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Off-label Prescribing Among Office-Based Physicians
Abstract
BACKGROUND: Unlike medicines prescribed for Food and Drug Administration-approved indications, off-label uses may lack rigorous scientific scrutiny. Despite concerns about patient safety and costs to the health care system, little is known about the frequency of off-label drug use or the degree of scientific evidence supporting this practice. METHODS: We used nationally representative data from the 2001 IMS Health National Disease and Therapeutic Index (NDTI) to define prescribing patterns by diagnosis for 160 commonly prescribed drugs. Each reported drug-diagnosis combination was identified as Food and Drug Administration-approved, off-label with strong scientific support, or off-label with limited or no scientific support. Outcome measures included (1) the proportion of uses that were off-label and (2) the proportion of off-label uses supported by strong scientific evidence. Multivariate analyses were used to identify drug-specific characteristics predictive of increased off-label use. RESULTS: In 2001, there were an estimated 150 million (95% confidence interval, 127-173 million) off-label mentions (21% of overall use) among the sampled medications. Off-label use was most common among cardiac medications (46%, excluding antihyperlipidemic and antihypertensive agents) and anticonvulsants (46%), whereas gabapentin (83%) and amitriptyline hydrochloride (81%) had the greatest proportion of off-label use among specific medications. Most off-label drug mentions (73%; 95% confidence interval, 61%-84%) had little or no scientific support. Although several functional classes were associated with increased off-label use (P<.05), few other drug characteristics predicted off-label prescription. CONCLUSIONS: Off-label medication use is common in outpatient care, and most occurs without scientific support. Efforts should be made to scrutinize underevaluated off-label prescribing that compromises patient safety or represents wasteful medication use.
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“A study mining US Health National Disease and Therapeutic Index (NDTI) prescription data showed that 21% of overall drug use is off-label, of which 73% had little or no scientific support (17).”
From DrugCentral 2023 extends human clinical data and integrates veterinary drugs (2023) · cites this paper as [17]
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“Among medications used off-label, 73% lacked evidence of clinical efficacy and only 27% were supported by strong scientific evidence ( 3 ).”
BackgroundStudies with Many Covariates and Few Outcomes
Patorno, E., Glynn, R. J., Hernández–Dı́az, S., Liu, J., & Schneeweiß, S. (2014) · Epidemiology · doi:10.1097/ede.0000000000000069 · Cited by 60
Shifting Terrain in the Regulation of Off-Label Promotion of Pharmaceuticals
Mello, M. M., Studdert, D. M., & Brennan, T. A. (2009) · New England Journal of Medicine · doi:10.1056/nejmhle0807695 · Cited by 59
Unlicensed and Off-Label Drug Use in Children Before and After Pediatric Governmental Initiatives
Corny, J., Lebel, D., Bailey, B., & Bussières, J. (2015) · The Journal of Pediatric Pharmacology and Therapeutics · doi:10.5863/1551-6776-20.4.316 · Cited by 57
Off‐label prescribing patterns of antidepressants in children and adolescents
Lee, E., Teschemaker, A. R., Johann‐Liang, R., Bazemore, G., Yoon, M., Shim, K., Daniel, M. G., Pittman, J., & Wutoh, A. K. (2011) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.2145 · Cited by 56
“in 2006, which indicated that approximately 73% of off‐label prescribing lacked scientific evidence of the drug’s effectiveness.(27) Further, prescribing decisions may have been influenced by patients, such as due to direct consumer advertisement.”
BackgroundAutomated Detection of Off-Label Drug Use
Jung, K., LePendu, P., Chen, W. S., Iyer, S. V., Readhead, B., Dudley, J. T., & Shah, N. H. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089324 · Cited by 56
“Estimates from office-based practices found that 21% of prescriptions are off-label [3].”
BackgroundSutherell, J. S., Hirsch, R., & Beekman, R. H. (2010) · Congenital Heart Disease · doi:10.1111/j.1747-0803.2009.00364.x · Cited by 55
Wilkes, M. S., & Johns, M. Z. (2008) · PLoS Medicine · doi:10.1371/journal.pmed.0050223 · Cited by 54
Sahragardjoonegani, B., Beall, R. F., Kesselheim, A. S., & Hollis, A. (2021) · Journal of Pharmaceutical Policy and Practice · doi:10.1186/s40545-020-00282-8 · Cited by 52
Off-Label Use of Topical Calcineurin Inhibitors in Dermatologic Disorders
Guenther, L., Lynde, C. W., & Poulin, Y. P. (2019) · Journal of Cutaneous Medicine and Surgery · doi:10.1177/1203475419857668 · Cited by 53
Vickers‐Smith, R., Sun, J., Charnigo, R. J., Lofwall, M. R., WALSH, S. L., & Havens, J. R. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.107709 · Cited by 55
The Prevalence and Cost of Unapproved Uses of Top-Selling Orphan Drugs
Kesselheim, A. S., Myers, J. A., Solomon, D. H., Winkelmayer, W. C., Levin, R., & Avorn, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031894 · Cited by 51
“Though the FDA approves drugs for specific indications, physicians freely prescribe products for other purposes or patient populations (‘‘off-label’’) [12].”
BackgroundZhou, L., Bhattacharjee, S., Kwoh, C. K., Tighe, P. J., Malone, D. C., Slack, M. K., Wilson, D. L., Brown, J. D., & Lo‐Ciganic, W. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm9010083 · Cited by 51
“reported that 83% of gabapentin prescriptions were for off-label use in 2001 [13].”
BackgroundLarkin, I., Ang, D., Avorn, J., & Kesselheim, A. S. (2014) · Health Affairs · doi:10.1377/hlthaff.2013.0939 · Cited by 50
Off-Label Use vs Off-Label Marketing of Drugs
Van Norman, G. A. (2023) · JACC: Basic to Translational Science · doi:10.1016/j.jacbts.2022.12.011 · Cited by 49
“Adapted from Radley et al.(3) J A C C : B A S I C T O T R A N S L A T I O N A L S C I E N C E V O L .”
MethodPrescribing Gabapentin off Label: Perspectives from Psychiatry, Pain and Neurology Specialists
Fukada, C., Köhler, J. C., Boon, H. S., Austin, Z., & Krahn, M. D. (2012) · Canadian Pharmacists Journal / Revue des Pharmaciens du Canada · doi:10.3821/145.6.cpj280 · Cited by 50
“indicated that gabapentin was among the medications with the highest proportion of off-label use, with 83% of its use being off label.(9) Gabapentin was initially approved in Canada in April 1994 as adjunctive therapy for the management of epilepsy among patients over 18 years of age who are not controlled by conventi…”
BackgroundHealth Care Transitions: A Review of Integrated, Integrative, and Integration Concepts
Johnson, C. D. (2009) · Journal of Manipulative and Physiological Therapeutics · doi:10.1016/j.jmpt.2009.11.001 · Cited by 48
Eguale, T., Winslade, N. E., Hanley, J. A., Buckeridge, D. L., & Tamblyn, R. M. (2010) · Drug Safety · doi:10.2165/11534580-000000000-00000 · Cited by 47
Increasing use of atypical antipsychotics and anticonvulsants during pregnancy
EPSTEIN, R. A., Bobo, W. V., Shelton, R. C., Arbogast, P. G., Morrow, J., Wang, W., Chandrasekhar, R., & Cooper, W. O. (2012) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.3366 · Cited by 48
A Short History of Dapsone, or an Alternative Model of Drug Development
Barr, J. (2010) · Journal of the History of Medicine and Allied Sciences · doi:10.1093/jhmas/jrq068 · Cited by 45
The Agenda for Continuing Medical Education — Limiting Industry's Influence
Morris, L., & Taitsman, J. K. (2009) · New England Journal of Medicine · doi:10.1056/nejmsb0905411 · Cited by 45
Peckham, A. M., Evoy, K. E., Covvey, J. R., Ochs, L. A., Fairman, K. A., & Sclar, D. A. (2018) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.2096 · Cited by 44
“Furthermore, only 20% of this prescribing was for indications with strong scientific evidence, whereas the remaining 80% had little to no support.(4) Although this evidence is alarming on its own, it is especially noteworthy in light of the increased volume of gabapentin prescriptions.”
BackgroundInfluentialDrug Repositioning for Alzheimer’s Disease: Finding Hidden Clues in Old Drugs
Ihara, M., & Saitô, S. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200049 · Cited by 45
Smithburger, P. L., Buckley, M. S., Culver, M. A., Sokol, S. S., Lat, I., Handler, S. M., Kirisci, L., & Kane‐Gill, S. L. (2015) · Critical Care Medicine · doi:10.1097/ccm.0000000000001022 · Cited by 43
“About 21% of medications prescribed in an outpatient setting were used for non-FDA-approved indications, with the vast majority (73%) having little or no evidence supporting their use (6).”
BackgroundOff-Label Medication Use in the Inpatient Palliative Care Unit
Kwon, J. H., Kim, M. J., Bruera, S., Park, M., Bruera, E. D., & Hui, D. (2017) · Journal of Pain and Symptom Management · doi:10.1016/j.jpainsymman.2017.03.014 · Cited by 43
“study of general outpatient practices found that 21% of prescribed medications or an estimated 150 million prescriptions were off-label (1), while another study in Quebec, Canada found off-label use to be 11.”
BackgroundZhou, L., Bhattacharjee, S., Kwoh, C. K., Tighe, P. J., Reisfield, G. M., Malone, D. C., Slack, M. K., Wilson, D. L., Chang, C., & Lo‐Ciganic, W. (2020) · Addiction · doi:10.1111/add.15189 · Cited by 43
Metadata
- Authors
- Radley, D. C., Finkelstein, S. N., & Stafford, R. S.
- Affiliations
- Dartmouth College (US)
- Venue
- Archives of Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2006-05-08
- Volume
- 166
- Issue
- 9
- Pages
- 1021
- ISSN
- 0003-9926 (ISSN-L)
- OpenAlex
- W2121487587
- Cited by
- 711
- References
- 25
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 24 · 2023: 23 · 2022: 37 · 2021: 45 · 2020: 30 · 2019: 32 · 2018: 40 · 2017: 31 · 2016: 34 · 2015: 54 · 2014: 43 · 2013: 44 · 2012: 53
- FWCI
- 31.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agency for Healthcare Research and Quality (R01-HS013405)
- Topics
- Health Sciences › Nursing › Issues, ethics and legal aspects › Pharmaceutical industry and healthcare
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Social Sciences › Economics, Econometrics and Finance › Economics and Econometrics › Pharmaceutical Economics and Policy
- Keywords
- off-label drug use, office-based physicians, prescribing patterns, cardiovascular drugs, antiepileptic drugs, gabapentin, amitriptyline, outpatient care, patient safety, medication use
- MeSH terms
- Gabapentin, Adult, Amines, Amitriptyline, Anticonvulsants, Cardiovascular Agents, Cyclohexanecarboxylic Acids, Drug Labeling, Female, gamma-Aminobutyric Acid, Humans, Male, Middle Aged, Practice Patterns, Physicians', Drug Prescriptions, United States, United States Food and Drug Administration, Multivariate Analysis, Drug Utilization Review
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