shelf life extension, 12 (80%)
`are currently in shortage or have been in
`shortage since 2013.4,12 Extending the expira-
`tion dates for these medications could possibly
`help some providers, pharmacists, and patients
`during medication shortages.
`
`Mayo Clin Proc. n November 2015;90(11):1471-1474 n http://dx.doi.org/10.1016/j.mayocp.2015.08.007
`www.mayoclinicproceedings.org n ª 2015 Mayo Foundation for Medical Education and Research
`
`1471
`
`AMNEAL EX. 1012
`
`

`

`MAYO CLINIC PROCEEDINGS
`
`Finally, it is possible that extending shelf
`lives could have a positive environmental
`effect. Scientists
`recently found evidence
`of contamination by many medications in
`water and sediment samples from Lake Mich-
`igan at concentrations that pose “medium or
`high ecological risk.”13,p2120 If longer shelf
`lives
`could reduce medication disposal,
`perhaps such a measure could also abate
`harmful environmental consequences.
`How do we implement a policy to
`establish more
`accurate
`expiration date
`labeling? One option is to require all phar-
`maceutical companies
`to complete long-
`term stability testing. Just as pharmaceutical
`companies must conduct ongoing moni-
`toring for adverse effects after releasing a
`new medication, they could continue effi-
`cacy testing to see how long their medica-
`tions truly last. Expiration dates could be
`preliminary and then updated. A second
`option is to create noncommercial, indepen-
`dent testing for the true lengths of medi-
`cation stability. SLEP has provided the
`chemistry and protocol for ongoing testing,
`and a similar protocol could be applied for
`civilian medications. Perhaps the FDA or
`the US Pharmacopeial Convention could
`preside over this initiative. These proposals
`would require funding, but
`the potential
`benefits of such initiatives at least deserve
`consideration of their feasibility.
`Or, we could take the current data from
`SLEP and extend expiration dates for top-
`performing medications, before they are
`dispensed, that have already been monitored
`for years. If the ciprofloxacin in the federal
`supplies was active for more than 20 years,
`the FDA might consider granting this medi-
`cation a shelf-life extension for the general
`public as well, at least in pharmacies that
`have maintained optimal storage conditions.
`At a minimum, individual states that keep
`supplies of medications in proper storage
`conditions so as to respond to a pandemic
`or terrorist attack before federal supplies
`arrive6 should be able to use SLEP data to
`extend the shelf lives of medications in their
`local stockpiles.
`Even the age-old adage of particular
`expired medications being toxic may no
`longer be true. Although degraded tetracycline
`is thought to cause renal tubular insufficiency,
`
`1472
`
`Mayo Clin Proc. n November 2015;90(11):1471-1474 n http://dx.doi.org/10.1016/j.mayocp.2015.08.007
`www.mayoclinicproceedings.org
`
`Continued on next page
`
`TABLE 1. SLEP Medication Stability Testing Results: All Lots Initially Extended4
`Extension time
`(mo) mean
`19
`23
`24
`25
`27
`31
`32
`32
`35
`40
`41
`42
`43
`43
`44
`44
`46
`46
`47
`48
`49
`49
`49
`50
`50
`50
`51
`51
`52
`52
`52
`53
`54
`55
`55
`55
`56
`56
`57
`57
`57
`57
`58
`59
`59
`59
`60
`60
`60
`60
`61
`63
`
`Form
`
`Capsules
`Tablets
`Capsules
`Injection solution
`Powder
`Autoinjector
`Autoinjector
`Suspension
`Capsules
`Syringe needles
`Cartridge needle
`Injection solution
`Injection solution
`Injection solution
`Injection solution
`Capsules
`Powder
`Injection solution
`Injection solution
`Liquid
`Capsules
`Injection solution
`Injection solution
`Injection solution
`Capsules
`Capsules
`Injection solution
`Injection solution
`Tablets
`Solution
`Tablets
`Injection solution
`Powder
`Powder
`Tablets
`Injection solution
`Powder
`Tablets
`Injection solution
`Injection solution
`Cream
`Capsules
`Tablets
`Inhalant
`Cream
`Injection solution
`Powder
`Powder
`Injection solution
`Injection solution
`Syringe needle
`Injection solution
`
`Medication
`Triamterene and hydrochlorothiazide
`Amoxicillin sodium
`Acetaminophen pseudoephedrine
`Dextrose 10%
`Doxycycline hyclate
`Atropine sulfate pralidoxime chloride
`Morphine sulfate
`Ciprofloxacin
`Flurazepam HCl
`Metaraminol bitartrate
`Mepivacaine HCl
`Cimetidine HCl
`Hydrocortisone sodium succinate
`Prochloroperazine edisylate
`Hetastarch in sodium chloride
`Benzonatate
`Cefoperzone sodium
`Ephedrine sulfate
`Dobutamine HCl
`Enflurane
`Ampicillin
`Calcium glucepate
`Bretylium tosylate
`Sodium chloride
`Tetracycline HCl
`Doxycycline hyclate
`Iothalamate meglumine
`Promethazine HCl
`Chlorpromazine HCl
`Ophthalmic irrigating
`Naproxen
`Ringer’s, lactated and dextrose
`Thiopental sodium
`Sodium polystyrene sulfonate
`Ciprofloxacin
`Sodium bicarbonate
`Oxacillin sodium
`Sulfisoxazole
`Ampicillin sodium
`Furosemide
`Sulfadiazine silver
`Cephalexin
`Mebendazole
`Amyl nitrite
`Mafenide acetate
`Tubocurarine chloride
`Ceftriaxone sodium
`Erythromycin lactobionate
`Neostigmine methylsulfate
`Phenylephrine HCl
`Dexamethasone sodium phosphate
`Phenytoin sodium
`
`AMNEAL EX. 1012
`
`

`

`EXTENDING SHELF LIFE JUST MAKES SENSE
`
`manufacturing was changed decades ago to
`substantially reduce the likelihood of tetra-
`cycline formulations breaking down.14 Of
`course,
`subsequent monitoring for
`and
`reporting of adverse effects in medications
`of extended shelf life would be essential for
`ensuring patient safety; however, contro-
`versies from decades ago may need to be
`revisited for their validity.
`For most medications, the concern is for
`loss of potency under imperfect conditions
`more than for degraded metabolites that
`are toxic. One could argue that people do
`not always keep their medications in ideal
`conditions, as occurred with our
`federal
`supplies. This is a valid concern given our
`currently limited understanding of
`long-term
`drug stability, but investment in rigorous testing
`and surveillance could resolve this uncertainty.
`Whereas many decisions in health care must
`balance the competing interests of cost and qual-
`ity, extending expiration dates to reflect the true
`amount of time that a medication is safe and
`effective might sacrifice neither. Implementing
`such a measure could decrease the amount of
`money spent on prescription medications in the
`United States due to reduced medication disposal
`and could also improve health care quality by
`improving access to pharmacologic treatment.
`The logistics of implementing shelf life exten-
`sions for the general population would not be
`simple, but the remarkable evidence provided
`by SLEP indicates that careful consideration is
`deserved. It only makes sense.
`certain
`a
`Expiration dates guarantee
`length of stability, but many drugs may
`have much longer shelf lives than is labeled
`because there is no requirement for long-
`term efficacy testing. SLEP, pioneered by the
`FDA to conserve drugs stockpiled by the mili-
`tary, provides convincing data about
`the
`safety and efficacy of many medications past
`their expiration dates. If we were to apply
`shelf life extensions more broadly, it might
`be possible to reduce national health care
`costs, reduce drug shortages, and provide
`medications to those who would otherwise
`be unable to afford them.
`
`ACKNOWLEDGMENTS
`We thank Tiffany Lieu, MD, for her help with
`the literature search.
`
`TABLE 1. Continued
`
`Medication
`
`Extension time
`(mo) mean
`Form
`64
`Injection solution
`Ketamine HCl
`64
`Injection solution
`Chloroquine HCl
`64
`Injection solution
`Dextrose and sodium chloride
`64
`Powder
`Protamine sulfate
`65
`Injection solution
`Dextrose (5%)
`65
`Ointment
`Povidone iodine
`65
`Injection solution
`Edrophonium chloride
`66
`Injection solution
`Mannitol
`67
`Liquid
`Halothane
`67
`Tablets
`Cimetidine HCl
`68
`Powder
`Undecylenic acid and zinc salt
`69
`Tablets
`Potassium iodide
`70
`Suspension
`Penicillin G benzathine
`72
`Powder
`Succinylcholine chloride
`72
`Irrigation
`Sodium chloride
`74
`Powder
`Cephapirin sodium
`74
`Injection solution
`Chlorpromazine HCl
`76
`Syringe needle
`Diphenhydramine HCl
`77
`Injection solution
`Naloxone HCl
`79
`Dermal
`Cellulose, oxidized, regenerated
`79
`Injection solution
`Pancuronium bromide
`81
`Injection solution
`Calcium chloride
`81
`Emulsion
`Hexachlorophene cleansing
`84
`Injection solution
`Fentanyl citrate
`85
`Extended-release tablets
`Guaifenesin
`88
`Injection solution
`Bupivacaine HCl
`89
`Syringe needle
`Morhpine sulfate
`89
`Injection solution
`Sodium nitrite
`89
`Injection solution
`Meperidine HCl
`131
`Injection solution
`Sodium thiosulfate
`254
`Granules
`Potassium iodide
`FDA ¼ Food and Drug Administration; HCl ¼ hydrochloride; SLEP ¼ Shelf Life Extension
`Program.
`
`TABLE 2. SLEP Medication Stability Testing Results: <50% of Lots Initially
`Extended4
`
`Medication
`
`Extension time (mo), mean
`Form
`NA
`Inhalant
`Albuterol
`NA
`Spray
`Diphenhydramine HCl
`22
`Injection solution
`Levarterenol bitartrate
`24
`Tablets
`Ergotamine tartrate and caffeine
`29
`Injection solution
`Lidocaine HCl and epineprhine
`31
`Injection solution
`Physostigmine salicylate
`36
`Tablets
`Mefloquine HCl
`45
`Injection solution
`Isoproterenol HCl
`56
`Cartridge needle
`Phenobarbital sodium
`70
`Powder
`Penicillin G procaine
`HCl ¼ hydrochloride; NA ¼ not available; SLEP ¼ Shelf Life Extension Program.
`
`Mayo Clin Proc. n November 2015;90(11):1471-1474 n http://dx.doi.org/10.1016/j.mayocp.2015.08.007
`www.mayoclinicproceedings.org
`
`1473
`
`AMNEAL EX. 1012
`
`

`

`MAYO CLINIC PROCEEDINGS
`
`Abbreviations and Acronyms: FDA = Food and Drug
`Administration; HCl = hydrochloride; SLEP = Shelf Life
`Extension Program
`
`Correspondence: Address to Dayna G. Diven, MD, 601 E
`15th St, CEC 2.443, Austin, TX 78701 (dgdiven@seton.org).
`
`2.
`
`REFERENCES
`1. Expiration dating and stability testing for human drug products.
`US Food and Drug Administration website. http://www.fda.gov/
`ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/
`ucm072919.htm. Accessed July 23, 2015.
`International Conference on Harmonization. Guidance for industry
`Q1A(R2) stability testing of new drug substances and pro-
`ducts. http://www.fda.gov/downloads/drugs/guidancecompliance
`regulatoryinformation/guidances/ucm073369.pdf.
`Published
`November 2003. Accessed July 23, 2015.
`3. SLEP: The DOD/FDA shelf life extension program. https://slep.
`dmsbfda.army.mil/portal/page/portal/SLEP_PAGE_GRP/SLEP_
`HOME_NEW. Accessed July 23, 2015.
`4. Lyon RC, Taylor JS, Porter DA, Prasanna HR, Hussain AS.
`Stability profiles of medication products extended beyond
`labeled expiration dates. J Pharm Sci. 2006;95(7):1549-1560.
`5. Cantrell L, Suchard JR, Wu A, Gerona RR. Stability of active
`ingredients in long expired prescription medications. Arch Intern
`Med. 2012;172(21):1685-1687.
`
`6. Courtney B, Easton J,
`Inglesby TV, SooHoo C. Maximizing
`state and local medical countermeasure stockpile investments
`through the Shelf-Life Extension Program. Biosecur Bioterror.
`2009;7(1):101-107.
`7. Hoekenga MT. The role of pharmaceuticals in the total health care
`of developing countries. Am J Trop Med Hyg. 1983;32(3):437-446.
`8. World Health Organization. Guidelines for drug donations. http://
`www.who.int/hac/techguidance/guidelines_for_drug_donations.
`pdf. Revised 1999. Accessed July 23, 2015.
`9. Text of the Prescription Drug Marketing Act of 1987. US Food and
`Drug Administration website. http://www.fda.gov/Regulatory
`Information/Legislation/SignificantAmendmentstotheFDCAct/
`PrescriptionDrugMarketingActof1987/ucm201702.htm. Updated
`March 1, 2010. Accessed July 23, 2015.
`10. American Society of Health-Systems. Drug shortages summit
`summary report. http://www.ashp.org/drugshortages/summit
`report. Published November 5, 2010. Accessed July 23, 2015.
`11. Ventola CL. The drug shortage crisis in the United States: Causes,
`impact, and management strategies. P T. 2011;36(11):740-757.
`12. Drug shortages. American Society of Health-System Pharmacists
`website. http://www.ashp.org/menu/DrugShortages. Accessed July
`23, 2015.
`13. Blair BD, Crago JP, Hedman CJ, Klaper RD. Pharmaceuticals and
`personal care products found in the Great Lakes above con-
`centrations of environmental concern. Chemosphere. 2013;
`93(9):2116-2123.
`14. Clendenning WE. Complications of tetracycline therapy. Arch
`Dermatol. 1965;91(6):628-632.
`
`1474
`
`Mayo Clin Proc. n November 2015;90(11):1471-1474 n http://dx.doi.org/10.1016/j.mayocp.2015.08.007
`www.mayoclinicproceedings.org
`
`AMNEAL EX. 1012
`
`