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Changes between generic products with different physical characteristics may cause confusion and result in reduced adherence 16 , 17 or prescription error. Therefore, we sought to determine whether switching among different-appearing pills is associated with changes in medication adherence in a national cohort of commercially insured patients.

We tested this question among users of antiepileptic drugs AEDs.

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While adherence and persistence are closely related concepts, this study technically measured persistence, the duration of time from initiation to discontinuation of therapy. Prescriptions claims data were linked by NDC number to the First DataBank National Drug Data File, which contains descriptive drug information, including the formulation type capsule, tablet, oral suspension, etc , dose strength, and precise color and shape.

We included patients filling prescriptions for drugs that 1 had been approved specifically for use in treating seizures, 2 were available in pill form, and 3 had at least 1 brand-name and 1 generic form available on the US market during the study period The 8 AEDs meeting these criteria were carbamazepine, carbamazepine extended-release, ethosuximide, lamotrigine, phenytoin sodium, valproic acid, gabapentin, and zonisamide all doses.

We excluded gabapentin because its use during this time period was nearly exclusively for off-label indications outside of epilepsy. We identified all patients who filled a first prescription after January 1, , for 1 of the 7 AEDs in our study, after a period of 6 months of continuous health plan enrollment during which they had not filled a prescription for any anticonvulsant, and defined this first dispensing as the index date.

If a patient was prescribed more than 1 eligible drug, we treated each record as a separate entry. Cases were patients who had incomplete persistence to their index AED, defined as failure to fill a new prescription for the drug within 5 days of the elapsed days supplied. To identify cases, we first created a supply diary of prescription drug filling after each patient's index date and then calculated the accumulated days' supply.

If a new dispensing occurred before the prior days' supply ran out, we carried the extra days over. To limit duplicate contributions to the pool of cases, we selected only the patient's first episode of nonpersistence for a given drug. For patients taking multiple AEDs, we conservatively allowed them to become a case only at the first observed episode of nonpersistence and did not allow them to be a case for subsequent episodes for other drugs.

Controls were identified using the same methodology but had no gap in therapy. We permitted controls to be matched up to more than 1 case and selected a maximum of 5 controls per case. Cases could be controls for other patients prior to an episode of nonpersistence. For each case and control, we evaluated the 2 refills prior to the outcome date. We excluded cases and controls in whom the 2 refills prior to the final date were for different doses of the drug, or if shape or color data were missing or unknown. We noted the rates of color discordance and shape discordance separately for all cases and controls.

We defined demographic characteristics of the cases and controls, including age at index date and sex. We also identified health services utilization for cases and controls during the 6 months prior to the index date, including the number of non-AED prescriptions, number of outpatient physician encounters, and number of emergency department visits or inpatient hospitalizations.

Finally, we collected data on diagnoses listed during the 6 months prior to the index date, including seizure disorder ICD-9 codes and We generated descriptive statistics and performed matched case-control analyses using bivariate and multivariate conditional logistic regression. The dependent variable in all regression analyses was a binary variable distinguishing cases from controls. After excluding the matching variables, we included all remaining baseline covariates in the adjusted model along with a variable to account for differences across drug type.

We then repeated the analysis in the subgroup of patients who had a seizure diagnosis in the 6 months prior to the index date and included the same covariates in the adjusted model. To test the sensitivity of our findings, we changed our definition of nonpersistence to be more 3 days and less 10 days restrictive. All analyses were conducted using the SAS statistical package version 9.

This group made up the pool of potential cases and controls for our study. Among cases and controls, antiepileptic drugs displayed 37 different color arrangements and 4 different shape types Table 1 and Table 2. Differences in pill shape variation were less common, with 4 drugs lamotrigine, zonisamide, ethosuximide, and phenytoin being produced nearly exclusively in a single shape, and the remainder being split mostly between 2 shapes. Table 3 shows that cases and controls were similar in terms of demographics.

About one-fifth of cases and controls were linked to a diagnosis of seizure disorder. Episodic mood disorder and pain disorders were slightly more common among cases than among controls. Both cases and controls averaged about 9 outpatient physician encounters in the past 6 months and about 30 filled prescriptions during that time. Overall, color and shape discordance occurred infrequently but was more common preceding cases of antiepileptic drug nonpersistence. In our full sample, color discordance occurred in cases 1.

Discordance rates were similar among the subset of antiepileptic drug use cases linked to diagnoses of seizure disorders 1. Cases were significantly more likely to have had preceding color discordance than controls Table 4. The odds of a shape discordance occurring was also greater in cases than in controls, but the difference was not statistically significant in either the full sample adjusted OR, 1.

In sensitivity analysis, we found that neither shortening the break in elapsed days supplied from 5 to 3 days nor lengthening it to 10 days substantially changed the ORs or the statistical significance of the results. Although the influence of pill appearance on patient behavior has long been a source of concern for clinicians, this is the first empirical analysis, to our knowledge, linking pill characteristics to patients' medication adherence.

Bioequivalent AEDs can have a variety of shapes and colors, and we found that patients who experience changes in pill color in particular have an increased risk of interruptions in medication use. Several potential explanations may account for these findings. First, drugs are commonly removed from their bottles to assist in organization, such as when patients or caregivers sort their medications into pill planners 27 or pharmacists provide blister packs to patients. In this sample of medications, changes to pill color may be more noticeable than changes in shapes, which were commonly of the more subtle round or circular to oblong variety.

Another alternative is that the smaller number of shape changes did not provide enough power to find a statistically significant effect. The placebo effect, a vital though often ignored part of therapeutic intervention, 29 may also contribute to our results. A pill's physical attributes have been linked to expectations of efficacy of both placebos and pharmacologically active prescription drugs.

Controversies over pill substitution are particularly salient among AEDs. In response to case reports 32 and observational studies 33 claiming that bioequivalent generic AEDs may not have the same clinical effects as their brand-name counterparts, some physician professional organizations 34 and patient advocates 35 have opposed the routine interchange of bioequivalent AEDs. Changes in pill appearance may create a self-fulfilling prophecy in which therapeutically bioequivalent regimens actually become less clinically effective owing to induced nonpersistence.

If replicated in other settings, these findings could have additional important implications. In caring for patients who are nonadherent, physicians might consider the contribution of varying pill color. In the near term, as more widely used brand-name drugs face generic competition, physicians should warn patients about the possibility that pill color might change, and pharmacists might take greater care to alert patients when changes in suppliers lead to new pill characteristics.

At pharmacies, the ability to alert consumers when pill features have changed may require adaptations to information technology systems. Educating consumers about the safety and efficacy of approved generic drugs—no matter what physical attributes the drug possesses—may also help mitigate the effect we observed in this study. Our study also supports a reconsideration of current regulatory policy that permits wide variation in the appearance of bioequivalent drugs. In the United States, the FDA has recently started rejecting generic drugs that are larger in size than their brand-name counterpart, citing safety and efficacy concerns, such as increased risk of choking and patient dissatisfaction.


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One pertinent precedent in this area occurred in the United Kingdom, which systematized color coding of metered-dose inhalers for asthma after noting that users frequently confused bronchodilators for steroid inhalers. Such legal protection requires that relevant attribute be nonfunctional, and our study demonstrates the functional importance of pill appearance in promoting therapeutic equivalence among AEDs. There are several limitations to this study.

First, while pharmacy claims have been used to track adherence in numerous studies, 44 , 45 a filled prescription does not prove that the patient actually took the medication. Similarly, what we observed as nonpersistence may have been physician-directed changes in medication dosing frequency. Second, the absolute magnitude of the effect observed in our study was small, so changing appearance may have a small overall effect on medication adherence.

However, previous research shows that patients with epilepsy who are nonadherent to their treatment have increased risk of seizure-related emergency department visits and even mortality. We also could not examine other changes within the pills, such as changes in the coating or filler, that might accompany changes in color and affect the way that patients with epilepsy perceive their medication.

Such changes have anecdotally increased the risk of nonadherence in patients with epilepsy, 47 but not conclusively demonstrated to reflect legitimate differences in the drugs. Finally, our focus on AEDs limits generalizability of these results, since patients on AEDs and their treating physicians may be particularly attentive to their pills' appearances. Despite these limitations, our study indicates that changes in pill color are associated with a significant increase in the risk of nonadherence.


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Promoting medication adherence is a difficult task, and it has been only partially addressed through strategies such as enhanced prescribing of generic drugs 49 and reducing drug copayments. Correspondence: Aaron S. Published Online: December 31, Author Contributions: Dr Kesselheim had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition of data : Kesselheim, Misono, Shrank, and Doherty. Drafting of the manuscript : Kesselheim, Misono, and Greene. Critical revision of the manuscript for important intellectual content : Kesselheim, Misono, Shrank, Greene, Doherty, Avorn, and Choudhry.

The History of Anti-epileptic Drugs

Statistical analysis : Shrank and Doherty. Administrative, technical, and material support : Misono, Shrank, and Doherty. Study supervision : Shrank, Avorn, and Choudhry. Role of the Sponsors: The funders had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

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Written permission has been obtained from all people mentioned. All Rights Reserved. Download PDF Comment. View Large Download. Table 1. Table 2. Table 3.

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Characteristics of Patients Serving as Cases and Controls. Table 4. Generic Pharmaceutical Association. Facts at a glance. Accessed October 4, Patent watch: the patent cliff steepens. Nat Rev Drug Discov. Extensions of intellectual property rights and delayed adoption of generic drugs: effects on Medicaid spending. Health Aff Millwood. Prescription drug cost sharing: associations with medication and medical utilization and spending and health. National Community Pharmacists Association.

Take as directed: a prescription not followed. Accessed August 3, World Health Organization. Adherence to long-term therapies: evidence for action. Thinking outside the pillbox: medication adherence as a priority for health care reform. N Engl J Med. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. Food and Drug Administration. Therapeutic equivalence of generic drugs: letter to health practitioners. The case for standardizing the appearance of bioequivalent medications. J Manag Care Pharm.

Indiana Law Rev. Black Market Medicine. Why do the same drugs look different? Generic immunosuppressants in hematopoietic cell transplantation. Biol Blood Marrow Transplant. The substance of the brand. Generic substitution: additional challenge for adherence in hypertensive patients? Curr Med Res Opin. Glaxo whistle-blower lawsuit: bad medicine [transcript].

December 29, Naming, labeling, and packaging of pharmaceuticals. Am J Health Syst Pharm. Health literacy: a barrier to pharmacist-patient communication and medication adherence. J Am Pharm Assoc Off-label prescribing among office-based physicians. Arch Intern Med. Association of antiepileptic drug nonadherence with risk of seizures in adults with epilepsy. Epilepsy Behav. AED discontinuation may be dangerous for seizure-free patients. J Neural Transm. Industry fights switch to generics for epilepsy.

Factors other than maternal dose may also correlate with fetal exposure. Drug properties including molecular weight and dissociation constant affect placental passage, with drugs weighing greater than daltons and those that are predominantly dissociated at physiologic pH passing incompletely. Maternal variation in placental transporter proteins also influences placental passage. Umbilical cord concentrations at delivery and calculation of umbilical cord to maternal concentration ratios can serve as a proxy for fetal exposure and a means to compare individual medication exposure.

The purpose of this study was to determine the umbilical cord concentrations and umbilical to maternal ratios for several commonly prescribed AEDs, and to determine whether higher AED umbilical cord concentrations or umbilical to maternal ratios are associated with an increased risk of neonatal complications. Women were informed of all available treatment options, and written informed consent was obtained. Only women who chose to continue AEDs during pregnancy and whose infants had umbilical cord AED levels drawn at the time of delivery were included in this cohort analysis.

Umbilical cord and maternal venous blood were collected at the time of delivery. All assays were completed blind to maternal dose. Free drug was assessed for patients taking carbamazepine, phenytoin, valproic acid, and lamotrigine. The therapeutic range of free lamotrigine is not established. Demographic information was collected at the time of enrollment. Medical records were obtained for review from the treating obstetrician, the delivery hospital, and the treating pediatrician. Neonatal complications evaluated included prematurity delivery prior to 37 weeks gestational age , small for gestational age birthweight, neonatal intensive care unit or special care nursery admission, major congenital malformations, and Apgar scores less than 7 at 1 and 5 minutes after delivery.

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Logistic regressions were performed to ascertain the effect of umbilical cord AED levels and umbilical to maternal AED ratios on neonatal complications. Umbilical cord samples were collected at delivery for 70 pregnancies. Two mother-newborn dyads were included in the study twice for two different pregnancies; each pregnancy was counted separately. Sixty-six mothers were taking one AED at the time of delivery. Four mothers were taking two AEDs. There were no significant differences between AED groups with regard to age, number of prior pregnancies, diagnosis epilepsy, bipolar disorder, or both , race, marital status, or education level.

All women received prenatal care for the majority of pregnancy. All were singleton pregnancies.

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For the four mothers taking two AEDs, umbilical cord samples were assayed for both medications, resulting in 74 umbilical cord AED concentration measurements. Nine of the mother-child pairs had only umbilical cord levels tested and thus 65 maternal samples were available for analysis of umbilical cord to maternal AED ratios. Maternal venous samples were collected a mean of Mean umbilical cord AED concentrations by medication are shown in Table 1. Mean umbilical to maternal ratios by medication are shown in Figure 1. Mean placental passage ratio of umbilical cord concentration to maternal concentration of total and free antiepileptic drugs by medication.

Four infants 5. Higher umbilical cord concentrations of the total drug as a percentage of the upper limit of the therapeutic range were not associated with increased likelihood of prematurity, small for gestational age birthweight, neonatal intensive care unit or special care nursery admission, major congenital malformation, or Apgar score lower than 7 at 1 minute after delivery, nor were higher umbilical cord concentrations of the free drug as a percentage of the upper limit of the therapeutic range for carbamazepine, phenytoin, and valproic acid.

Higher umbilical to maternal total ratios were not associated with increased likelihood of prematurity, small for gestational age birthweight, neonatal intensive care unit or special care nursery admission, major congenital malformations, or Apgar scores lower than 7 at 1 minute after delivery, nor were higher umbilical to maternal free ratios for carbamazepine, phenytoin, and valproic acid. Umbilical cord AED concentrations at the time of delivery, especially when compared to maternal concentrations, provide valuable information about fetal AED exposure in utero.

Previously reported umbilical to maternal ratios for total drug concentrations include 0. These studies were largely limited by small sample sizes of 5—35 patients, with the exception of Kacirova et al. The umbilical to maternal ratios observed in this study are comparable to those reported in prior studies. Despite this exposure, however, few infants had neonatal complications. Reassuringly, higher umbilical cord AED concentrations and higher umbilical to maternal ratios were not associated with an increased likelihood of adverse neonatal outcomes.

Carbamazepine had the highest placental passage of free drug. This may be explained by its high dissociation constant, which causes it to be minimally ionized at physiologic pH and thus transfer completely or near-completely across the placenta. Conversely, valproate had the lowest placental passage of free drug, perhaps due to its low dissociation constant and incomplete transfer across the placenta. Despite this, in utero valproate exposure is associated with significantly lower IQ scores at 3, 4.

Our study is limited by the small sample size with relatively few adverse neonatal outcomes overall. We also comment only on AED concentrations at delivery. Additionally, the umbilical and maternal samples in this study were collected in the early to mids; current fetal AED exposure may differ as AED selection and dosing practices have changed over time.

A larger prospective study could help clarify the relationship between the amount of prenatal AED exposure at different gestational ages with a variety of child outcomes including long-term cognitive and behavioral outcomes.


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  • Umbilical cord concentrations and umbilical to maternal ratios vary among AEDs, but with most ratios approximating unity. Our findings confirm prior reports demonstrating complete placental passage of several commonly prescribed AEDs. In this small sample, higher umbilical cord concentrations and umbilical to maternal ratios were not associated with adverse neonatal outcomes. A larger study is warranted to determine if individual fetal exposure is a major determinant of adverse outcomes, and further if maternal daily dose is a viable proxy for fetal exposure.

    Such data could have a significant impact on balancing the clinical response to changes in AED clearance in pregnancy with the risks of fetal exposure. Conflict of Interest Statement:. Anna M. Bank has no conflicts to disclose. Zachary N. He has served on advisory boards for GSK. He has never served as a consultant to any biomedical or pharmaceutical corporations. Neither he nor family members have ever held equity positions in biomedical or pharmaceutical corporations.

    James C.