Topiramate in Migraine Prevention: A 2016 Perspective.

BACKGROUND: In evidence-based guidelines published in 2000, topiramate was a third-tier migraine preventive with no scientific evidence of efficacy; recommendation for its use reflected consensus opinion and clinical experience. Its neurostabilizing activity, coupled with its favorable weight profile, made topiramate an attractive alternative to other migraine preventives that caused weight gain. When guidelines for migraine prevention in episodic migraine were published in 2012, topiramate was included as a first-line option based on double-blind, randomized controlled trials involving nearly 3000 patients. The scientific and clinical interest in topiramate has generated a large body of data from randomized controlled trials, meta-analyses, patient registries, cohort studies, and claims data analyses that have more fully characterized its role as a migraine preventive. AIM: This article will review the profile of topiramate that has emerged out of the past decade of research and clinical use in migraine prophylaxis. It will also address the rationale for extended-release (XR) formulations in optimizing topiramate therapy in migraine. SUMMARY: Topiramate has activity at multiple molecular targets, which may account for why it is effective in migraine and most other, more specific, anticonvulsants are not. Based on randomized controlled trials, topiramate reduces migraine frequency and acute medication use, improves quality of life, and reduces disability in patients with episodic migraine and in those with chronic migraine with or without medication overuse headache. Its efficacy in chronic migraine is not improved by the addition of propranolol. Topiramate's ability to prevent progression from high-frequency episodic migraine to chronic migraine remains unclear. Consistent with clinicians' perceptions, migraineurs are more sensitive to topiramate-associated side effects than patients with epilepsy. Paresthesia is a common occurrence early in treatment but is rarely cause for terminating topiramate treatment. Cognitive problems occur much less frequently than paresthesia but are more troublesome in terms of treatment discontinuation. Cognitive complaints can often be managed by slowly increasing the topiramate dose in small increments to allow habituation. As with other carbonic anhydrase inhibitors, topiramate has metabolic effects that favor the development of metabolic acidosis and possibly renal stones. Because migraineurs have an increased risk of renal stones independent of topiramate exposure, clinicians should counsel all migraine patients to maintain hydration. Abrupt onset of blurring, other visual disturbances, and/or ocular pain following topiramate's initiation should be evaluated promptly since this may indicate rare but potentially sight-threatening idiosyncratic events. Postmarketing evidence has shown that first-trimester exposure to topiramate monotherapy is associated with increased occurrence of cleft lip with or without cleft palate (Pregnancy Category D). Even though topiramate's long half-life would seemingly support q.d. dosing, randomized controlled migraine trials used b.i.d. administration of immediate-release (IR) topiramate, which has more favorable plasma concentration-time profile (ie, lower peak concentrations and higher trough concentrations) than q.d. IR dosing. Given the sensitivity of migraineurs to topiramate-related adverse events, particularly cognitive effects, pharmacokinetic profiles should be considered when optimizing migraine outcomes. The extended-release (XR) formulations Qudexy® XR (Upsher-Smith Laboratories) and Trokendi XR® (Supernus Pharmaceuticals) were specifically designed to achieve the adherence benefits of q.d. dosing but with more favorable (ie, more constant) steady-state plasma concentrations over the 24-hour dosing interval vs IR topiramate b.i.d. Intriguing results from a study in healthy volunteers showed consistently less impairment in neuropsychometric tests of verbal fluency and mental processing speed with an XR topiramate formulation (Trokendi XR) vs IR topiramate b.i.d. These findings suggest a pharmacodynamic effect associated with significantly reducing plasma concentration fluctuation when topiramate absorption is slowed. Results of retrospective studies in migraineurs treated with XR topiramate appear to support a clinically meaningful benefit of XR topiramate vs IR topiramate in terms of significantly fewer cognitive effects, improved adherence, and overall better outcomes of migraine prophylaxis with topiramate.

Clinical utility of topiramate extended-release capsules (USL255): Bioequivalence of USL255 sprinkled and intact capsule in healthy adults and an in vitro evaluation of sprinkle delivery via enteral feeding tubes.

OBJECTIVE: The objectives of these two studies were to determine if beads from extended-release topiramate capsules sprinkled onto soft food are bioequivalent to the intact capsule and if beads from the capsule can be passed through enteral gastrostomy (G-) and jejunostomy (J-) feeding tubes. METHODS: Bioequivalence of 200-mg USL255 (Qudexy XR [topiramate] extended-release capsules) sprinkled onto soft food (applesauce) versus the intact capsule was evaluated in a phase 1, randomized, single-dose, crossover study (N=36). Pharmacokinetic evaluations included area under the curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax), and terminal elimination half-life (t1/2). If 90% confidence intervals (CI) of the ratio of geometric least-squares means were between 0.80 and 1.25, AUC and Cmax were considered bioequivalent. In separate in vitro experiments, 100-mg USL255 beads were passed through feeding tubes using gentle syringe pressure to develop a clog-free bead-delivery method. Multiple tube sizes (14- to 18-French [Fr] tubes), dilutions (5 mg/15 mL-25 mg/15 mL), and diluents (deionized water, apple juice, Ketocal, sparkling water) were tested. RESULTS: Area under the curve and Cmax for USL255 beads sprinkled onto applesauce were bioequivalent to the intact capsule (GLSM [90% CI]: AUC0-t 1.01 [0.97-1.04], AUC0-∞ 1.02 [0.98-1.05]; Cmax 1.09 [1.03-1.14]). Median Tmax was 4h earlier for USL255 sprinkled versus the intact capsule (10 vs 14 h; p=0.0018), and t1/2 was similar (84 vs 82 h, respectively). In 14-Fr G-tubes, USL255 beads diluted in Ketocal minimized bead clogging versus deionized water. Recovery of USL255 beads diluted in deionized water was nearly 100% in 16-Fr G-, 18-Fr G-, and 18-Fr J-tubes. SIGNIFICANCE: For patients with difficulty swallowing pills, USL255 sprinkled onto applesauce offers a useful once-daily option for taking topiramate. USL255 beads were also successfully delivered in vitro through ≥14-Fr G- or J-tubes, with tube clogging minimized by portioning the dose and using glidant diluents for smaller tubes.

Long-term safety and sustained efficacy of USL255 (topiramate extended-release capsules) in patients with refractory partial-onset seizures.

OBJECTIVE: The aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults. METHODS: Patients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy-Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55weeks of treatment and efficacy by patient age and drug-resistant status. RESULTS: Of the 217 patients who completed PREVAIL (USL255, n=103; placebo, n=114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥50years of age. Improvements in CGI-C and QOLIE-31-P were also observed. SIGNIFICANCE: The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS.

A review of the efficacy and safety of extended-release topiramate in the adjunctive treatment for refractory partial-onset seizures.

Topiramate has been widely utilized worldwide as an effective medication against partial- and generalized-onset seizures. Extended-release topiramate was developed to provide patients with the convenience of once-daily dosing and potentially improved tolerability by reducing serum concentration fluctuation. USL255 is a once-daily, extended-release formulation of topiramate, which was recently approved in the USA. Compared with immediate-release topiramate taken twice daily, once-daily USL255 provides equivalent topiramate exposure with a 26% reduction in plasma fluctuations. A multinational, phase III, randomized, double-blind, placebo-controlled clinical trial in patients with refractory partial-onset seizures demonstrated that USL255 (200 mg/day) significantly improved seizure control and was well tolerated with low overall neuropsychiatric and neurocognitive adverse events.