Epilepsy is a chronic neurologic disorder characterized by recurrent episodes that may vastly affect health, daily functioning, and quality of life (QoL). Although many antiepilepsy drugs (AEDs) are available (see Table 1),1–14 a substantial proportion of patients with epilepsy experience seizures that are inadequately controlled because of the ineffectiveness of or nonadherence to their current regimen.
Nonadherence is a significant problem in patients with epilepsy.15–17 A retrospective analysis of claims data from a large US adult managed care population noted an overall nonadherence rate of 39 % in patients with epilepsy following AED initiation (based on a medication possession ratio of <0.8).16 According to a patient survey by Cramer et al., 71 % of patients reported missing at least one dose of medication, with a mean of two missed doses per month.17
Poor adherence is associated with negative patient outcomes.15–18 In a patient survey by Cramer et al., 45 % of respondents who had missed a dose of AED at least once monthly reported that they experienced a seizure thereafter.17 Based on healthcare insurance claims, individuals with epilepsy who are nonadherent to treatment are significantly more likely to experience seizures,15 have increased morbidity,18 require emergency department care and hospitalization,16 and incur higher inpatient costs compared with adherent patients.16 Analysis of a large insurance claims database revealed nonadherent adult patients withepilepsy were 21 % more likely to experience a seizure than were adherent patients (hazard ratio [HR] = 1.205, 95 % confidence interval [CI] 1.092–1.330; p=0.0002).15 In an open cohort analysis of Medicaid claims from adults with epilepsy, mortality was approximately three times greater among patients nonadherent to their prescribed AED regimen compared with adherent patients (HR=3.32, 95 % CI 3.11–3.54).18 Nonadherence to AEDs was also linked to a 50 % higher incidence of emergency room visits (incident rate ratio [IRR] = 1.50, 95 % CI 1.49– 1.52) and an 86 % higher frequency of hospitalizations (IRR=1.86, 95 % CI 1.84–1.88).18
Despite the harmful consequences of missing doses, full adherence to epilepsy pharmacotherapy remains an elusive treatment goal and an unmet medical need. Patient- and drug-related factors that may contribute to nonadherence include younger age, adverse events (AEs), inconvenience, and social stigma.19–23 In a study by Buck et al., 6 % of patients ≥60 years of age (n=180) missed a dose at least once a month, while 16 % of teenagers (n=25) did.19 In the same study, AEs were noted as a factor in nonadherence in 16 % of patients (n=326).19 Among persistent AEs that have been reported by patients taking AEDs that could potentially contribute to nonadherence were dizziness, somnolence, nausea, weight gain, irritability, diplopia, and cognitive impairment.24 These AEs can be associated with peak AED blood levels for some AEDs.25 Another aspect related to nonadherence is the complexity or inconvenience of the drug regimen. In general, more frequent doses are associated with lower adherence19,21 as it increases the need to have sufficient medication onhand at work, school, or when performing daily activities. Furthermore, when taking AEDs in public settings, some patients may be embarrassed and experience a feeling of stigmatization.22,23 Patients subsequently may avoid taking AEDs in public, make excuses for using AEDs, or stop taking medication to avoid this perceived social stigma.22
One approach that has aided in improving adherence has been the reformulation of several immediate-release (IR) and delayed-release (DR) AEDs that are dosed as twice daily or more frequently to extendedrelease (ER) preparations that are dosed as once daily.13,26 ER formulations (also denoted as XR) have the advantages of minimizing peak to troughvariations seen with IR formulations, thereby reducing AEs associated with peak concentrations while allowing for more consistent plasma levels and reducing the number of daily doses. Furthermore, ER or XR formulations maximize the use of the therapeutic window by allowing necessary modest increases in the total daily dose for better efficacy while keeping maximum concentration (Cmax) below the upper limit of the therapeutic range, thus avoiding peak-related AEs. These improvements in the pharmacokinetic properties of an individual particular AED by reformulation to an ER (or XR) preparation can vary and are dependent on the characteristics of the original molecule, such as bioavailability, solubility, and permeability properties, and the particular ER technology used. In the preparation of ER formulations, crystalline matrix, modified-release eroding matrix, film-coated tablet, osmotic release delivery system, and enteric coating technologies have been used. ER AEDs are dosed less frequently than IR formulations, either once or twice daily (see Table 1).1–14
This review will compare patient adherence patterns for ER AEDs with those observed with their IR counterparts (or equivalents), as well as assess patient preferences for these formulations. Furthermore, factors associated with patient adherence, such as AEs, tolerability, effectiveness, efficacy, and QoL will be discussed for the ER and other formulations of AEDs.
Adherence Patterns and Patient Preference for Extended-release Antiepilepsy Drugs Compared with Immediate-release Antiepilepsy Drugs
Various studies have shown increased adherence when patients were switched from an IR AED to an ER AED formulation (see Table 2).21,27–34 In one prospective, observational study involving 2,031 patients, adherence improved from 40 % to 71 % (p<0.001) upon switching from an IR to an ER AED formulation of valproate.21 Improved adherence was also seen in patients (n=358) switching from carbamazepine IR to carbamazepineER (Carbatrol®, Shire, Wayne, PA) with 59 % of patients on the ER formulation stating that they ‘strongly agreed’ they rarely skipped or missed a dose of their medication compared with 39 % on the IR formulation.27 Furthermore, in a recent pharmacokinetic switch study of adult patients with epilepsy (n=61) who were surveyed after switching from IR twice-daily topiramate (Topamax®, Janssen Pharmaceuticals, Inc., Titusville, NJ) to a once-daily XR formulation (SPN-538; Supernus Pharmaceuticals, Inc., Rockville, MD), 92 % expressed preference for the once-daily dosing and believed it facilitated treatment adherence after switching to the XR formulation.29
Similar concordance of patient preference with improved adherence with ER formulations of two other AEDs was also reported. In a study of 41 adult patients with epilepsy who switched from divalproex DR to divalproex ER, 71 % of patients preferred the ER formulation.33 In a small pharmacokinetic study of lamotrigine ER involving 44 patients, 69 % of patients preferred the once-daily regimen while 17 % reported no preference.34
Properties of Extended-release Antiepilepsy Drugs Associated With Adherence
Reduced Adverse Events and Increased Tolerability A tolerability advantage of long-acting AED formulations has been observed in various published reports for a number of different AEDs (see Table 3).21,30,32–47 Several investigators have proposed that improved tolerability is likely due to lower Cmax values and reduced peak-to-trough differences in plasma drug concentration over the post-dose period, resulting in less fluctuation of drug plasma levels.13,36,40
In a double-blind, crossover study of IR versus ER carbamazepine conducted in 48 patients, significantly fewer patients experienced AEs with carbamazepine ER treatment compared with carbamazepine IR (6 versus 26; p<0.001).40 Additionally, a global evaluation of tolerability was significantly better with carbamazepine ER, with 31 patients giving a ‘very good’ ranking compared with 6 for the IR formulation (p<0.001). In one of the largest open-label IR to ER switch studies reported, Ficker et al. compared AEs following a switch from carbamazepine IR to carbamazepine ER among 453 patients older than 12 years with partial epilepsy.30 In adults, investigators reported significant reductions from baseline in AE profile total scores, as well as in central nervous system (CNS) side-effect scores measured by the AE profile (p<0.0001 for both). In adolescents, they also reported significant reductions at study conclusion in both the Hague Side Effect total score and sedation and confusion subscales compared with baseline (p<0.01 for each). Similarly, in a 2-year retrospective chart review of patients (n=61) switched from carbamazepine IR to carbamazepine ER, Miller et al. reported a significant decrease in CNS AEs.36 When receiving carbamazepine IR, 49 % of patients experienced sedation, diplopia, ataxia, confusion, or dizziness, while only 20 % of patients while receiving carbamazepine ER experienced such AEs (p=0.001). Of the patients who experienced CNS AEs with carbamazepine IR, 80 % reported complete resolution after switching to carbamazepine ER.
Treatment-emergent AEs (TEAEs) were compared for levetiracetam ER and levetiracetam IR in an analysis of pooled individual patient data derived from three similarly designed, randomized, double-blind, placebocontrolled clinical trials (n=555).38 A significantly lower risk for TEAEs was observed for levetiracetam ER versus levetiracetam IR for CNS disorders (risk difference [RD] = –18 %; p=0.03), but not for psychiatric disorders (RD = –11 %; p=0.08), or metabolism and nutrition disorders (RD = –3 %; p=0.08).
ER formulations were also shown to decrease AEs associated with valproate in an open-label trial in which 41 patients taking multiple daily doses of valproate DR were switched to a once- or twice-daily regimen of valproate.37 During 3 months of follow-up after switching to valproate ER, complaints of tremor, weight gain, and nausea/vomiting were decreased while other AEs, such as hair loss, remained unchanged. In an earlier study involving 2,031 patients, Doughty et al. reported a significant reduction in the mean side-effect score 3 months after patients switched from valproate IR to valproate ER (32.8 versus 28.5; p<0.001).21 Smith et al. conducted a meta-analysis of pooled individual patient data from nine short-term, open-label studies of divalproex ER versus divalproex DR, which included 213 patients with epilepsy and 108 patients with psychiatric disorders.35 Among patients with either epilepsy or a psychiatric disorder, fewer patients reported TEAEs with divalproex ER. Compared with divalproex IR, divalproex ER had a lower incidence of tremor, weight gain, and gastrointestinal complaints (p<0.001 for each comparison). In a phase II study evaluating the safety and efficacy of oxcarbazepine XR in 366 patients with epilepsy, 30 % discontinued treatment at the highest dose due to AEs,42 while in another study, 67 % of patients (n=694) discontinued treatment at the highest dose of oxcarbazepine IR due to AEs.48
However, not all AEDs clearly show an improvement in the tolerability profile with the ER formulation. Mixed results were seen in studies comparing divalproex ER versus divalproex DR (or equivalent).33,35 In a trial of 41 adult patients with epilepsy who switched from divalproex DR to divalproex ER, no change was found in the AE profile after 6 months, including gastrointestinal disorders and weight gain.33 The effect of tremors on daily activities and the Archimedes spiral score were also not significantly changed with divalproex ER (p=0.07 and p=0.79, respectively). One should not be too surprised to see no significant difference in the AE profile of two formulations of an AED that are designed to reduce AEs associated with the IR formulation of that drug. Though the DR valproate formulation is not ‘extended’ release to the extent the ER formulation is, nonetheless, it is more ‘extended’ than the IR formulation, thus reducing the difference in the impact of the slower-absorption formulations (DR and ER) on AEs.
Of interest, the ER formulation of lamotrigine does not appear to have an improved AE and tolerability profile compared with the IR formulation. In a pooled analysis of three clinical trials evaluating the long-term safety and tolerability of lamotrigine ER (n=662), 69 % of patients reported one or more AEs, which led to premature withdrawal in 7 % of patients, similar to previous reports with lamotrigine IR.41
Simplicity of Regimen and Convenience of Dosing
Studies that have evaluated the relationship between dosing frequency and adherence in patients with epilepsy suggest that increased dosing frequency usually contributes to decreased medication adherence.17,49 Based on the results of a questionnaire answered by 661 patients, there was a 27 % increase in the odds of missing a dose of AED for each increase in the number of times per day the AED was taken (p=0.09).17 In a separate study, the effect of dosing frequency of AEDs on adherence over a period of 3,428 days was evaluated using a medication event monitoring system.49 Adherence rates increased as the number of daily doses decreased from four times a day to once daily (39 %, 77 %, 81 %, and 87 %, respectively). However, in a recent study of 108 patients by Bautista et al., better adherence (higher mean medication possession ratio) was observed with thrice- and twice-daily dosing compared with once-daily dosing (1.02 and 0.93, respectively, versus 0.86; p<0.001).50
Increase in Effectiveness and Efficacy
While effectiveness may refer to the totality of effects produced when considering all factors of a product following its administration to patients, including efficacy, safety, tolerability, pharmacokinetics, and ease of use, efficacy refers to the ability of a product to produce a desired effect. Therapeutic plasma drug concentrations of ER-AEDs are more stable, which may lead to enhanced effectiveness through improved seizure control (see Table 3).21,30,32–47
In a double-blind crossover study by Canger and colleagues, a significant decrease in seizure frequency from 9.3 to 6.3 (p=0.013) was seen with carbamazepine ER compared with carbamazepine IR in 48 patients after 1 month of optimal therapy.40 Similarly, in a retrospective chart review of 61 patients with up to 1 year of follow-up after switching from carbamazepine IR to carbamazepine ER, 46 % of patients had a ≥50 % decrease in seizure frequency after switching and 27 % became seizurefree. 36 However, seizure frequency per month was comparable with thatprior to the switch.
In a trial where 2,031 patients with epilepsy were switched from an IR to ER valproate formulation, improved adherence was observed that was accompanied by a 23 % increase in the proportion of patients who were seizure-free. Importantly, this improvement was also accompanied by a statistically significant decrease (19 %; p<0.001) in the proportion of patients experiencing one or more seizures per month.21 Furthermore, in a comparison of two open-label trials (n=63) comparing outcomes following a divalproex DR to divalproex ER medication switch, a significantly smaller proportion of patients experienced seizures during treatment with divalproex ER (19 % versus 32 %; p=0.02).35
However, in some studies with divalproex, comparable or only slightly improved efficacy was seen for a given ER formulation compared with other formulations of divalproex. A small head-to-head comparative trial of divalproex DR versus divalproex ER was conducted in 43 adolescent and adult patients with generalized seizures that were well controlled on a stable dose of divalproex or valproate.39 These patients had a lengthy history of treatment success prior to the switch, with 91 % seizure-free in the previous year. During the 12 weeks of treatment after switching to divalproex ER, no statistical difference in seizure control was seen with divalproex ER (93 %) compared with divalproex DR (95 %; p=0.564). These results may be associated with the slow release of the DR formulation, as described above. In a 6-month, open-label prospective study in adult patients with epilepsy, patients reported a nonstatistically significant decrease in monthly seizure frequency (0.7 versus 0.85; p=0.14) with divalproex ER treatment versus divalproex IR.33 At study end, a higher percentage of patients taking divalproex ER were seizure-free (42 %) compared with baseline divalproex IR treatment (32 %), although these improvements did not reach statistical significance (p=0.06).
Because of the enhanced tolerability of ER AEDs, clinicians may potentially safely prescribe higher therapeutic doses in patients who require them clinically (e.g., those experiencing breakthrough seizures). Breakthrough seizures may be reduced by maintaining higher minimum plasma drug concentrations, thereby decreasing the potential for concentrations to fall into the subtherapeutic range.13,51 Some support for this concept has been described in an investigation of five patients experiencing breakthrough seizures who were able to tolerate higher doses of valproate after being switched to the ER formulation, with no increase in AEs.37 Four of the five patients had not been able to tolerate similar increases of their valproate IR formulation. One patient became seizure-free and three patients had decreased seizure frequency.
Improved Quality of Life
As with any drug regimen that must be maintained over a long period of time, the tolerability, complexity, and convenience of AED therapy can have a profound impact on patient QoL. Such QoL concerns include limitations on the ability of the patient to drive, socialize, and work as well as effects on their physical and mental state. Relatively few investigations have examined QoL in patients with epilepsy (see Table 2),21,27–34 particularly comparing ER and IR formulations. In one such study, the QoL of patients before and after switching from IR to ER oxcarbazepine were compared. A significant improvement in QoL (as measured by Quality of Life in Epilepsy [QOLIE]-10) was observed (p<0.001), with 23 of 27 patients reporting improvements.31 In the results from a separate prospective open-label investigation whereby patients were switched from IR to ER carbamazepine (n=453), a significant improvement in QOLIE-31 scores, from 62.8 to 68.3, was found (p<0.001).30
Conclusion
In general, patients preferred and were more adherent to the ER (XR) formulations, probably because of decreased AEs, increased tolerability, dosing convenience, increased efficacy, and improved QoL (see Figure 1). This increased patient preference for and adherence to ER formulations, however, may differ depending on the given AED, which may reflect differences in the AEDs. For example, while AEs have generally been reported to be reduced with the ER formulation of carbamazepine,30,36,40 no difference was seen between the ER and IR formulations of lamotrigine.41
There are times when physicians may prefer the IR formulation. Concerns exist that the ‘forgiveness’ period, or time period one can delay taking the prescribed dose, is shorter with ER versus IR formulations.25 On the contrary, we believe that if patients forget to take their once-daily AED in the morning, they have the whole day to take it before going to bed. Likewise, if they forget to take their once-daily bedtime dose, they can take it upon awakening. We strongly recommend the use of a pill-box (with a schedule) for all patients to readily discover whether a particular dose was forgotten. Also, some physicians believe that the ER formulation does not provide complete therapeutic coverage throughout the dosing interval.25 It is in this situation that we recommend full use of the therapeutic range by making the necessary modest increases in the dose since the lesser peak–trough fluctuations in plasma concentrations make such adjustments with ER formulations more permissible. While it is easy to assume that XR formulations provide low Cmax (hence less side effects) and higher minimum concentration (Cmin) (hence less breakthrough seizures theoretically) compared with IR formulations, some XR formulations showed a slightly lower Cmin (i.e., lamotrigine, levetiracetam, and divalproex) than IR counterparts. This could be partly due to the fact that not all XR formulations are bioequivalent to IR formulations milligram for milligram. One should refer to the manufacturer’s instructions for dosage conversions when switching patients from IR to XR formulations of the same AED. This may not be a factor when a healthcare provider starts a patient on an XR formulation de novo.
Overall, it is extremely important that the patient is educated on his/her treatment options. When discussing AED regimens with patients, it is important for physicians to give patients options and encourage them to communicate their concerns, problems, and preferences regarding their medication regimen.
In doing so, the individual treatment strategy may be tailored for each patient and may thereby result in better long-term adherence. Epilepsy therapy is not ‘one size fits all,’ and many patients require individualized medication regimens. Extended-release AEDs offer several potential advantages over IR counterparts. In addition to benefits in tolerability and the potential for improved efficacy, they may also include improved QoL, and, ultimately, better patient satisfaction. Consequently, these improved attributes can lead to better patient adherence.
