Pill Shape, Color Linked to Adherence with Anti-Epileptics

Shape and color differences between branded and generic drugs may be associated with medication discontinuation, according to the findings of a nested case-control study.

Aaron S. Kesselheim, MD, JD, MPH, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues published their findings online December 31, 2012, in the Archives of Internal Medicine.

The authors assert that differences in the appearance of bioequivalent drugs may have severe consequences on patient care. "Changes between generic products with different physical characteristics may cause confusion and result in reduced adherence or prescription error," the authors write. "However, we could find no empirical studies of the consequences of changes in pill appearance in a population-based analysis."

Therefore, the authors collected medical and pharmacy data from the Health-Core Integrated Research Database to clarify the relationship between pill characteristics and patient adherence for 8 antiepileptic drugs. Among 11,472 patients with episodes of antiepileptic drug nonpersistence (defined by a failure to fill a new prescription within 5 days of the elapsed days supplied) and 50,050 control patients (matched for age, sex, number of refills, and seizure disorder diagnosis) with no episodes of nonpersistence, differences in color were associated with a 27% greater likelihood of medication nonpersistence (adjusted odds ratio [aOR], 1.27; 95% confidence interval [CI], 1.04 - 1.55).

The participants included patients who received at least 3 dispensings (the initial fill and 2 refills) of the same drug, dose, and route. In addition, the researchers performed multivariate analysis with adjustment for patient characteristics such as age and sex and drug type.

Among patients with a seizure disorder, differences in pill color were associated with a 53% greater likelihood of medication nonpersistence (aOR, 1.53; 95% CI, 1.07 - 2.18). Changes in pill shape were associated with increased odds of pill discordance both for the entire sample (aOR, 1.47; 95% CI, 0.85 - 2.54) and for patients with a seizure disorder (aOR, 3.15; 95% CI, 0.82 - 12.1), although the researchers indicate that these differences were not significant.

The authors also note that differences in color were more common than differences in shape, with ethosuximide, for example, being available in 19 different color combinations.

The limitations of the study included the lack of monitoring of pill usage and the potentially limited generalizability of the findings because of the focus on antiepileptic drugs.

The authors conclude that measures are needed to ensure that patients continue to take their medicines after switching between bioequivalent drugs. "Promoting medication adherence is a difficult task, and it has been only partially addressed through strategies such as enhanced prescribing and generic drugs and reducing drug copayments," the authors write. "Taking steps to permit (or even require) similarity in pill appearance among bioequivalent brand-name and generic drugs may offer another way to achieve better patient adherence to essential medication regimens."

Michael Privitera, MD, director of the UC Health Cincinnati Epilepsy Center in Ohio, agreed that differences in color and shape could result in patient noncompliance. "Generic products are typically required to look different from the brand, and usually from one another," Dr. Privitera told Medscape Medical News by email. "For the patient taking 5 or more medications per day (not unusual in older patient groups), the switches in pill color and shape could be contributing to problems with generic performance."

He continued, "For example, many retrospective studies have suggested that once switched to generics, people with epilepsy may have more adverse effects and/or reduced seizure control. The FDA's position is that the testing for generic products is adequate to assure the public that generic drugs are equivalent to brand products. However, changes in adherence could possibly explain some of the variability in clinical performance of generic drugs."

Dr. Kesselheim reports having received research funding from the Agency for Healthcare Research and Quality and the Robert Wood Johnson Foundation. One coauthor received grants from CVS Caremark, Aetna, the Commonwealth Fund, and the Robert Wood Johnson Foundation. One coauthor received research funding from CVS Caremark, Aetna, Teva, Lilly, and the National Association of Chain Drug Stores. The other authors have disclosed no relevant financial relationships. Dr. Privitera reports having received research funding from the FDA, UCB, and Eisai, and he serves on safety monitoring boards for Lilly and Upsher Smith Laboratories.

Arch Intern Med. Published online December 31, 2012. Abstract