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Original Research |

Burden of Changes in Pill Appearance for Patients Receiving Generic Cardiovascular Medications After Myocardial Infarction: Cohort and Nested Case–Control StudiesBurden of Changes in Pill Appearance

Aaron S. Kesselheim, MD, JD, MPH; Katsiaryna Bykov, PharmD, MS; Jerry Avorn, MD; Angela Tong, MS; Michael Doherty, MS; and Niteesh K. Choudhry, MD, PhD
[+] Article, Author, and Disclosure Information

From Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Financial Support: Dr. Kesselheim was supported by a career development award from the Agency for Healthcare Research and Quality (K08HS18465-01), the Greenwall Faculty Scholars Program in Bioethics, the Harvard Program in Therapeutic Science, and a Robert Wood Johnson Foundation Investigator Award in Health Policy Research. Dr. Kesselheim and Dr. Avorn receive research support from the FDA Office of Generic Drugs. Dr. Choudhry was supported by unrestricted research grants from CVS Caremark, Aetna, The Commonwealth Fund, and the Robert Wood Johnson Foundation.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2381.

Reproducible Research Statement:Study protocol: Available from Dr. Kesselheim (e-mail, akesselheim@partners.org). Statistical code: Not available. Data set: Available to approved persons through written agreements with the authors and data partner.

Requests for Single Reprints: Aaron S. Kesselheim, MD, JD, MPH, Division of Pharmacoepidemiology and Pharmacoeconomics, 1620 Tremont Street, Suite 3030, Boston, MA 02120; e-mail, akesselheim@partners.org.

Current Author Addresses: Drs. Kesselheim, Bykov, Avorn, and Choudhry; Ms. Tong; and Mr. Doherty: Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA 02120.

Author Contributions: Conception and design: A.S. Kesselheim, K. Bykov, J. Avorn, N.K. Choudhry.

Analysis and interpretation of the data: A.S. Kesselheim, K. Bykov, J. Avorn, M. Doherty, N.K. Choudhry.

Drafting of the article: A.S. Kesselheim, K. Bykov.

Critical revision of the article for important intellectual content: A.S. Kesselheim, J. Avorn, N.K. Choudhry.

Final approval of the article: A.S. Kesselheim, K. Bykov, J. Avorn, M. Doherty, N.K. Choudhry.

Provision of study materials or patients: J. Avorn.

Statistical expertise: K. Bykov, N.K. Choudhry.

Obtaining of funding: A.S. Kesselheim.

Administrative, technical, or logistic support: K. Bykov, J. Avorn, A. Tong.

Collection and assembly of data: A.S. Kesselheim, K. Bykov, M. Doherty.

Ann Intern Med. 2014;161(2):96-103. doi:10.7326/M13-2381
Text Size: A A A

Background: Generic prescription drugs made by different manufacturers may vary in color or shape, and switching among these drug products may interrupt medication use.

Objective: To determine whether nonpersistent use of generic drugs among patients with cardiovascular disease after myocardial infarction (MI) is associated with inconsistent appearance of their medications.

Design: Cohort and nested case–control studies.

Setting: Claims from a commercial health insurance database in the United States.

Patients: Patients discharged after hospitalization for MI between 2006 and 2011 who initiated treatment with a generic β-blocker, angiotensin-converting enzyme inhibitor, angiotensin II–receptor blocker, or statin. Case patients discontinued their index medication for at least 1 month; control patients continued treatment. Control patients were matched to case patients on therapeutic class, number of dispensings before nonpersistence, sex, and age.

Measurements: Rates of changes in pill color and shape during the year after MI were calculated. Next, 2 refills preceding nonpersistence were evaluated to determine whether pill color or shape had changed. Odds of discordance among case and control patients were compared using conditional logistic regression.

Results: A total of 29% of patients (3286 of 11 513) had a change in pill shape or color during the study. Statins had the most changes in appearance, whereas β-blockers had the fewest. A total of 4573 episodes of nonpersistence was matched to 19 881 control episodes. The odds of nonpersistence in case patients increased by 34% after a change in pill color (adjusted odds ratio, 1.34 [95% CI, 1.12 to 1.59]) and 66% after a change in pill shape (adjusted odds ratio, 1.66 [CI, 1.43 to 1.94]).

Limitation: Only 3 categories of drugs indicated after MI were evaluated, and clinical outcomes were not addressed.

Conclusion: Variation in the appearance of generic pills is associated with nonpersistent use of these essential drugs after MI among patients with cardiovascular disease.

Primary Funding Source: Agency for Healthcare Research and Quality and the Harvard Program in Therapeutic Science.


Grahic Jump Location

Organization of cohort and nested case–control studies.

MI = myocardial infarction.

* No history in the prior 6 mo of receiving any drugs in the same therapeutic class.

† Control patients were selected from members of the cohort who were receiving the same class of drugs as case patients; were still under observation when case patients discontinued their index medication; and were further matched on age (±5 y), sex, and the number of dispensings of the index medication.

Grahic Jump Location
Grahic Jump Location
Appendix Figure.

Study flow diagram.

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II–receptor blocker; MI = myocardial infarction.

Grahic Jump Location




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Submit a Comment/Letter
Changes in Generic Pill Appearance and Errors
Posted on July 18, 2014
Stephen Pauker MD MACP
Tufts Medical Center, Boston
Conflict of Interest: None Declared
Kesselheim and co-authors (1) provide data on the burden of changes in the appearance of generic medications in terms of patients' discontinuing their generic medication. Although this is an important finding, it is only the tip of the iceberg of risk for generic medications. As a caregiver for my elderly mother and as a patient, both with a suite of chronic conditions requiring multiple medications, I believe a far greater problem is that changes in the appearance generic pills greatly increase the likelihood of medication errors. Although all medications a neatly are delivered in labeled, but difficult to open , containers, they are often decanted into one day per week pill boxes for convenience and to enhance compliance. As such, patients with limited vision often rely on pills' shape, size and color to distinguish among them. When a pill's appearance is changed, it can cause confusion and errors.

Even generic medications are regulated by the FDA in terms of purity, strength, and potency. I believe there should be no reason that such regulation cannot be extended to a pill's appearance. This is an issue of patient safety and bears immediate attention. [191 words]

Stephen G. Pauker, MD, MACP
Professor of Medicine and Psychiatry
Tufts Medical Center
Boston, MA 02111
617-636-5910 (o) 781-647-9692 (h)

1. Kesselheim AS, Bykov K, Avorn J, Tong A, Doherty M, Choudhry NK: Burden of changes in pill appearance for patients receiving generic cardiovascular medications after myocardial infarction : Cohort and nested case–control studies
Allowable Changes in Generic Pill Appearance
Posted on August 15, 2014
Kathleen Uhl, MD, John R Peters, MD
FDA/CDER/Office of Generic Drugs
Conflict of Interest: None Declared
There are many reasons for patient non-adherence with a prescribed therapeutic regimen. In the July 15, 2014 article, “Burden of Changes in Pill Appearance…,” the authors (Kesselheim, et al) identify an important contributor: variability in the appearance (e.g., shape, color, and size) of tablets and resulting effects on patient adherence and clinical response. We realize that changes in pill appearance and packaging can contribute to patient non-compliance and FDA has published draft guidances addressing certain aspects of these concerns , , Since generic drugs currently represent nearly 85% of prescriptions dispensed [to patients], patients will continue to experience changes in pill appearance, as economic forces lead to product turnover in pharmacies and mail-order houses. These points of distribution may not carry the same manufacturer’s generic product between initial dispensing and refill. Additionally, appearance changes are not just an issue with generic drugs; brand name drugs sometimes undergo post-approval manufacturing changes that impact patient acceptance. For example, in 2007 the appearance of Dilantin was changed from a white capsule with a red stripe to a larger white capsule with orange on one end. Following this change there was an increase in reports of break through seizures.
Additionally, the legal protections for drug product characteristics known as “trade dress” are extensive. Even characteristics such as color can constitute a defensible trademark. Drs. Greene and Kesselheim have previously reviewed this issue for interchangeable generic drugs. Given the broad protections for many aspects of the physical characteristics of a branded drug, an FDA requirement that a generic drug have the same or similar size, shape, and color as the reference drug could effectively eliminate the ability to market a generic product in many cases, thus restricting/limiting patient access to more affordable medicines.
FDA has become more sophisticated in providing protocols and methodologies that ensure bioequivalence of generic products. We recognize the importance of the physical characteristics of drugs and packaging as factors in a patient’s smooth transition from brand-to-generic and generic-to-generic. Short of significant changes in the legal protections for trade dress and trademark, two options exist for the FDA to address the issue: (1) advice to manufacturers through guidance documents; and (2) surveillance of the approved generic products to identify any potential failure of therapeutic effect or change in risk profile relative to the branded reference product. We note that the authors have received FDA funding to investigate the social science aspects of the very issue raised in their paper.
FDA has worked within the limits of its legal authority to use both of these options to ensure the continued safety, efficacy, and substitutability of bioequivalent products for the public. Differing pill appearances confuse both patients and physicians. In the current system, the dispensing pharmacist has the responsibility of explaining these differences to concerned patients.
Kathleen Uhl, MD
Acting Director, Office of Generic Drugs
Center for Drug Evaluation and Research
Food and Drug Administration
Silver Spring, MD, 20993

John R Peters, MD
Acting Director, Office of Bioequivalence
Office of Generic Drugs
Center for Drug Evaluation and Research
Food and Drug Administration
Silver Spring, MD, 20993
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