Changing color of antiepileptic pills raises risk of patients’ non-adherence, study shows

Changing the color of antiepileptic tablets is associated with an increased risk of patients with seizure disorder stopping taking them as prescribed, a US study has found.1

Researchers analyzed a national database of prescription records of patients with health insurance who started taking an antiepileptic drug between 2001 and 2006. They identified 11 472 patients as being “non-persistent,” defined as failing to fill a prescription within five days of the date required to take the drug as prescribed.

They assessed changes in pill color and shape of generic drugs dispensed in the two refills before patients became non-persistent and compared them with 50 050 controls who had no delay in refilling their prescription, matched for age, sex, and duration of antiepileptic treatment.

“We found that changes in pill color significantly increase the odds that patients will stop taking their drugs as prescribed,” said Aaron Kesselheim, assistant professor of medicine in the Division of Pharmacoepidemiology at the Brigham and Women’s Hospital in Boston, Massachusetts. He was the principal investigator of the study, which was funded by the Agency for Healthcare Research and Quality, the US federal organization that works to improve the quality, safety, and effectiveness of healthcare.

Non-persistent patients were 27% more likely than controls to have seen a change in color of the antiepileptic tablets in their two previous prescriptions. Tablet color changed in 136 non-persistent cases (1.2%) and in 480 controls (0.97%), giving an odds ratio of 1.27 (95% confidence interval 1.04 to 1.55).

The impact of color change was even more pronounced in people with confirmed seizure disorder (odds ratio 1.53 (1.07 to 2.18)).

“Pill appearance has long been suspected to be linked to medication adherence, yet this is the first empirical analysis that we know of that directly links the physical characteristics of pills to patients’ adherence behavior,” said Kesselheim.

“Non-adherence is a really important issue, not only in epilepsy but also in other conditions,” he said, adding that patients often express concern about changes in pill color in consultations in his work as an internist. The study showed that generic antiepileptic drugs were dispensed in a wide range of colors. For example, patients received extended release carbamazepine in eight different colors, ranging from pink to blue-green.

“Physicians and pharmacists could do better in educating patients that even though the physical appearance of their prescribed drugs might change, the effectiveness won’t,” he suggested. “But our study also supports a reconsideration of current regulatory policy that permits wide variation in the appearance of bioequivalent drugs.”

In an accompanying editorial,2 Lawrence Yu and Gregory Geba from the Office of Generic Drugs at the US Food and Drug Administration said that the study’s “intriguing finding—that changes in pill color in particular may undermine patient compliance,” echoed concerns previously expressed by neurology and epilepsy associations. Yu and Geba explained that the Office of Generic Drugs had started to include “the visual dimensions of product dimensions that could have an impact on patient compliance” in its reviews.

As the use of generic drugs continued to increase, “generic drug manufacturers will be challenged to consider . . . pill size, shape, and color with more consistent regard,” wrote Yu and Geba.