CNS Drugs DOI 10.1007/s40263-016-0344-5

ADIS DRUG EVALUATION

Topiramate Extended Release: A Review in Epilepsy Sheridan M. Hoy1

 Springer International Publishing Switzerland 2016

Abstract Once-daily oral topiramate extended release (USL255; hereafter referred to as topiramate XR) [QUDEXY XR] is approved in the USA for use as initial monotherapy and adjunctive therapy in patients aged C2 years with partial-onset seizures (POS) or primary generalized tonic-clonic seizures and as adjunctive therapy in patients aged C2 years with seizures associated with Lennox–Gastaut syndrome. Compared with twice-daily topiramate immediate release at the same total daily dose, topiramate XR provided bioequivalent exposure, an extended absorption rate (permitting convenient once-daily dosing) and more constant therapeutic plasma concentrations (potentially minimizing topiramate-associated adverse events). Switching between the two formulations did not affect the maintenance of topiramate concentrations. Moreover, the contents of a topiramate XR capsule may be sprinkled on to soft food for patients who have difficulty swallowing. In a multinational phase III study in adults with refractory POS, adjunctive topiramate XR was associated with significantly greater improvements from baseline in weekly median seizure frequency and the proportion of patients achieving a C50 % reduction in seizure frequency compared with placebo. These benefits were sustained

The manuscript was reviewed by: M. Bialer, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; I. Blatt, Department of Neurology, The Chaim Sheba Medical Center, Tel Hashomer, Israel; R. E. Hogan, Washington University in St. Louis, St. Louis, MO, USA.

during a 55-week open-label extension study. Adjunctive topiramate XR was generally well tolerated in these studies, with the majority of treatment-emergent adverse events being mild or moderate in intensity. In conclusion, current evidence suggests once-daily topiramate XR extends the treatment options currently available for patients aged C2 years with epilepsy, with its dosing regimen potentially delivering tolerability and adherence advantages over AEDs that require more frequent administration.

Topiramate extended release: clinical considerations Approved for use in all epilepsy indications in which topiramate immediate release (IR) is approved Relative to topiramate IR, provides bioequivalent exposure, an extended absorption rate and more constant therapeutic plasma concentrations As adjunctive therapy, reduces weekly seizure frequency compared with placebo in adults with refractory partial-onset seizures, with benefits maintained in a 55-week extension study Generally well tolerated; is associated with a low incidence of neurocognitive and neuropsychiatric adverse events

1 Introduction & Sheridan M. Hoy [email protected] 1

Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand

The management of epilepsy relies heavily on medication adherence to effectively control seizures whilst avoiding adverse events, with poor adherence associated with

S. M. Hoy

increased morbidity and mortality [1, 2]. Nonadherence can be intentional (i.e. owing to potential or actual adverse events, lifestyle choices and a patient’s treatment expectations) or non-intentional (i.e. failing to adhere owing to forgetfulness, misunderstanding or uncertainty regarding their clinician’s expectations) [1, 2]. Various strategies have been suggested to enhance medication adherence, including patient education and reminders, and simplifying the dosing regimen [1]. Indeed, switching to an extendedrelease (XR) anti-epileptic drug (AED) could permit a drug to be taken less frequently and to maintain reasonably constant plasma drug concentrations, potentially resulting in fewer adverse events, greater adherence levels and improvements in patient-reported quality of life [2, 3]. This article provides a narrative review of pharmacological, therapeutic efficacy and tolerability data relevant to the oral use of topiramate XR (USL255; QUDEXY XR) in patients with epilepsy (Sect. 6).

2 Pharmacodynamic Properties of Topiramate Each capsule of topiramate XR contains topiramate as coated beads [4]. Topiramate is a sulfamate-substituted derivative of the monosaccharide D-fructose [4, 5]. Its exact mechanism of action is unclear; however, it appears to exert its antiepileptic effects by blocking voltage-dependent sodium channels, enhancing the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizing the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate subtype of the glutamate receptor and inhibiting the carbonic anhydrase enzyme (predominately isoenzymes II and IV) [4]. Topiramate has displayed antiepileptic activity in a variety of innate or induced rodent seizure models, including rat and mouse maximal electroshock seizure (MES) models, spontaneous epileptic rat (SER) models, DBA/2 mouse models, rat amygdala-kindled seizure models, and rat ischaemia-induced seizure models [4, 5]. Topiramate only weakly blocks clonic seizures induced by pentylenetetrazole (a GABA-A receptor antagonist) [4].

3 Pharmacokinetic Properties of Topiramate XR 3.1 Absorption 3.1.1 Single Dose The pharmacokinetics of topiramate XR are linear and dose-proportional, and demonstrate low variability over a 50–1400 mg dose range [as assessed by area under the

concentration-time curve (AUC) and maximum concentration (Cmax) values in healthy volunteers], which should result in predictable changes in plasma drug concentrations when a patient’s dosage is adjusted [6]. The administration of a single dose of topiramate XR 200 mg to healthy volunteers in the fed or fasted state resulted in bioequivalent (to two doses of topiramate immediate release (IR) 100 mg administered 12 h apart) AUC and Cmax values, indicating no food effect [7]. Moreover, administering the contents of a topiramate XR 200 mg capsule sprinkled on soft food (applesauce) was bioequivalent to administering an intact capsule, suggesting that topiramate XR would be a useful AED option for patients who have difficulty swallowing [8]. 3.1.2 Multiple Doses Steady state plasma concentrations were achieved by days 5 and 7 following the administration of once-daily topiramate XR 200 mg and twice-daily topiramate IR 100 mg, respectively, to healthy volunteers [9]. Topiramate XR provided bioequivalent plasma exposure to an equal daily dose of topiramate IR, but exhibited a slower (extended) rate of absorption (as reflected by its longer time to Cmax and longer peak occupancy time) (Table 1) [9], enabling once-daily dosing. Moreover, Cmax was significantly lower and the minimum concentration (Cmin) was significantly higher with topiramate XR than with topiramate IR (post hoc analyses), resulting in a reduced fluctuation index with topiramate XR therapy (Table 1) [9]. Notably, more constant plasma concentrations (versus fluctuating plasma concentrations) can minimize concentration-related adverse events [3]. Switching between the two formulations resulted in bioequivalent AUC from time 0 to 24 h, Cmax, Cmin and average concentration values on the first day following the switch, with no observable effects on steady-state plasma concentrations reported following the switch [9]. This indicates that switching does not affect the maintenance of topiramate concentrations. 3.2 Distribution, Metabolism and Elimination Over the blood concentration range of 0.5–250 lg/mL, topiramate is 15–41 % bound to human plasma proteins, with the fraction of bound topiramate decreasing as the blood concentration increases [4]. Topiramate is not extensively metabolized; approximately 70 % of an administered dose is eliminated unchanged in the urine [4]. Six topiramate metabolites, formed by glucuronidation, hydrolysis and hydroxylation, have been identified in humans; none constitute more than 5 % of the administered dose. Of note, the renal tubular

Topiramate Extended Release: A Review Table 1 Pharmacokinetic parameters of oral topiramate extended release versus oral topiramate immediate release in healthy adults [9] Steady-state plasma parameter (mean value unless otherwise specified)

Topiramate XR 200 mg once daily (n = 36)

Topiramate IR 100 mg twice daily (n = 36)

GLSM ratio (topiramate XR : topiramate IR) [90 % CI]a

AUC from time 0 to 24 h (mg
h/L)

158

153

104 % [102–105]

Maximum concentration (mg/L)

7.9**

8.4

93 % [90–97]

Minimum concentration (mg/L)

5.3**

5.0

106 % [103–109]

Average concentration (mg/L)

6.6

6.5

Not calculated

Median time to maximum concentration (h)

6.0

1.0

Not calculated

Peak occupancy timeb (h)

13*

4

Not applicable

Fluctuation index (%)

38

53

74 % [68–80]c

AUC area under the concentration-time curve, GLSM geometric least squares mean, IR immediate release, XR extended release * p \ 0.05, ** p \ 0.001 versus topiramate IR (post hoc analyses) a

Bioequivalence was assumed if the 90 % CIs were within the range of 0.80–1.25

b

Defined as the time period during which the plasma concentration deviated from Cmax by \20 %

c

Post hoc analysis

reabsorption of topiramate has been shown to occur in rats, but has yet to be evaluated in humans [4]. Following oral administration in adults, the plasma clearance of topiramate is approximately 20–30 mL/min [4]. 3.3 Special Patient Populations and Potential Drug Interactions Compared with subjects with a creatinine clearance (CRCL) of [70 mL/min/1.73 m2, the clearance of topiramate was reduced by 42 and 54 % in subjects with a CRCL of 30–69 mL/min/1.73 m2 and a CRCL of \30 mL/min/ 1.73 m2, respectively [4]. Thus, the starting and maintenance dose of topiramate should be reduced by one-half in patients with a CRCL \70 mL/min/1.73 m2. As topiramate is cleared by haemodialysis, such patients may require a supplemental dose [4]. In vitro, topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4 [4]. The coadministration of topiramate XR with phenytoin or carbamazepine (both hepatic enzyme-inducing AEDs) reduced mean plasma topiramate AUC values by 48 and 40 %, respectively, in patients with epilepsy. Therefore, dose adjustments of topiramate XR may be required when phenytoin and/or carbamazepine are added or withdrawn from adjunctive topiramate XR therapy; a dosage adjustment of phenytoin may also be required when phenytoin is coadministered with topiramate XR. According to the US prescribing information, the interaction of topiramate XR with standard AEDs is not expected to differ from that observed with topiramate IR [4]. Local prescribing information should be consulted for recommendations regarding the coadministration of topiramate XR with these and other (e.g. valproic acid) AEDs, and other agents.

4 Therapeutic Efficacy of Topiramate XR The approval of oral topiramate XR was based on clinical studies assessing oral topiramate IR (previously reviewed in Drugs [10]) and the demonstration of pharmacokinetic bioequivalence between topiramate XR and topiramate IR (Sect. 3) [4]. However, a randomized, double-blind, placebo-controlled, multinational, phase III study (PREVAIL) [11] was still conducted to evaluate the short-term efficacy of topiramate XR as adjunctive therapy in adults with refractory partial-onset seizures (POS) and is the focus of this section. Longer-term efficacy data from an open-label extension of this study (PREVAIL OLE) [12], which was primarily designed to evaluate the safety and tolerability of topiramate XR, are also reviewed. 4.1 PREVAIL PREVAIL enrolled patients aged 18–75 years with a diagnosis of refractory POS, with or without secondary generalization, for C1 year [11]. Patients had to have experienced C8 POS and B21 consecutive seizure-free days in the 8 weeks prior to randomization, and to be on a stable dosing regimen of 1–3 AEDs for C4 weeks (or C12 weeks for phenobarbital and primidone) prior to screening. A vagus nerve stimulator could be considered an AED provided it was in place for C6 months and on a stable setting for C1 month prior to screening [11]. Benzodiazepines could be considered an AED if they were taken more than once weekly for any indication [11], and could be used as rescue medication for a prolonged convulsive seizure (NCT01142193) [13]. Patients were excluded if they had, among other criteria, a history of psychogenic nonepileptic seizures or status epilepticus

S. M. Hoy

within the 3 months prior to screening, or a history of a lack of efficacy with topiramate despite adequate exposure (200 mg/day), or if they were previously or currently taking felbamate (in the 18 months leading up to screening), topiramate (in the 6 months leading up to screening) or vigabatrin [11]. Following an 8-week baseline period, patients received once-daily topiramate XR or matching placebo [11]. The target dosage of topiramate XR of 200 mg/day was achieved after a 3-week titration period (in which the dosage was increased by 50 mg each week) and then maintained at 200 mg/day throughout an 8-week maintenance period. Mean treatment adherence was high in both treatment groups (99 % of 124 topiramate XR recipients and 100 % of 125 placebo recipients) [11]. Following completion of the maintenance period, patients could enter a 55-week open-label extension study or discontinue the study medication over 3 weeks [11, 12]. At baseline, patients had a median weekly (partial-onset) seizure frequency per week of 2.5; 75 % of the 249 patients were receiving two or three concomitant AEDs [11]. The primary efficacy endpoint was the median percentage reduction from baseline to the end of the maintenance period in weekly seizure frequency [11]. The key secondary endpoint was the proportion of patients with a C50 % reduction in weekly seizure frequency (i.e. responders) relative to baseline. Analyses were conducted in the intent-to-treat (ITT) population [11]. Adjunctive therapy with topiramate XR was efficacious during short-term (11 weeks) therapy [11]. Compared with placebo, topiramate XR was associated with significantly greater improvements from baseline in weekly seizure frequency during the titration plus maintenance, titration and maintenance periods (Table 2). A treatment effect in favour of topiramate XR was observed as early as week 1 (at which time patients were receiving topiramate XR 50 mg/day or placebo), with topiramate XR therapy

associated with a significantly (p = 0.02) greater improvement from baseline in weekly seizure frequency than placebo at this timepoint (28.6 vs. 9.2 %). Post hoc analyses of this endpoint during the first 4 and last 4 weeks of the maintenance period support the findings of the a priori analyses, with results significantly (p = 0.002) favouring topiramate XR over placebo [11]. The effect of topiramate XR on the median percentage reduction from baseline in weekly seizure frequency was consistent across several subgroups, according to post hoc analyses [11, 14]. Significant (p \ 0.05) differences in this endpoint favouring topiramate XR over placebo were observed in patients who experienced complex partial seizures or partial seizures with secondary generalization, those receiving C3 concomitant AEDs, those considered to have ‘highly’ drug-resistant seizures (i.e. receiving C2 concomitant AEDs and C4 lifetime AEDs) and those considered to have ‘less’ drug-resistant seizures (i.e. receiving 1 concomitant AED or \4 lifetime AEDs) [11, 14]. No significant between-group difference in this endpoint was observed in patients who experienced simple partial seizures with motor signs, although this subgroup was small (n = 22 and 20 for the topiramate XR and placebo groups) [11]. The proportion of responders during the titration plus maintenance, titration and maintenance periods was significantly higher with topiramate XR than with placebo (Table 2) [11]. Post hoc analyses of this endpoint during the first 4 weeks and last 4 weeks of the maintenance period support the findings of the a priori analyses, with results significantly (p \ 0.05) favouring topiramate XR over placebo [11]. Beneficial effects with topiramate XR therapy on responder rates were also observed in the following patient subgroups: complex partial seizures or partial seizures with secondary generalization; C3 concomitant AEDs; ‘highly’ drug-resistant seizures (all p \ 0.05 vs. placebo) [11, 14]. No significant between-

Table 2 Short-term (11 weeks’ duration) efficacy of oral topiramate extended release, as adjunctive therapy to other antiepileptic drugs, in adults with partial-onset seizures. Summary of the multinational phase III PREVAIL study [11] Endpoint

TOP XR (n = 124)

PL (n = 125)

Median treatment difference (95 % CI)

Median percentage reduction from baseline in partial-onset seizure frequency per week During the titration plus maintenance periodsa During the titration period

39.5*** 33.9***

21.6 8.6

During the maintenance period

45.7***

22.1

18.5 (8.53–28.1)

Proportion of patients with C50 % reduction from baseline in partial-onset seizure frequency per week During the titration plus maintenance periods

37.9*

23.2

During the titration period

33.9**

17.6

During the maintenance period

44.2*

30.8

PL placebo, TOP topiramate, XR extended release * p \ 0.05, ** p = 0.007, *** p B 0.001 versus placebo a

Primary endpoint

14.7 (2.05–26.5)

Topiramate Extended Release: A Review

group difference in proportion of responders was observed in patients experiencing simple partial seizures with motor signs, although the subgroup was small (n = 22 and 20 for the topiramate XR and placebo groups), or those considered to have ‘less’ drug-resistant seizures [11, 14]. In terms of other endpoints, the proportion of patients achieving seizure freedom (i.e. a 100 % reduction in weekly seizure frequency) did not significantly differ between the topiramate XR and placebo groups during the titration plus maintenance period (3.2 vs. 1.6 %) and the maintenance period (7.1 vs. 3.3 %) [11]. In a post hoc analysis, seizure freedom for C21 days prior to the last dose of the study medication occurred in significantly more topiramate XR than placebo recipients (16.1 vs. 5.6 %; p = 0.006) [11]. Compared with placebo, adjunctive topiramate XR significantly improved clinical status, as assessed at the end of the maintenance period by the clinician-reported Global Impression of Change (CGI-C) [11]. The overall mean CGI-C score was significantly (p \ 0.001) lower in topiramate XR than placebo recipients [2.9 vs. 3.5; n = 119 and 124] [11]. In post hoc analyses, significant improvements in this endpoint with topiramate XR versus placebo therapy were observed, irrespective of whether patients had ‘highly’ drug-resistant seizures (p = 0.003) or ‘less’ drug-resistant seizures (p = 0.013) [14]. Moreover, in further post hoc analyses, significantly more topiramate XR than placebo recipients achieved CGI-C scores corresponding to improvement [i.e. scores of 1 (‘very much improved’) or 2 (‘much improved’)] (37.8 vs. 19.4 %; p = 0.002) [11], including in patients who had ‘highly’ drug-resistant seizures (33.3 vs. 11.1 %; p = 0.005) [14]. In terms of health-related quality of life, the overall mean patient-reported Quality of Life in Epilepsy–Problems (QOLIE-31-P) score at the end of the maintenance period did not significantly differ between topiramate XR (n = 100) and placebo (n = 108) recipients [11]. A significant (p \ 0.001) between-group difference favouring topiramate XR was observed in the seizure worry subscale score, but not in the other six subscale scores [11]. In post hoc analyses, a significant (p = 0.003) difference favouring topiramate XR over placebo was observed in the seizure worry subscale score, but not in the other subscale scores, in patients with ‘less’ drug-resistant seizures, with no significant between-group differences in any subscale scores in patients with ‘higher’ drug-resistant seizures [14]. 4.2 PREVAIL OLE Patients who completed PREVAIL were eligible to enter a multinational extension study (PREVAIL OLE) consisting of a 3-week double-blind conversion period and a 52-week

open-label period [12]. Almost all (97 %) patients who completed PREVAIL enrolled in PREVAIL OLE. During the double-blind period of PREVAIL OLE, patients who had previously received placebo (n = 111) were transitioned to topiramate XR 200 mg/day (initiated at a dosage of 50 mg/day and increased by 50 mg each week); the starting dosage for patients who had previously received topiramate XR 200 mg/day (n = 99) was 200 mg/day. Topiramate XR and concomitant AED dose adjustments were permitted after 11 weeks. The mean duration of topiramate XR exposure was 336 and 320 days for patients previously receiving topiramate XR or placebo, respectively, with the majority of patients receiving topiramate XR 200–350 mg. Analyses were conducted in the ITT population; all seizure rate comparisons used PREVAIL baseline values [12]. The antiepileptic efficacy of adjunctive topiramate XR B400 mg/day was sustained during longer-term (55 weeks) treatment [12]. The median percentage reduction from baseline in weekly seizure frequency was 51 % during the double-blind conversion period and 59 % during the open-label period. Generally similar findings were observed between patients originally treated with topiramate XR and those originally treated with placebo during the open-label period [12]. A C50 % reduction from baseline in weekly seizure frequency was achieved by 52 and 62 % of patients during the double-blind conversion and open-label periods, respectively [12]. Responder rates during the open-label period among patients originally treated with topiramate XR (n = 96) and those originally treated with placebo (n = 104) were 62 and 61 %. A C25, C75 and 100 % reduction from baseline in weekly seizure frequency during the open-label period was achieved by 79, 31 and 10 % of patients originally treated with topiramate XR, respectively, and 84, 32 and 0 % of patients originally treated with placebo, respectively. Seizure-free intervals of 4, 12, 24, 36 and 48 weeks were observed in 51, 19, 11, 7.2 and 2.4 % of patients, respectively [12]. At week 55 or early termination, 49 % of evaluated patients (n = 92) were considered ‘very much improved’ or ‘much improved’ in CGI-C scores, with generally similar findings observed regardless of whether patients were originally treated with topiramate XR or placebo [12]. The mean improvement (i.e. increase) from baseline in the overall QOLIE-31-P score in evaluable patients (n = 88) was 5.0. The greatest improvement (10.8) was in the QOLIE-31-P seizure worry subscale score. Therapy with topiramate XR did not negatively affect daily activities, emotions, energy, feelings of distress or mental activities, although a slight worsening in the medication effects subscale score was noted in patients originally treated with placebo [12].

S. M. Hoy

5 Tolerability and Safety of Topiramate XR 5.1 Short-Term Tolerability and Safety Adjunctive topiramate XR was generally well tolerated in adults with refractory POS in the PREVAIL study [11]. Over the 11-week titration plus maintenance period, C1 treatment-emergent adverse event (TEAE) was reported in a significantly higher proportion of topiramate XR than placebo recipients (66.1 % of 124 vs. 50.4 % of 125 patients; p = 0.015), although the majority (90 %) of these were mild or moderate in intensity. Severe TEAEs occurred in 6.5 versus 4.8 % of patients receiving topiramate XR versus placebo. As expected, the proportion of topiramate XR, but not placebo, recipients experiencing C1 TEAE generally increased with increasing numbers of concomitant AEDs, with the proportion greatest amongst those receiving C3 concomitant AEDs (no quantitative data reported) [11]. A recent Cochrane review of topiramate for drug-resistant partial epilepsy, which included 1401 patients participating in 11 randomized controlled studies, determined that ataxia, concentration difficulties, dizziness, fatigue, paraesthesia, somnolence, ‘thinking abnormally’ and weight loss were significantly associated with topiramate therapy [15]. In the PREVAIL study, the most common (incidence C5 %) TEAEs occurring in the topiramate XR and placebo groups were somnolence (12.1 vs. 2.4 % of patients), dizziness (7.3 vs. 5.6 %), paraesthesia (6.5 vs. 2.4 %), weight loss (6.5 vs. 0 %), fatigue (5.6 vs. 4.8 %) and headache (4.0 vs. 5.6 %) [11]. Over the 11-week titration plus maintenance period, at least one treatment-related adverse event was reported in 51.6 versus 31.2 % of patients receiving topiramate XR versus placebo [11]. Serious adverse events were reported in 1.6 % of patients in both groups, with none of those reported in the topiramate XR group (lobar pneumonia and physical assault) considered related to treatment. No deaths were reported in either treatment group [11]. TEAEs leading to treatment discontinuation occurred in 8.9 and 4.0 % of patients receiving topiramate XR or placebo [11]. Somnolence [n = 2 (topiramate XR) and 0 (placebo)] and attention disturbances [n = 2 (topiramate XR) and 1 (placebo)] were the only TEAEs resulting in treatment discontinuation in more than one patient [11]. The incidence of neurocognitive and neuropsychiatric TEAEs was low [11]. Apart from attention disturbances (which occurred in 2.4 vs. 3.2 % of topiramate XR versus placebo recipients), neurocognitive and neuropsychiatric TEAEs (e.g. memory impairment, psychomotor slowing) each occurred in\3 % of patients receiving topiramate XR or placebo [11]. There were no reports of suicidal behavior in the topiramate XR group; one placebo recipient experienced

two types of suicidal behavior (preparatory acts/behavior and suicidal behaviour). One topiramate recipient experienced a single event of suicidal ideation, with three placebo recipients experiencing a total of six suicidal ideations [11]. Therapy with topiramate is associated with hyperchloraemic, non-anion gap, metabolic acidosis (i.e. a reduction in serum bicarbonate levels below the normal reference range in the absence of chronic respiratory alkalosis) and secondary angle closure glaucoma [4]. In PREVAIL, reductions from baseline in serum bicarbonate levels generally fell within the normal reference range, with no reports of secondary angle closure glaucoma [11]. Moreover, other known safety concerns associated with long-term topiramate therapy (e.g. decreased sweating, increased body temperature and kidney stones) were not reported, although the length (11 weeks) of the PREVAIL study may have prevented their detection. A statistically significant reduction in bodyweight was observed with topiramate XR versus placebo (1.87 vs. 0.04 kg; p \ 0.001); such a reduction was commensurate with those reported with topiramate IR therapy [11]. 5.2 Longer-Term Tolerability and Safety Longer-term therapy with adjunctive topiramate XR was generally well tolerated in adults with refractory POS [12]. At least one TEAE was reported in 69.5 % of 210 patients (61.6 vs. 76.6 % of patients who had received topiramate or placebo in the initial study). The majority of TEAEs were mild to moderate in intensity. The most common (incidence C5 %) TEAEs were headache (7.6 % of patients), weight loss (7.6 %), somnolence (7.1 %), dizziness (6.2 %), aphasia (5.2 %) and fatigue (5.2 %). Apart from aphasia, the nature of TEAEs reported in the extension study were similar to those reported in PREVAIL. Of note, the incidences of aphasia, somnolence, fatigue and dizziness were numerically higher in patients originally treated with placebo (9.9, 9.0, 8.1 and 6.3 %, respectively) than in those originally treated with topiramate XR (0, 5.1, 2.0 and 6.1 %, respectively) [12]. Approximately half (48.6 %) of patients experienced at least one treatment-related adverse event (42.4 vs. 54.1 % of patients who had received topiramate or placebo in the initial study) [12]. Twenty (9.5 %) patients discontinued therapy due to adverse events, with aphasia, asthenia, convulsion and diarrhoea each resulting in treatment discontinuation in more than one patient. Serious TEAEs occurred in 14 (6.7 %) patients, eight of whom were originally receiving placebo and six of whom were originally receiving topiramate XR. Only two serious TEAEs [cholelithiasis and volvulus (n = 1 each)] were considered related to topiramate XR therapy. One death (considered unrelated to topiramate XR therapy) [ischaemic stroke] was reported [12].

Topiramate Extended Release: A Review Table 3 Summary of the US dosage recommendations for oral topiramate extended release [4] Indication

Dosage

Monotherapy (POS or primary generalized tonic-clonic seizures) Patients aged C10 years

The initial dosage is 50 mg od, with the dose increased by 50 mg every week for 4 weeks and then by 100 mg every week for 2 weeks up to a maximum dosage of 400 mg od

Patients aged 2 to \10 years

The initial dosage is 25 mg od (administered at night) for 1 week, with the dose increased to 50 mg od in the second week and thereafter by 25–50 mg every week during weeks 5–7 [with titration to the minimum maintenance dosage (150–250 mg od, BW dependent)] with further titration up to a maximum dosage of 250–400 mg od (BW dependent), based upon tolerability and clinical response

Adjunctive therapy (POS or primary generalized tonic-clonic seizures or LGS) Patients aged C17 years

The initial dosage is 25–50 mg od, with the dose increased by 25–50 mg every week up to a maximum dosage of 200–400 mg od (POS or LGS) or 400 mg od (primary generalized tonic-clonic seizures)

Patients aged 2–16 years

The initial dosage is 25 mg od (based on 1–3 mg/kg/d) [administered at night] for the first week, with the dose increased by 1–3 mg/kg every 1 or 2 weeks up to a maximum dosage of 5–9 mg/kg od

Dose titration should be guided by clinical outcomes, with capsules swallowed whole or administered by sprinkling the entire contents on a teaspoon of soft food BW bodyweight, LGS Lennox-Gastaut syndrome, od once daily, POS partial-onset seizures

Individual neurocognitive TEAEs each occurred in \3 % of patients, apart from aphasia (5.2 %), with the incidence of neurocognitive TEAEs generally consistent over the 55-week treatment period [12]. Five patients (2.4 %) developed clinically significant changes from baseline in neurological examinations. There were no reports of decreased sweating, increased body temperature, kidney stones, metabolic acidosis or suicidal behavior, although one patient experienced suicidal ideation. Reductions from baseline in serum bicarbonate levels were not significant. Bodyweight reductions from baseline were observed regardless of prior therapy during PREVAIL, with reductions of 5.4 and 4.0 % seen in patients originally treated with topiramate XR or placebo [12].

6 Dosage and Administration of Topiramate XR In the USA, topiramate XR is approved for [4]: •

•

POS and primary generalized tonic-clonic seizures: initial monotherapy in patients 2 years of age and older with partial-onset or primary generalized tonic-clonic seizures and adjunctive therapy in patients 2 years of age and older with partial-onset or primary generalized tonic-clonic seizures; LGS: adjunctive therapy in patients 2 years of age and older with seizures associated with LGS.

Table 3 presents a summary of the dosage recommendations. Concomitant therapy with topiramate XR and metformin is contraindicated in patients with metabolic acidosis [4]. Local prescribing information should be consulted for further detailed information regarding dosage modifications, drug interactions, use in special patient populations, and warnings and precautions.

7 Current Status of Topiramate XR Optimal antiepileptic therapy requires the maintenance of stable and effective plasma AED concentrations, without extensive peak–trough fluctuations [16]. Minimizing the fluctuations observed with IR AEDs can be accomplished by increasing the dosing frequency (although such a strategy may adversely affect adherence) or reformulating the AED into a once-daily XR preparation [16], with current evidence showing that AEDs administered less frequently per day significantly aid adherence [2]. The approval of once-daily topiramate XR was based in part on the demonstration of pharmacokinetic bioequivalence between topiramate XR and twice-daily topiramate IR (Sect. 3). Specifically, in healthy volunteers, topiramate XR provided a steady-state plasma exposure bioequivalent to topiramate IR at the same total daily dose. However, compared with topiramate IR, it exhibited an extended absorption rate (permitting convenient once-daily dosing) and more constant therapeutic plasma concentrations (potentially minimizing topiramate-associated adverse events) that may improve patient quality of life and adherence to treatment. Switching between the two formulations did not affect the maintenance of topiramate concentrations, and neither the extent nor the peak of topiramate XR’s absorption was affected by food. Moreover, the contents of a topiramate XR capsule may be sprinkled on soft food for patients who have difficulty swallowing (Sect. 3). In the multinational PREVAIL study in adults with refractory POS, adjunctive topiramate XR reduced the weekly median seizure frequency from baseline by approximately 40 %, with over one-third of patients achieving a C50 % reduction in seizure frequency (Sect. 4.1). Notably, for the most part, improvements in weekly seizure frequency and response rates with adjunctive

S. M. Hoy

topiramate XR were approximately twice as high as those observed with placebo. Compared with placebo, topiramate XR significantly reduced the effect of seizure worry without causing significant unwanted physical or mental medication adverse events, and improved patients’ clinical status (Sect. 4.1). The benefits of treatment observed during short-term therapy were sustained during continued therapy in the 55-week extension study of PREVAIL (Sect. 4.2). Failure to achieve complete seizure control with the use of two appropriate AEDs greatly reduces the likelihood of success with subsequent regimens [17]. However, post hoc subgroup analyses found that topiramate XR significantly improved weekly median seizure frequency from baseline relative to placebo, regardless of a patient’s level of drug resistance at baseline (Sect. 4.1). Robust data on the efficacy of topiramate XR in patients considered to have ‘highly’ drug-resistant seizures would be of interest. AEDs, either as monotherapy or as part of combination therapy, have the potential to produce adverse events [2]. Adjunctive topiramate XR was generally well tolerated by patients in the PREVAIL study (Sect. 5.1) and its extension (Sect. 5.2). In PREVAIL, TEAEs were generally mild or moderate in intensity, with somnolence, dizziness, paraesthesia, weight loss and fatigue the most frequently reported following adjunctive topiramate XR therapy. The incidence of neurocognitive and neuropsychiatric TEAEs following short- and longer-term topiramate XR therapy was low, which may reflect the more constant therapeutic plasma concentrations of topiramate XR. In conclusion, current evidence suggests once-daily topiramate XR extends the treatment options currently available for patients aged C2 years with epilepsy. In the absence of head-to-head studies, definitive conclusions on the comparative efficacy and tolerability of topiramate XR versus other existing AED XR formulations are not yet possible. In the meantime, its once-daily dosing regimen may deliver tolerability and adherence advantages over AEDs that require more frequent administration. Data selection sources: Relevant medical literature (including published and unpublished data) on topiramate XR was identified by searching databases including MEDLINE (from 1946), PubMed (from 1946) and EMBASE (from 1996) [searches last updated 25 April 2016], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: USL-255, topiramate, Upsher. Study selection: Studies in patients with focal (partial) epilepsy, tonic-clonic epilepsy, and Lennox-Gastaut syndrome who received topiramate XR (USL-255). When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Acknowledgments During the peer review process, the manufacturer of topiramate XR was also offered an opportunity to review this

article. Changes resulting from comments received were made on the basis of scientific and editorial merit. Compliance with Ethical Standards Funding The preparation of this review was not supported by any external funding. Conflict of interest Sheridan Hoy is a salaried employee of Adis/ Springer, is responsible for the article content and declares no relevant conflicts of interest.

References 1. Al-Aqeel S, Al-Sabhan J. Strategies for improving adherence to antiepileptic drug treatment in patients with epilepsy. Cochrane Database Syst Rev. 2011;(1):CD008312. 2. Eatock J, Baker GA. Managing patient adherence and quality of life in epilepsy. Neuropsychiatr Dis Treat. 2007;3(1):117–31. 3. Bialer M. Extended-release formulations for the treatment of epilepsy. CNS Drugs. 2007;21(9):765–74. 4. Upsher-Smith Laboratories Inc. QUDEXY XR (topiramate) extended-release capsules, for oral use: US prescribing information. 2015. http://www.fda.gov/. Accessed 3 May 2016. 5. Shank RP, Gardocki JF, Streeter AJ, et al. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000;41(Suppl 1):S3–9. 6. Clark AM, Halvorsen MB, Braun TL, et al. USL255 extendedrelease topiramate: dose-proportional pharmacokinetics and tolerability in healthy volunteers. Epilepsia. 2014;55(7):1069–76. 7. Lambrecht LJ, Shekh-Ahmad T, Todd WM, et al. Comparative pharmacokinetic analysis of USL255, a new once-daily extendedrelease formulation of topiramate. Epilepsia. 2011;52(10):1877–83. 8. Clark AM, Pellock JM, Holmay M, et al. 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. Epilepsy Behav. 2016;57(Pt A):105–10. 9. Bialer M, Shekh-Ahmad T, Braun TL, et al. Comparative steadystate pharmacokinetic evaluation of immediate-release topiramate and USL255, a once-daily extended-release topiramate formulation. Epilepsia. 2013;54(8):1444–52. 10. Lyseng-Williamson KA, Yang LP. Topiramate: a review of its use in the treatment of epilepsy. Drugs. 2007;67(15):2231–56. 11. Chung SS, Fakhoury TA, Hogan RE, et al. Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study. Epilepsia. 2014;55(7):1077–87. 12. Chung SS, Hogan RE, Blatt I, et al. Long-term safety and sustained efficacy of USL255 (topiramate extended-release capsules) in patients with refractory partial-onset seizures. Epilepsy Behav. 2016;59:13–20. 13. Data on file, Upsher-Smith Laboratories Inc., 2015. 14. Hogan RE, Blatt I, Lawson B, et al. Efficacy of once-daily extended-release topiramate (USL255): a subgroup analysis based on the level of treatment resistance. Epilepsy Behav. 2014;41:136–9. 15. Pulman J, Jette N, Dykeman J, et al. Topiramate add-on for drugresistant partial epilepsy. Cochrane Database Syst Rev. 2014;2:CD001417. 16. Leppik IE, Hovinga CA. Extended-release antiepileptic drugs: a comparison of pharmacokinetic parameters relative to original immediate-release formulations. Epilepsia. 2013;54(1):28–35. 17. Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011;365(10):919–26.