Paediatric Postmarketing Pharmacovigilance Using Prescription-Event Monitoring
- 136 Downloads
Background: Using postmarketing pharmacovigilance data collected shortly after market authorization of lamotrigine in the UK, a study was conducted to compare the adverse event (AE) profiles of children and adults taking lamotrigine, using modified signal detection methods.
Methods: Data from the lamotrigine Prescription Event Monitoring (PEM) study, an observational cohort study, were stratified by age and examined using summary statistics for adverse drug reactions (ADRs), reasons for stopping treatment, deaths and follow-up information. Incidence densities of AEs in children (0–17 years) and adults (≥18 years) in the first month of treatment were compared with months 2–6 to examine whether the AE rates were different in these two periods. AE rates in children were compared with those in adults (proportional reporting ratio [PRR] and incidence rate ratios), to compare the AE profiles between these age groups.
Results: The cohort included 2457 children and 7379 adults. Differences in the AE profiles between children and adults were observed. Rash (PRR 1.2) and Stevens-Johnson syndrome (PRR 4.5) were more commonly reported in children, and confusion more frequently in adults (PRR 6.3). In children, 33% of ADRs were reported to the Regulatory Authority compared with 44% in adults. A higher proportion of children stopped treatment due to lack of effectiveness (45% vs 38%). No deaths were attributed to lamotrigine.
Conclusions: This study demonstrated that signal detection methods can be used to detect quantitative and qualitative differences in the AE profiles between the first children and adults taking a newly licensed drug.
KeywordsLamotrigine Adverse Event Signal Incidence Density Proportional Reporting Ratio Prescription Event Monitoring
We would like to record our keen appreciation of the cooperation of the general practitioners and numerous other colleagues, including Mr Shayne Freemantle, who have helped in this study. We would also like to thank, for their important participation, the Prescription Pricing Division of the NHS Business Services Authority (formerly known as the Prescription Pricing Authority) in England. In addition, we wish to thank Mrs Lesley Flowers for assistance with the preparation of this manuscript.
The Drug Safety Research Unit (DSRU) is a registered independent charity (no. 327206). It receives unconditional donations from pharmaceutical companies. The companies have no control over the conduct or publication of the studies conducted by the DSRU. The Unit has received such funds from Wellcome, the original manufacturer of lamotrigine. After the conclusion and initial report of this study, B. Aurich-Barrera took up employment with GlaxoSmithKline in 2006 (which merged in 2001 with Wellcome) and later, in October 2009, took up employment with Novartis. L. Wilton, D. Brown and S. Shakir have declared no conflicts of interest related to the content of this study.
- 1.European Parliament and Council of the European Union. Regulation (EC) No. 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No. 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No. 726/2004. Official Journal of the European Union: L 378/1 (27.12.2006 a)Google Scholar
- 2.European Parliament and the Council of the European Union. Regulation (EC) No. 1902/2006 of the European Parliament and of the Council of 20 December 2006 amending Regulation 1901/2006 on medicinal products for paediatric use. Official Journal of the European Union: L 378/20 (27.12.2006 b)Google Scholar
- 3.Senate and House of Representatives of the United States of America in Congress assembled, 2002. Best Pharmaceuticals for Children Act, 2002 Jan 4: Public Law No. 107–9Google Scholar
- 4.Committee for Medicinal Products for Human Use. Guideline on conduct of pharmacovigilance for medicines used by the paediatric population [online]. Available from URL: http://www.tga.gov.au/docs/pdf/euguide/phvwp/23591005en.pdf [Accessed 2010 Jul 20]
- 5.European Commission. Volume 9A “Pharmacovigilance for drugs for human use” of the rules governing medicinal products in the European Union; EMEA [online]. Available from URL: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-9/pdf/vol9a_09-2008.pdf [Accessed 2009 Jan 18]
- 6.CIOMS/WHO. International guidelines for biomedical research involving human subjects. Geneva: CIOMS/WHO, 2002Google Scholar
- 7.Royal College of Physicians of London. Guidelines on the practice of ethics committees in medical research involving human subjects. London: RCP, 1996Google Scholar
- 8.General Medical Council. Good practice in research [online]. Available from URL: http://www.gmc-uk.org/guidance/current/library/research.asp#Projects%20which%20are%20not%20approved%20by%20research%20ethics%20committees [Accessed 2009 Jan 18]
- 9.Shakir S. PEM in the UK. In: Mann RD, Andrews EB, editors. Pharmacovigilance. Chichester: John Wiley & Sons, 2007: 307–16Google Scholar
- 10.Strom B. Sample size considerations for pharmacoepidemiology studies. In: Strom B, editor. Pharmacoepidemiology. Chichester: John Wiley & Sons, 2005: 29–36Google Scholar
- 11.International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: clinical investigation of medicinal products in the pediatric population, E11, Step 4 [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA487.pdf [Accessed 2009 Jan 18]
- 12.Shakir SAW. Causality and correlation in pharmacovigilance. In: Talbot J, Waller P, editors. Stephens’ detection of new adverse drug reactions. Chichester: John Wiley & Sons, 2004: 329–43Google Scholar
- 14.GlaxoSmithKline. Lamictal: summary of product characteristics 2009 [online]. Available from URL: http://emc.medicines.org.uk/medicine/4228/SPC/Lamictal+Combined+Tablets/ [Accessed 2009 Nov 2]
- 15.Wellcome. Lamictal (lamotrigine) tablets [data sheet]. London: Wellcome, 1991Google Scholar
- 18.Wellcome. Lamital (lamotrigine) tablets, lamictal (lamotrigine) dispersible [data sheet]. London: Wellcome, 1994Google Scholar
- 21.Campbell AGM, McIntosh N, editors. Forfar and Arneil’s textbook of paediatrics. Edinburgh: Churchill Livingstone, 1998Google Scholar
- 24.Burton ME, Shaw LM, Schentag JJ, et al. Special pharmacokinetic considerations in children. In: Evans WE, Schentag JJ, Jusko WJ, et al., editors. Applied pharmacokinetics and pharmacodynamics: principles of therapeutic drug monitoring. Baltimore (MD): Lippincot, Williams and Wilkins, 2006: 10–32Google Scholar
- 40.Boerus LO. Drug-receptor interactions and biologic maturation. In: Mirkin BL, editor. Clinical pharmacology and therapeutics. Chicago (IL): Year Book Medical Publishers Inc, 1978: 3–22Google Scholar