Topiramate Extended-Release Options: A Focus on Efficacy and Safety in Epilepsy and Comorbidities

Abstract

Topiramate (TPM) is effective for multiple seizure types and epilepsy syndromes in children and adults. Topiramate has adverse effects (including cognitive, depression, renal stones), but many of these are low incidence when started at a low dose and slowly titrated to 100 to 200 mg/day. Also, TPM has proven benefit for migraine, obesity, eating disorders, and alcohol use disorders, which can be comorbid in patients with epilepsy and may also be effective in subpopulations within specific psychiatric diagnoses. Recently approved extended-release formulations of TPM (Trokendi and Qudexy in the United States) have reliable data supporting their safety and efficacy for patients with epilepsy. They have potential for more rapid titration within 1 month to 200 mg/day and have better patient retention than TPM immediate-release, but there are no robust double-blind randomized controlled trials comparing the different formulations. We expect the once per day extendedrelease formulations to improve medication adherence compared with the twice per day formulations. This has significant potential to improve outcomes in epilepsy and the other TPM-responsive disorders.

The pharmacokinetics of single oral dose extended‐release topiramate and adverse effects after multi‐dose administration in healthy cats

“…Antiseizure medications usually require protracted or life‐long therapy so more severe anemia could occur with a longer duration of exposure. Most adverse effects of topiramate in humans are dose‐dependent (Gilliam et al, 2003; Silberstein, 2017; Wang et al, 2017). If the same is true for this documented anemia, it is possible that the upper end of the reference range in humans is too high for cats, and lower dosages could minimize adverse effects.…”

“…Topiramate's primary antiseizure mechanisms of action include blocking voltage‐gated sodium channels and enhancing gamma‐aminobutyric acid activity and may also include negatively modulating L‐type calcium channels (Chung, 2015; Wang et al, 2017; Zhang et al, 2000). Aside from its antiseizure properties, topiramate's other mechanisms of action include antagonizing A‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainite receptors and weakly inhibiting carbonic anhydrase II and IV isoenzymes (Wang et al, 2017). In addition to an immediate release formulation, there are two extended‐release (XR) formulations, Trokendi XR® (TXR; Supernus Pharmaceuticals, Inc.) and Qudexy® XR (QXR; Upsher‐Smith Laboratories, LLC), approved for human use.…”

“…Qudexy® XR is manufactured in capsules that contain coated beads, which allow for slow‐release of the medication over a 24‐hour period. These capsules can be opened and sprinkled directly onto soft foods to facilitate administration without altering its extended‐release properties (Wang et al, 2017). In people, the therapeutic plasma concentration of topiramate ranges between 2 and 25 μg/mL with concentrations >9.91 μg/mL being associated with better seizure control (Gilliam et al, 2003; Wang et al, 2017).…”

“…These capsules can be opened and sprinkled directly onto soft foods to facilitate administration without altering its extended‐release properties (Wang et al, 2017). In people, the therapeutic plasma concentration of topiramate ranges between 2 and 25 μg/mL with concentrations >9.91 μg/mL being associated with better seizure control (Gilliam et al, 2003; Wang et al, 2017). The most common adverse effects reported in people include somnolence, dizziness, paresthesia, weight loss, diarrhea, fatigue, and headaches (Bialer et al, 2013; Chung, 2015; Chung et al, 2014; Clark et al, 2014).…”

“…Metabolic acidosis and nephrolithiasis have been documented and most commonly occur following chronic administration, with nephrolithiasis being more common in patients treated for several months to years (Chung et al, 2014; Maalouf et al, 2011; Salek et al, 2017; Welch et al, 2006). Acute secondary angle closure glaucoma has also been reported as a rare adverse effect, typically developing within the first 2 weeks of treatment, with resolution within 1 week following topiramate discontinuation (Aminlari et al, 2008; Chen et al, 2003; Wang et al, 2017).…”