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CLINICAL CONSEQUENCES OF GENERIC SUBSTITUTION OF LAMOTRIGINE FOR PATIENTS WITH EPILEPSY

CLINICAL CONSEQUENCES OF GENERIC SUBSTITUTION OF LAMOTRIGINE FOR PATIENTS WITH EPILEPSY To the Editor: LeLorier et al.1 studied the risks associated with patients switching to and from generic antiepileptic drugs (AEDs) in Quebec. The authors did not consider that such changes could be attributed to promotionally driven doctor and patient preferences. Industry representatives vigorously promote the idea that generics are less potent (“up to 20% less effective”) than their brand name equivalents despite Food and Drug Administration (FDA) assertions to the contrary.2 Study patients taking generics underwent dose escalations. The authors suggest that dose escalations were in response to increased side effects, but this is counterintuitive. More plausibly, anxietyinduced dose escalations contributed to side effects and, in turn, switch-backs. The unspoken hypothesis that switches to generic led to more seizures is unaddressed by the presented data, which blur psychiatric and neurologic indications for lamotrigine (LTG). LTG is used heavily in psychiatry and most recent growth in sales is driven by the psychiatric market.3 A single claim submitted with a code for epilepsy is considered sufficient evidence that LTG is being prescribed as an AED, but this is unlikely. The leading outpatient diagnostic code as well as four of five diagnostic codes for outpatient visits and two of three diagnostic codes for inpatient hospitalizations were not for epilepsy. By contrast, all comparator non-AED drugs in this study lent themselves to readily available objective efficacy assessment (blood pressure and lipid levels). There is no such equivalent for any LTG indication. FDA standards for generic bioequivalence are the same standards applied to branded medication for between-batch variability.2 Bioequivalence is complex.4 For example, the area under the curve and maximum concentration but not time to maximum (tmax) concentration are used by the FDA in determining bioequivalence. Manufacturer disclosures of bioequivalence data indicate that branded LTG tmax varies from half an hour to 6 hours for various formulations of the 100 mg tablets.5 Clinical relevance of FDA-permitted variance within a brand or between brand and generic medication is unclear. Millions of doses of generic medications have been dispensed with no well-documented instances of therapeutic failures for medications produced in accordance with existing FDA standards.4 It is clear that promotional activity influences prescribing behavior. Furthermore, under experimental conditions, expensive placebos are more effective.6 Not only patients but neurologists are anxious about generic medications encouraged in this regard by controversial American Academy of Neurology (AAN) policies on generic substitution of AEDs.7 The authors should compare switches to and from generics by specialty of the prescriber (neurologist, psychiatrist, primary care) and by first indication for which the medication was prescribed, stratifying by promotional dollars spent per indication and specialty.