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Clobazam and Clonazepam Use in Epilepsy: Results from a UK

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Clobazam and Clonazepam Use in Epilepsy: Results from a UK Epilepsy Research 123 (2016) 68–74 CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Contents lists available at www.sciencedirect.com Epilepsy Research journa l homepage: www.elsevier.com/locate/epilepsyres Clobazam and clonazepam use in epilepsy: Results from a UK database incident user cohort study a,∗ b c d d Martin J. Brodie , Steve Chung , Alan Wade , Céline Quelen , Alice Guiraud-Diawara , e d f f Clément Franc¸ ois , Patrice Verpillat , Vivienne Shen , Jouko Isojarvi a Epilepsy Unit West Glasgow, ACH-Yorkhill, Glasgow G3 8SJ, Scotland, UK b Neuroscience Institute, Banner University Medical Center, 1111 McDowell Road, Phoenix, AZ, USA c Patients Direct, 3 Todd Campus, Glasgow G20 OXA, Scotland, UK d Health Economics and Epidemiology and Global Analytics, Lundbeck SAS, Quai du Président Roosevelt 37-45, 92445 Issy-les-Moulineaux, France e Health Economics and Outcomes Research, Lundbeck LLC, 4 Parkway North Suite 200, Deerfield, IL 60015, USA f Medical Affairs, Lundbeck LLC, 4 Parkway North Suite 200, Deerfield, IL 60015, USA a r t a b i c l e i n f o s t r a c t Article history: Objective: To compare patient characteristics and treatment patterns among clobazam (CLB) and clon- Received 17 July 2015 azepam (CZP)-treated patients with epilepsy in a longitudinal primary care database. Received in revised form 14 March 2016 Methods: In this pharmacoepidemiological study, real-life usage data from the Clinical Practice Research Accepted 8 April 2016 Database (CPRD) were evaluated. The CPRD collects data from approximately 690 primary care practices Available online 11 April 2016 throughout the UK. Data included were from patients with ≥1 incident CLB or CZP prescription from 1995 to 2011 and were present in the database for ≥182 days prior to the index date (date patient was first Keywords: prescribed CLB or CZP within the study period). Cohort studies Results: Of 21,099 patients who met inclusion criteria, 18.4% were receiving CLB and 81.6% were receiving All epilepsy/seizures CZP. More patients used CLB for epilepsy than CZP (76.1% vs 8.7%). CLB-treated adults (≤18 years) were Antiepileptic drugs ≤ Outcome research younger than those treated with CZP (41.0 vs 48.2 years; p < 0.001), while CLB-treated children ( 18 Clobazam years) were older than those treated with CZP (8.8 vs 7.3 years, p < 0.001). The median CLB dosage did Clonazepam not change from baseline to last follow-up, while median CZP dosage increased 25% in adults and 50% in children. Median treatment duration, as well as retention rate up to 10 years, was similar between CLB and CZP in each age group. Conclusions: 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. © 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction Benzodiazepines (BZDs) have been used to treat a variety of disorders, including anxiety, depression, insomnia, alcohol withdrawal, and seizures. While BZDs are the most commonly prescribed class of psychotropic medications (Olfson et al., 2015), Abbreviations: AED, antiepileptic drug; BNF, British National Formulary; BZD, select few are used to treat epilepsy: diazepam and lorazepam for benzodiazepine; CLB, clobazam; CZP, clonazepam; CPRD, Clinical Practice Research seizure emergencies; midazolam for refractory status epilepticus Database; ISAC, Independent Scientific Advisory Committee; LGS, Lennox–Gastaut and seizure emergencies; nitrazepam for myoclonic seizures, infan- syndrome; MHRA, Medicines and Healthcare Products Regulatory Agency; NDD, numeric daily dosage; NICE, National Institute for Health and Care Excellence. tile spasms and other childhood seizures; clorazepate, clonazepam ∗ Corresponding author at: Medicine and Clinical Pharmacology, Epilepsy Unit and clobazam for long-term epilepsy management (Riss et al., 2008; West Glasgow, ACH-Yorkhill Glasgow G3 8SJ, Scotland UK. Schatzberg and Nemeroff, 2009). Though BZDs are the drugs of first E-mail addresses: [email protected] (M.J. Brodie), choice for seizure emergencies (De Waele et al., 2013), their use as [email protected] (S. Chung), [email protected] (A. Wade), maintenance treatments declined over recent decades due to con- [email protected] (C. Quelen), [email protected] (A. Guiraud-Diawara), cerns regarding potential for abuse, tolerance, excessive sedation [email protected] (C. Franc¸ ois), [email protected] (P. Verpillat), [email protected] (V. Shen), [email protected] (J. Isojarvi). http://dx.doi.org/10.1016/j.eplepsyres.2016.04.003 0920-1211/© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4. 0/). M.J. Brodie et al. / Epilepsy Research 123 (2016) 68–74 69 and cognitive decline with chronic use (Olfson et al., 2015; Paterniti Characteristics of patients with epilepsy at follow-up included et al., 2002; Sankar et al., 2014; Stewart, 2005). The availability of time of follow-up, treatment duration, and drug dosage. Drug several new antiepileptic drugs (AEDs) for maintenance therapy dosage was not directly available in the database and was therefore also reduced BZD use for epilepsy. computed at the last prescription date using the following formula: ® The BZDs clobazam (CLB; Onfi , Deerfield, IL, US) and clon- dosage = substance strength × numeric daily dosage (NDD), where ® azepam (CZP; Klonopin , San Francisco, CA, US) have been used NDD corresponds to number of pills/tablets/milliliters per day. No worldwide since the 1970s. CZP is approved in the EU for all forms imputation was performed when NDD was 0 or missing. of epilepsy and for panic attacks in adults, and in the US for panic The evaluation of the development of dependence was a disorder and as mono- or adjunct therapy in a broad range of seizure secondary objective of the study. Drug dependency cases were disorders, including Lennox–Gastaut syndrome (LGS). CLB has been identified by the presence of one record with a drug dependence successfully used for many years in the EU as both an AED and diagnosis (Read code: E24*—Drug dependence, Eu19211—[X] an anxiolytic, but was approved only recently in the US (October Drug addiction NOS) or a drug dependence detoxification (Read 2011) for the adjunctive treatment of seizures associated with LGS code: 8BA9*—Detoxification dependence drug) during follow-up. in patients ≥2 years (Ng et al., 2011). Patients with a history of drug dependency before treatment initi- As use of CLB in the EU has been well established, data from ation were not included in this analysis. the UK-based Clinical Practice Research Datalink were evaluated to compare real-world use of CLB versus CZP for epilepsy. 2.4. Statistical analysis 2. Methods Statistical comparisons between CLB- and CZP-treated groups were performed using the student t test for continuous variables 2 2.1. Data source and either the X or Fisher exact tests for categorical variables. For treatment duration and analysis of drug dependence, curves were The Clinical Practice Research Datalink (CPRD), which fur- drawn using the Kaplan-Meier method and statistical comparisons thers the research developments of the General Practice Research were performed using the log-rank test. For the analysis of drug Database (GPRD) (Lawson et al., 1998), comprises more than 62 dependence, the incidence rate per person year was also calculated: million patient-years of data collected from approximately 10 million patients throughout the United Kingdom (UK). It is the Incidence rate / person-year = largest computerized database of anonymous, longitudinal, pri- mary care clinical records. CPRD data, which are currently being Number of patients with drug dependency collected from 690 primary care practices, are directly generated by Total time of exposure to treatment for all patients (years) computer from general practitioner (GP) practices equipped with specialized software. Data from the CPRD have been extensively used in over 890 clinical reviews and papers, including numer- 2.5. Standard protocol approvals, registrations, and patient ous pharmacoepidemiological studies. The principal information consents available for analysis includes patient demographics, prescriptions of medicine, clinical diagnoses, hospital or specialist referrals, and All research undertaken using data obtained from CPRD is laboratory test results (Garcia Rodriguez and Perez Gutthann, 1998; approved by, as appropriate, an ethics committee, a scientific com- Wood and Martinez, 2004). mittee, and the National Information Governance Board Ethics and Confidentiality Committee. Protocol 13 043R entitled “Treatment 2.2. Study design and inclusion criteria Patterns in Patients With Epilepsy in Primary Care in the UK” was approved April 3, 2013 by the Independent Scientific Advisory Com- In this historical, longitudinal, incident-user (Johnson et al., mittee (ISAC) for Medicines and Healthcare Products Regulatory 2012) cohort study, patient data were obtained from the externally Agency (MHRA) Database Research for CPRD. validated CPRD database (Jick et al., 1991; Jick et al., 2003). Epilepsy patients who had at least one incident prescription of CLB or CZP 3. Results within the study period (1995–2011) were included in the analysis (Fig. 1). To ensure patients had not been previously prescribed CLB 3.1. CPRD patient population or CZP, patient data must have been present in the database for at least 182 days prior to the index date and without any prescription Of 21,099 patients who met inclusion criteria, 3882 (18.4%) for CLB or CZP. The index date is defined as the date of first CLB or received CLB and 17,217 (81.6%) received CZP (Fig. 1). Overall, CLB CZP prescription within the study period.
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