Variations in Pill Appearance Linked to Adherence with AEDs

Despite the clinical bioequivalence between branded and generic drugs, findings of a nested case-control study showed changes in pill color significantly increased the odds of nonpersistence among patients taking antiepileptic drugs (AEDs) [JAMA Intern Med. 2013;173(2):202-208].

The differences in the appearance of bioequivalent drugs may have serious consequences for patient care. “Changes between generic products with different physical characteristics may cause confusion and result in reduced adherence or prescription error,” explained the investigators. “However, we could find no empirical studies of the consequences of changes in pill appearance in a population-based analysis.”

Using information culled from medical and pharmacy data from the HealthCore Integrated Research Database, researchers sought to clarify the difference between pill characteristics and patient adherence for 7 AEDs. The study included patients refilling prescriptions for drugs that had been approved specifically for use in treating seizures, were available in pill form, and had at least 1 brand name and 1 generic available on the US market during the study period (2001-2006). The AEDs meeting these criteria were carbamazepine, carbamazepine extended-release, ethosuximide, lamotrigine, phenytoin sodium, valproic acid, and zonisamide.

The study population included participants who received at least 3 dispensings (the initial fill and 2 refills) of the same drug, dose, and route. Further, the researchers conducted a multivariate analysis with an adjustment for baseline characteristics and drug type. The researchers identified 11,472 patients with episodes of AED nonpersistence (defined as a failure to fill a prescription within 5 days of the elapsed days supplied) and 50,050 control patients (matched by sex, age, number of refills, and seizure disorder diagnosis).

The mean age of participants was 42.9 years, and the mean total number of AED refills was 6.6 for cases and 6.4 for controls. Episodic mood disorder and pain disorders were slightly more common among cases than among controls. Both cases and controls averaged about 9 outpatient physician visits in the past 6 months and about 30 filled prescriptions during that time.

The results found that AEDs dispensed had 37 colors and 4 shapes. In the multivariate analysis, color and shape discordance occurred infrequently, but was more prevalent preceding cases of AED nonpersistence. Color discordance preceded 136 cases (1.20%), but only 480 controls (0.97%). Cases were significantly more likely to have had preceding color discordance than controls with a 27% greater likelihood of medication nonpersistence (adjusted odds ratio [AOR], 1.27; 95% confidence interval [CI], 1.04-1.55).

Among patients with a seizure disorder, difference in pill color was associated with a 53% greater likelihood of medication nonpersistence (AOR, 1.53%; 95% CI, 1.07-2.18). The odds of shape discordance occurring was also greater in cases than controls (0.16% vs 0.11%, respectively), but the difference was not statistically significant in either the full sample (AOR, 1.47; 95% CI, 0.85-2.54) or patients linked to a seizure diagnosis disorder (AOR, 3.15; 95% CI, 0.82-12.1).

The researcher also analyzed pill shape and color variations. They noted that valproic acid displayed the fewest color variations (100% were orange) compared with ethosuximide, which was available in 19 color possibilities. Difference in pill shape variation was less common with lamotrigine, zonisamide, ethosuximide, and phenytoin sodium, and the remaining 3 being split mostly between 2 shapes.

In summary, the researchers said that, “Promoting medication adherence is a difficult task, and it has been only partially addressed through strategies such as enhanced prescribing of generic drugs and reducing drug copayments. Taking steps to permit [or even acquire] similarity in pill appearance among bioequivalent brand-name and generic drugs may offer another way to achieve better patient adherence to essential medication regimens.”