Clobazam and clonazepam use in epilepsy: Results from a UK database incident user cohort study

Brodie, Martin J.; Chung, Steve S.; Wade, Alan G; Quelen, Céline; Guiraud-Diawara, Alice; François, Clément; Verpillat, Patrice; Shen, Vivienne; Isojärvi, Jouko

doi:10.1016/j.eplepsyres.2016.04.003

Cited by 18 publications

(14 citation statements)

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“…Adverse events profile of these drugs might have also affected the rate of treatment discontinuation and switch. Treatment patterns in LGS patients have not been extensively evaluated; although in the UK study noted above, treatment duration differed from that reported in the current study [15]. The median treatment duration was similar between the epilepsy patients treated with clobazam or clonazepam.…”

Section: Discussioncontrasting

confidence: 59%

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Use and cost comparison of clobazam to other antiepileptic drugs for treatment of Lennox-Gastaut syndrome

François

Stern

Ogbonnaya

et al. 2017

Journal of Market Access & Health Policy

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Background: Lennox-Gastaut syndrome (LGS) is a severe form of childhood-onset epilepsy associated with serious injuries due to frequent and severe seizures. Of the antiepileptic drugs (AEDs) approved for LGS, clobazam is a more recent market entrant, having been approved in October 2011. Recent AED budget impact and cost-effectiveness analyses for LGS suggest that adding clobazam to a health plan formulary may result in decreased medical costs; however, research on clinical and economic outcomes and treatment patterns with these AED treatments in LGS is limited.Objectives: To compare the baseline characteristics and treatment patterns of new initiators of clobazam and other AEDs among LGS patients and compare healthcare utilization and costs before and after clobazam initiation among LGS patients.Methods: A retrospective study of probable LGS patients was conducted using the MarketScan® Commercial, Medicare Supplemental, and Medicaid databases (10/1/2010-3/31/2014).Results: In the Commercial/Medicare Supplemental population, clobazam users were younger, had fewer comorbidities, and more prior AED use than non-clobazam users. In the 12 months pre-treatment initiation, clobazam users had significantly more seizure-related inpatient stays and outpatient visits and higher total seizure-related (P < 0.001) and all-cause (P < 0.001) costs than non-clobazam users. Among clobazam users, when compared to the 12 months pre-clobazam initiation, seizure-related medical utilization and costs were lower in the 12 months post-clobazam initiation (P = 0.004). Total all-cause (P < 0.001) and seizure-related (P = 0.029) costs increased post-clobazam initiation mainly due to the increase in outpatient pharmacy costs. Similar results were observed in the Medicaid population.Conclusions: Baseline results suggest a prescribing preference for clobazam in severe LGS patients. Clobazam users had a reduction in seizure-related medical utilization and costs after clobazam initiation. The improvement in medical costs mostly offset the higher prescription costs following clobazam initiation.

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Section: Discussioncontrasting

confidence: 59%

“…Similar findings were observed in a database study conducted in adult epilepsy patients in the United Kingdom (UK). In that study, prior to treatment initiation, patients initiating clobazam treatment were younger and had greater use of concomitant AEDs than those receiving clonazepam [15]. …”

Section: Discussionmentioning

confidence: 99%

Use and cost comparison of clobazam to other antiepileptic drugs for treatment of Lennox-Gastaut syndrome

François

Stern

Ogbonnaya

et al. 2017

Journal of Market Access & Health Policy

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“…For example, a comparison of real-world use of clobazam and clonazepam in patients with epilepsy in the United Kingdom showed that median clonazepam dosages increased by 25% and 50% for adults and children, respectively, while median clobazam dosages did not change from baseline to the last follow-up (adults, 5.2–5.5 years; children, 5.5–6.3 years). 26 It is also important to note that clobazam is structurally different from classic benzodiazepines: the 2 nitrogen components at the core of all benzodiazepines have a 1,5 configuration in clobazam compared to a 1,4 configuration in the classic benzodiazepines (e.g., diazepam, lorazepam, and clonazepam). Clobazam and its active N -desmethyl metabolite also appear to display significantly greater binding affinity to the α2 vs α1 subunit of the GABA-A receptor.…”

Section: Discussionmentioning

confidence: 99%

Deconstructing tolerance with clobazam

et al. 2016

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Objective:To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome.Methods:Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg−1·d−1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg−1·d−1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ≥40% and increasing seizure rates.Results:Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ≥75% responders demonstrated a consistent response over time. Few patients had a dosage increase ≥40% associated with an increase in seizure rates.Conclusions:Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated.ClinicalTrials.gov identifier:NCT00518713 and NCT01160770.Classification of evidence:This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment.

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“…This approach has been employed in other similar CPRD studies using these two variables. 77,78 Random samples of 50,000 patients from these limited samples were then taken to form the five main analysis samples (Table 12). Product codes (CPRD unique code for treatment selected by the GP) associated with relevant prescriptions used in the treatment of five case study conditions were used to select the patients to be included in the samples.…”

Section: Methodsmentioning

confidence: 99%

“…Appropriate methods to impute these variables are, however, limited, and our approach was similar to other studies using CPRD data. 77,78 Third, the identification of patients within CPRD with the five case study conditions (see Table 11) was based solely on product codes, rather than on a specific medical diagnosis (identified using Read codes in CPRD). This was straightforward for four of the five conditions, but required additional assumptions for the secondary prevention of myocardial infarction cohort.…”

Section: Limitations Of the Cost Analysismentioning

confidence: 99%

Clinical effectiveness and cost-effectiveness of issuing longer versus shorter duration (3-month vs. 28-day) prescriptions in patients with chronic conditions: systematic review and economic modelling

Miani

Martin

Exley

et al. 2017

Health Technol Assess

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BackgroundTo reduce expenditure on, and wastage of, drugs, some commissioners have encouraged general practitioners to issue shorter prescriptions, typically 28 days in length; however, the evidence base for this recommendation is uncertain.ObjectiveTo evaluate the evidence of the clinical effectiveness and cost-effectiveness of shorter versus longer prescriptions for people with stable chronic conditions treated in primary care.Design/data sourcesThe design of the study comprised three elements. First, a systematic review comparing 28-day prescriptions with longer prescriptions in patients with chronic conditions treated in primary care, evaluating any relevant clinical outcomes, adherence to treatment, costs and cost-effectiveness. Databases searched included MEDLINE (PubMed), EMBASE, Cumulative Index to Nursing and Allied Health Literature, Web of Science and Cochrane Central Register of Controlled Trials. Searches were from database inception to October 2015 (updated search to June 2016 in PubMed). Second, a cost analysis of medication wastage associated with < 60-day and ≥ 60-day prescriptions for five patient cohorts over an 11-year period from the Clinical Practice Research Datalink. Third, a decision model adapting three existing models to predict costs and effects of differing adherence levels associated with 28-day versus 3-month prescriptions in three clinical scenarios.Review methodsIn the systematic review, from 15,257 unique citations, 54 full-text papers were reviewed and 16 studies were included, five of which were abstracts and one of which was an extended conference abstract. None was a randomised controlled trial: 11 were retrospective cohort studies, three were cross-sectional surveys and two were cost studies. No information on health outcomes was available.ResultsAn exploratory meta-analysis based on six retrospective cohort studies suggested that lower adherence was associated with 28-day prescriptions (standardised mean difference –0.45, 95% confidence interval –0.65 to –0.26). The cost analysis showed that a statistically significant increase in medication waste was associated with longer prescription lengths. However, when accounting for dispensing fees and prescriber time, longer prescriptions were found to be cost saving compared with shorter prescriptions. Prescriber time was the largest component of the calculated cost savings to the NHS. The decision modelling suggested that, in all three clinical scenarios, longer prescription lengths were associated with lower costs and higher quality-adjusted life-years.LimitationsThe available evidence was found to be at a moderate to serious risk of bias. All of the studies were conducted in the USA, which was a cause for concern in terms of generalisability to the UK. No evidence of the direct impact of prescription length on health outcomes was found. The cost study could investigate prescriptions issued only; it could not assess patient adherence to those prescriptions. Additionally, the cost study was based on products issued only and did not account for underlying patient diagnoses. A lack of good-quality evidence affected our decision modelling strategy.ConclusionsAlthough the quality of the evidence was poor, this study found that longer prescriptions may be less costly overall, and may be associated with better adherence than 28-day prescriptions in patients with chronic conditions being treated in primary care.Future workThere is a need to more reliably evaluate the impact of differing prescription lengths on adherence, on patient health outcomes and on total costs to the NHS. The priority should be to identify patients with particular conditions or characteristics who should receive shorter or longer prescriptions. To determine the need for any further research, an expected value of perfect information analysis should be performed.Study registrationThis study is registered as PROSPERO CRD42015027042.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Clobazam and clonazepam use in epilepsy: Results from a UK database incident user cohort study

Abstract: Among adult and pediatric patients in the UK, CLB is more often prescribed for epilepsy than CZP. The median CLB dosage used by both adults and children remained stable over the 16-year study period, while the median CZP dosage increased in both adults and children.

Cited by 18 publications

References 20 publications

Use and cost comparison of clobazam to other antiepileptic drugs for treatment of Lennox-Gastaut syndrome

Use and cost comparison of clobazam to other antiepileptic drugs for treatment of Lennox-Gastaut syndrome

Deconstructing tolerance with clobazam

Clinical effectiveness and cost-effectiveness of issuing longer versus shorter duration (3-month vs. 28-day) prescriptions in patients with chronic conditions: systematic review and economic modelling

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