In summary, pharmacoepidemiology is uniquely useful for quantifying the risks of adverse events and risk factors for adverse events within populations larger and more diverse than those exposed during clinical development. It is also useful for obtaining essential data to assess whether adverse events may be related to the background condition being treated. To be more specific, the data on the incidence of SUD in epilepsy were instrumental in addressing regulatory questions regarding the rate of this event during clinical trials and, during the early postmarketing phase, regarding reported deaths in people taking lamotrigine. These data, along with the demonstration that length of status epilepticus was a major risk factor for MOF, confirmed that serious events occurring in people with epilepsy can be related to seizures.

Serious rash in association with lamotrigine use has been of interest to GW and to regulatory bodies throughout the world. The first observation that the risk of serious rash was higher in children taking lamotrigine than in adults arose during the PEM study, and these results triggered hypothesis-generating to explain this pattern. Possible explanations included high dosing in children related to lack of available pediatric formulations. The PEM Study, the GPRD Study, the German Registry, and the International Case-Control Study consistently suggested together that the absolute risk to children in general clinical practice was not as high as that observed in the early clinical trials. These observational data were crucial for assessing the risk-benefit of lamotrigine when an early pediatric clinical trial yielded a single case of serious rash within a small number of children. The Saskatchewan and Medicaid studies, although sometimes criticized because of the difficulty of classifying serious rash without photographs, demonstrated that the risk associated with the initiation of older anticonvulsant therapies was not as low as that previously estimated. In addition, these observational record linkage studies were consistent with the case-control study which demonstrated that the principal at-risk period for these medications is during the first eight weeks of therapy.

Clinicians and patients have been keenly interested in any information which can provide a perspective on expected risks in pregnancies involving lamotrigine exposures. The literature shows that women with epilepsy and using anticonvulsant medications during pregnancy have elevated risk of major birth defects compared with the general population (Samren, 1997; Canger et al., 1999), and some anticonvulsants have been associated with an elevated frequency of specific major malformations (DiLiberti et al., 1984; Ardinger et al., 1988; Dravet, 1992; Lindhout et al., 1992; Omtzigt et al., 1992; Arpino et al., 2000). Even without statistical power to compare medications, results have been crucial for providing to patients and clinicians information key to the management of pregnancies in women using this chronic medication. In addition, the results of other pregnancy registries will provide important information on all new anticonvulsant medications and updated information on older anticonvulsants.

In summary, pharmacoepidemologic studies have been instrumental in addressing questions posed by regulatory bodies and clinicians. The funding of pharmacoepidemiologic efforts has been an integral part of the overall cost of drug development and continued safety surveillance. By providing quantitative real-world data on some risks related to epilepsy and the frequency of serious rash related to lamotrigine treatment and to some alternative treatments, the approach has provided regulatory bodies, clinicians and patients with the information needed to understand lamo-trigine treatment in the world of diverse patients and clinician approaches.

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