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P T. 2013;38(9): 535, 537-540

Identifying Knowledge Gaps in the Labeling of Medications for Geriatric Patients

Trevor Hinshaw
Joan Kapusnik-Uner PharmD
Barbara Zarowitz PharmD
Karl Matuszewski MS, PharmD

INTRODUCTION

The long-held belief that information about pediatric drugs (e.g., efficacy, safety, and dosage) is often lacking in manufacturers’ product labeling in the U.S. has been recently confirmed; only 41% of medications approved from 2002 to 2008 have labeling specific to pediatrics.1 Similar suspicions apply to the content of the prescribing information about medications intended for geriatric patients.

In 2012, the U.S. Government Accountability Office (GAO) indicated that few patients older than 65 years of age were enrolled in drug trials for New Drug Applications (NDAs) from January 2001 through June 2004, and it encouraged a re-examination of the guidance and regulations governing drug approvals.2

It is well established that older patients show considerable differences in drug tolerance and in pharmacokinetic and pharmacodynamic responses to medications, compared with non-geriatric groups.3 Further, the U.S. Census Bureau anticipates a doubling of the geriatric population by 2040.4 With the projected rapid increase in the number of elderly people needing health care, clinicians must have sufficient knowledge about new drugs so that they can safely prescribe them to this patient population and avoid unnecessary adverse effects and hospitalizations.5,6

An editorial published in 2011 underscored the problem by emphasizing the inadequacy of current guidance for medication use in the elderly, particularly individuals older than 75 years of age.7 Because some adverse effects, as well as the potential for exaggerated clinical, biobehavioral, or functional consequences of drug therapy, may be more prevalent in the elderly, adequate information is essential in guiding drug selection, dosage regimens, and monitoring. Modeling and simulation studies often fail to provide sufficient data to ensure drug safety in geriatric patients.

We conducted a study to assess the labeling content in the product information of drugs approved relatively recently in the U.S. (from 2002 to 2011). We were primarily interested in reviewing the adequacy of the labeling used to inform prescribers and other health care professionals about medications for elderly patients. Our goal was to determine whether a knowledge gap existed in the labeling of drugs intended for older patients.

METHODS

For this investigation, we adopted the definition of the term “geriatric,” as used by the FDA, to mean patients 65 years of age or older.8 We obtained a listing of all new molecular entities (NMEs) and biologics approved by the FDA in the previous decade from the agency’s Web site (www.fda.gov). Drug indications, geriatric information, and dosages were extracted from current FDA-approved labeling, as found in the National Library of Medicine’s DailyMed repository.9

Drugs were reviewed to determine whether they would be expected to have a geriatric use or whether age-specific dosing might be required. Of a total of 235 medications, 12 drugs (contraceptives and sunscreens) were excluded from further analysis because a lack of geriatric labeling was unlikely to constitute a knowledge gap. A schema of the study flow is provided in Figure 1.

Two of the authors (T. H. and J. K.-U.) rated the 223 drugs remaining as having either sufficient or insufficient information in the manufacturer’s FDA-approved labeling to be prescribed safely to a geriatric patient. The schema shown in Table 1, created by the authors, was based on the premise that labeling information might be helpful but not always explicit regarding how medicine is practiced in the “real world.” We based the classifications in Table 1 on the adequacy of prescribing information specifically related to the geriatric population.

We evaluated the product information (the FDA-approved label) of each medication and gave a score based on points assigned for three rating criteria:

  • reference to a sample of studied geriatric patients, such as from the package insert for cetuximab (Erbitux, Bristol-Myers Squibb/ImClone): “363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.”
  • inclusion of geriatric-specific information about dosage, such as from the package insert for vilazodone (Viibryd, Forest): “no dose adjustment is recommended on the basis of age.”
  • availability of focused information on the safe use of the drug in patients with renal insufficiency, such as from the prescribing information for cabazitaxel (Jevtana, Sanofi-Aventis): “no significant difference was observed in the pharmacokinetics of cabazitaxel between patients > 65 years ... and older.”
  • The maximum score for a well-studied drug could be 5 points. A score of 3 or lower was considered to constitute a knowledge gap, and a score of 4 or higher was considered to constitute no knowledge gap.

    We subsequently sent product information from medications that were rated preliminarily as having inadequate labeling to be reviewed by four clinicians with expertise in geriatric medicine. All of these experts had at least 15 years of clinical practice in geriatrics, were board-certified in geriatric pharmacy, and had written review articles and research publications in the geriatric and pharmacy literature. The reviewers were asked whether the drug (1) had potential use (i.e., relevance) in geriatric patients and (2) was an “important” entity for the geriatric population.

    All drugs that were considered by at least two experts to have potential use were included in the analysis. We excluded some drugs if fewer than two experts considered them to have a geriatric use. Therefore, we excluded nine more drugs (in addition to the 12 previously excluded) that were not considered to be associated with a geriatric knowledge gap. The excluded drugs and their indications can be found in Table 2.

    RESULTS

    Our expert panel considered 214 of the 235 drugs (91%) that were approved by the FDA within the previous decade to be relevant for geriatric patients. The year-by-year breakdown for NMEs is presented in Table 3.

    Of the 214 medications that underwent further evaluation, 143 (67%) were considered to be associated with a labeling knowledge gap, as determined by a score of 3 or less by our rating schema. Of the drugs associated with a knowledge gap, 90 of the total number evaluated (42%) were considered to be “important” by the experts (Table 4). The summary “point score” of the medications judged to be relevant to geriatrics and with a knowledge gap is depicted in Table 5.

    Medications that were considered to be both associated with and not associated with a geriatric knowledge gap are categorized by therapeutic class in Table 6.

    Figure 2 displays the annual number of geriatric-relevant medications associated with a knowledge gap, approved by the FDA between 2002 and 2011, compared with the total number of NMEs approved in the same time period. A knowledge gap was judged to apply to more than one-third of geriatric-relevant NMEs approved each year during this time period.

    DISCUSSION

    In our analysis, two-thirds of medications (143/214) relevant to geriatrics and FDA-approved in the previous 10 years were found to lack adequate prescribing information about efficacy and safety data for use in older populations. With the anticipated exponential growth of the baby-boomer age group, health care practitioners must have sufficient data on safety and efficacy when they prescribe or monitor newly approved drugs often indicated for patients older than age 65 or 75. Federal legislation and FDA regulations require that drugs be tested for safety and efficacy in specific populations, at a specific dosage, and for a specific time period before they are approved for clinical use. The use of drugs that have not undergone this level of testing by the manufacturer is broadly classified as “off-label.”10

    CONCLUSION

    Clinicians are left with few options other than to start elderly patients with the lowest doses available and to titrate the doses upward slowly. Although recent efforts by the American Geriatrics Society to update a long-stagnant list of potentially inappropriate drugs for use in the elderly are helpful,11 perhaps the time has come for additional incentives (e.g., tax credits, extended patent protection) to be provided to drug manufacturers to study and incorporate more robust prescribing information into their product labels for drugs used in geriatric patients.

    Figures and Tables

    Schema of study data flow.

    Number of relevant drugs compared with relevant drugs with knowledge gap. NME = new molecular entity.

    Rating Schema for Adequacy of Labeling Information in Medications for Geriatric Patients

    No. of Geriatric Patients Studied Available Geriatric Dosing Guidance Renal Concerns
    No comment/none studied = 0 point No comment = 0 point No comment = 0 point
    Small number, but some information described = 1 point Geriatric caution advised = 1 point Information available = 1 point
    Adequately studied = 2 points Explicit recommendation = 2 points

    Medications Excluded From Analysis Because of Limited Geriatric Use (n = 21)

    Drug Name Indication
    Lisdexamfetamine dimesylate (Vyvanse) Treatment of attention-deficit/hyperactivity disorder
    Nitisinone (Orfadin) Adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type-1
    Benzyl alcohol Topical treatment of head lice infestation in patients 6 months of age and older
    Spinosad (Natroba suspension) Topical treatment of head lice infestation in patients 4 years of age and older
    Mecasermin rinfabate [rDNA origin] injection (Iplex); preservative-free Treatment of growth failure in children with severe primary IGF-1 deficiency or with growth hormone gene deletion who have developed neutralizing antibodies to growth hormone (not for long-term treatment)
    Mecasermin [rDNA origin] injection (Increlex); benzyl alcohol, sodium chloride, polysorbate 20, and acetate Treatment of growth failure in children with severe primary IGF-1 deficiency or with growth hormone gene deletion who have developed neutralizing antibodies to growth hormone (long-term treatment)
    Estradiol valerate/dienogest (Natazia)
    • Used by women to prevent pregnancy
    • Treatment of heavy menstrual bleeding in women without organic pathology who use an oral contraceptive
    Ulipristal acetate (ella) Prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure; not intended for routine use as a contraceptive
    Hyaluronidase (Hydase; Vitrase) Adjuvant
    • Used to treat hypodermoclysis
    • Used to increase dispersion and absorption of other injected drugs
    • Used in subcutaneous urography to improve resorption of radiopaque agents
    Hyaluronidase, human [recombinant DNA] injection (Hyenex) Adjuvant
    • Used in subcutaneous fluid administration to achieve hydration
    • Used to increase dispersion and absorption of other injected drugs
    • Used in subcutaneous urography to improve resorption of radiopaque agents
    Hyaluronidase, ovine (Amphadase) Adjuvant
    • Used in subcutaneous fluid administration to achieve hydration
    • Used to increase dispersion and absorption of other injected drugs
    • Used in subcutaneous urography to improve resorption of radiopaque agents
    Avobenzone (Parsol), ecamsule (Mexoryl), octocrylene Sunscreen lotion protection against ultraviolet A and B light
    Alglucosidase alfa (Myozyme, Lumizyme) Treatment of Pompe disease (acid alpha-glucosidase deficiency)
    Idursulfase (Elaprase) Treatment of Hunter syndrome (MPS type-II)
    Galsulfase (Naglazyme) Treatment of Maroteaux–Lamy syndrome (MPS type-VI)
    Clofarabine (Clolar) Treatment of pediatric patients 1 to 21 years of age with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens
    Pentetate calcium trisodium (pentetic acid) injection Treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination
    Pentetate zinc trisodium (Zn-DTPA) Treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination
    Ferric hexacyanoferrate (Prussian Blue) Treatment of patients with known or suspected internal contamination with radioactive cesium and/or radioactive or non-radioactive thallium to increase rates of elimination
    Carglumic acid (Carbaglu)
    • Adjunctive therapy for acute hyperammonemia caused by a deficiency of the hepatic enzyme NAGS
    • Maintenance therapy for chronic hyperammonemia caused by a deficiency of the hepatic enzyme NAGS

    IGF = insulin growth factor; MPS = mucopolysaccharidosis; NAGS = N-acetylglutamate synthase; rDNA = recombinant DNA.

    Results of the Geriatric Knowledge Gap Analysis

    Year 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Overall
    Total No. of NMEs approved 17 21 36 20 22 18 24 26 21 30 235
    NMEs considered relevant for geriatrics 16 20 31 15 19 17 24 25 18 29 214
    NMEs with a geriatric knowledge gap (%)* 9 (56) 12 (60) 20 (65) 11 (73) 13 (68) 14 (82) 14 (67) 16 (64) 15 (83) 19 (66) 143 (67)
    NMEs considered important with a knowledge gap (%)* 4 (25) 8 (40) 15 (48) 9 (60) 8 (42) 9 (53) 11 (52) 8 (32) 8 (44) 10 (35) 90 (42)

    *Percentage of new molecular entities (NMEs) considered relevant for geriatrics.

    Drugs Associated With a Knowledge Gap but Considered Important in Geriatrics (n = 90)

    Trypan Blue (e.g., VisionBlue) Retapamulin (Altabax) Gadoxetate disodium (Eovist)
    Difluprednate (Durezol) Lapatinib (Tykerb) Romiplostim (Nplate)
    Tetrabenazine (Xenazine) Ambrisentan (Letaris) Eltrombopag olamine (Promacta)
    Natalizumab (Tysabri) Etravirine (Intelence) Vigabatrin (Sabril)
    Panitumumab (Vectibix) Certolizumab pegol (Cimzia) Golimumab (Simponi)
    Ixabepilone (Ixempra) Regadenoson (Lexiscan) Pralatrexate (Folotyn)
    Temsirolimus (Torisel) Gadofosveset trisodium (Ablavar) Dalfampridine (Ampyra)
    Crizotinib (Xalkori) Degarelix (Firmagon) Gabapentin enacarbil (Horizant)
    Perflexane (Imagent) and perflutren (Definity) phospholipid microspheres Tolvaptan (Samsca) Nepafenac (Nevanac)
    Icodextrin (Extraneal, Adept) Romidepsin (Istodax) Alfuzosin HCl (Uroxatral)
    Fulvestrant (Faslodex) Pazopanib (Votrient) Pegaptanib sodium (Macugen)
    Enfuvirtide (Fuzeon) Tocilizumab (Actemra) Aliskiren (Tekturna)
    Abarelix (Plenaris), withdrawn Eribulin mesylate (Halaven) Dronedarone HCl (Multaq)
    Gefitinib (Iressa) Fingolimod HCl (Gilenya) Denosumab (Prolia)
    Bortezomib (Velcade) Cabazitaxel (Jevtana) Aflibercept (Eylea)
    l-Glutamine Rilpivirine (Edurant) Rasagiline mesylate (Azilect)
    Omega-3-acid ethyl esters (Lovaza, Vascepa) Belatacept (Nulojix) Ranolazine (Ranexa)
    Lanthanum carbonate hydrate (Fosrenal) Abiraterone acetate (Zytiga) Rotigotine (Neupro)
    Bevacizumab (Avastin) Ipilimumab (Yervoy) Silodosin (Rapaflo)
    Palifermin (Kepivance) Ioflupane I-123 injection (DaTScan) Prasugrel (Effient)
    Tipranavir (Aptivus) Treprostinil sodium (Tyvaso) Ticagrelor (Brilinta)
    Pramlintide acetate (Symlin) Emtricitabine (Emtriva) Memantine HCl (Namenda)
    Tigecycline (Tigacil) Palonosetron HCl (Aloxl) Liraglutide (Victoza)
    Conivaptan HCl (Vaprisol) Acamprosate calcium (Campral) Solifenacin succinate (Vesicare)
    Darunavir (Prezista) Iloprost (Ventavis) Insulin glulisine (Apidra)
    Lubiprostone (Amitiza) Apomorphine HCl (Apokyn) Ramelteon (Rozarem)
    Decitabine (Dacogen) Ziconotide (Prialt) Exenatide (Byetta, Bydureon)
    Sunitinib malate (Sutent) Gadobenate dimeglumine (MultiHance) Insulin detemir (Levemir)
    Maraviroc (Selzentry) Abatacept (Orencia) Dabigatran etexilate (Pradaxa)
    Raltegravir potassium (Isentress) Vorinostat (Zolinza) Rivaroxaban (Xarelto)

    Evaluation of Relevant Drugs in the Elderly Included in the Knowledge Gap Analysis

    Point score 0 1 2 3 4 5
    No. of drugs 15 18 66 44 43 28
    Total and interpretation Knowledge gap further reviewed by experts (n = 143, 67%) No knowledge gap (n = 71, 33%)

    Therapeutic Class by Drug Score (Top 10 Classes)

    Drug Class No. of Drugs Scoring
    0–3 Points: Knowledge Gap 4–5 Points: No Knowledge Gap
    Unclassified 29 8
    Antineoplastic 32 7
    Anti-infective (antimicrobial, antiviral) 18 5
    Dermatological 9 1
    Diagnostic 9 1
    Hematological 6 7
    Gastrointestinal 7 4
    Cardiovascular 4 5
    Psychotherapeutic 2 10
    Neurological 5 3
    Author bio: 
    At the time of this study, Mr. Hinshaw was employed at First Databank, Inc. He is currently a student at Gordon College in Wenham, Massachusetts. Dr. Matuszewski, Associate Editor-in-Chief of P&T, is Vice President at First Databank, Clinical and Editorial Knowledge Base Services, in South San Francisco, California. Dr. Kapusnik-Uner is Director of Clinical Editorial at First Databank. Dr. Zarowitz is Chief Clinical Officer at Omnicare in Cincinnati, Ohio.

    References

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