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Brivaracetam (Brivlera) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 Feb.
Brivaracetam (Brivlera) is indicated as adjunctive therapy in the management of partial-onset seizures (POS) in adult patients (≥ 18 years) with epilepsy who are not satisfactorily controlled with conventional therapy.1 Brivaracetam is available in 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg tablets at a market price of $4.32 for all strengths. The recommended starting dose of brivaracetam is 50 mg twice daily, with the dose adjusted to between 25 mg and 100 mg twice daily, depending on response. The daily cost of brivaracetam is $8.64. The manufacturer is requesting reimbursement in line with the Health Canada indication, with similar criteria to that of lacosamide, perampanel, and eslicarbazepine.
The manufacturer submitted a cost-minimization analysis2 comparing brivaracetam with lacosamide, perampanel, and eslicarbazepine when used as adjunctive therapy to concomitant antiepileptic drugs (AEDs) in the management of POS in adult patients who are not satisfactorily controlled with conventional therapy. The perspective was that of a Canadian public drug plan with a time horizon of one year. The assumption of “broad similarity” was based on the results of an unpublished network meta-analysis (NMA). Costs for lacosamide, perampanel, and eslicarbazepine were derived using Ontario Drug Benefit (ODB) Formulary list prices. Costs for brivaracetam were derived using the current market price of $4.32 per tablet. All costs included an 8% markup with an $8.83 dispensing fee applied every 30 days, and were dose-weighted using a uniform distribution across the recommended maintenance dose ranges in the respective product monographs.
The manufacturer concluded that, at $3,513 per patient, the dose-weighted average annual cost of brivaracetam was $275 less than that of lacosamide ($3,788 per patient, based on a minor mathematical correction by the CADTH Common Drug Review [CDR]), $319 less than that of perampanel ($3,833 per patient), and $363 less than that of eslicarbazepine ($3,876 per patient).
There are no head-to-head trials comparing brivaracetam with active comparators in patients with POS inadequately controlled with conventional AEDs. In the submitted NMA, no significant differences in efficacy, all-cause discontinuation, discontinuation due to treatment-emergent adverse events serious adverse events, dizziness, fatigue, or somnolence were found between brivaracetam and lacosamide, perampanel, retigabine/ezogabine (not approved in Canada), and eslicarbazepine; however, brivaracetam had a statistically significantly increased risk of nausea compared with perampanel and a reduced risk of nausea compared with eslicarbazepine. The wide credible intervals associated with the NMA estimates for brivaracetam versus the other treatments increase uncertainty in the manufacturer’s assumption of similarity across drugs, as statistically non-significant differences do not necessarily imply treatment equivalence or non-inferiority. Of note, a published indirect treatment comparison3 of brivaracetam and levetiracetam showed no statistical differences with respect to efficacy and adverse events.
The manufacturer compared brivaracetam with lacosamide, perampanel, and eslicarbazepine, but did not include any other drugs used in Canada as adjunctive therapy in refractory POS (e.g., lamotrigine, topiramate, gabapentin). While many of these drugs have broader indications and/or reimbursement criteria and, therefore, may have been used earlier in therapy, they are all less expensive than brivaracetam, and their safety, tolerability, and efficacy relative to brivaracetam are unknown (Table 1). Of particular interest is levetiracetam, a less expensive drug ($536 to $1,294 per patient per year, depending on dose) in the same class as brivaracetam. A published indirect treatment comparison found few significant differences in efficacy between the two drugs.3
Cost Comparison Table for AEDs for the Treatment of Partial-Onset Seizures in Adult Patients With Epilepsy Who Are Not Satisfactorily Controlled With Conventional Therapy.
The manufacturer assumed a uniform dose distribution across the monograph–recommended maintenance doses for all comparators, omitting the lowest-strength tablet available for each comparator. A uniform dose distribution is unlikely and may have overestimated the average annual cost of lacosamide (the only comparator with graduated pricing, i.e., price of higher-strength tablets is greater than that of lower strengths), resulting in overestimation of the savings associated with brivaracetam. As well, lower doses of brivaracetam, particularly the 25 mg strength, are likely to replace at least some of the utilization of lower strengths of its comparators (Table 11). Utilization data from QuintilesIMS retrieved by CDR indicate that 35% of perampanel claims, 37% eslicarbazepine claims, and 31% of lacosamide claims reimbursed by the ODB Program in the first quarter of 2016 were for strengths excluded in the manufacturer’s analysis, supporting the necessity of considering lower strengths in the cost calculations. Additionally, the utilization data indicate considerable use of lower-strength tablets to achieve daily doses could be achieved in a more cost-efficient manner through the use of higher strengths (e.g., two lacosamide 50 mg tablets administered twice daily rather than one 100 mg tablet administered twice daily). Therefore, omission of lower-strength tablets in the manufacturer’s analysis is likely to result in underestimation of the average daily costs across all comparators, with the effect most pronounced for flat-priced comparators such as brivaracetam. In the absence of sufficient utilization data for brivaracetam, it is difficult to estimate what the real-world average daily cost of therapy will be for this drug in relation to its comparators.
The actual costs paid by Canadian public drug plans for perampanel, lacosamide, and eslicarbazepine are likely lower than those listed on publicly available formularies, which reduce the relative attractiveness of the submitted price of brivaracetam. See Appendix 1 for price-reduction analyses exploring this possibility.
The clinical expert consulted by CDR noted that, in some situations, physicians may consider combining brivaracetam with perampanel, lacosamide, or eslicarbazepine rather than substituting one for another. These combinations would be more costly than several other combinations of AEDs, particularly those consisting of older AEDs.
Like lacosamide,4 perampanel,5 and eslicarbazepine,6 brivaracetam is not indicated for pediatric patients.1 However, according to the clinical expert consulted by CDR, lacosamide is frequently used in children and adolescents with refractory POS; perampanel is beginning to be used for this population, and it is likely that eslicarbazepine will be as well. Thus, it is also likely that brivaracetam will be used in pediatric patients as clinicians gain familiarity with it.
The patents for lacosamide (Vimpat) are due to expire in early 2017,7 with market exclusivity ending in September 2018,8,9 which may lead to the availability of less expensive generic versions, making the relative cost of brivaracetam at the submitted price less attractive thereafter.
CDR performed a reanalysis to address the identified limitations associated with the dose distribution of lacosamide, and to remove dispensing fees and markups from the calculations. At the currently marketed price of $4.32 per tablet, and using the manufacturer’s dosing assumptions, the average annual cost of brivaracetam ($3,154 per patient) was less than that of lacosamide ($3,408 per patient), perampanel ($3,449 per patient), and eslicarbazepine ($3,489) at 2016 ODB Formulary list prices; however, due to cost-inefficient dispensing patterns, there is considerable uncertainty in the relative costs for all four comparators in the real-world setting. Brivaracetam is considerably more expensive than levetiracetam ($397 to $1,098), and a published indirect treatment comparison found no significant differences in efficacy between these drugs. Brivaracetam is more expensive than most other comparators used for patients with refractory POS. The combination of brivaracetam with perampanel, lacosamide, or eslicarbazepine would be more costly than other combinations of AEDs.
The clinical expert consulted by CDR deemed the comparator treatments presented in Table 1 to be appropriate. Costs are manufacturer list prices, unless otherwise specified. Existing Product Listing Agreements are not reflected in the table and as such may not represent the actual costs to public drug plans.
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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