Evaluation of Switching Patterns in FDA’s Sentinel System: A New Tool to Assess Generic Drugs

Compulsory generic substitution of antiepileptic drugs (AEDs) may lead to adverse effects in epilepsy patients because of seizure recurrence or increased toxicity. The study objectives were (a) to quantify and compare the switchback rates from generic to brand-name AEDs versus non-AEDs, and (b) to assess clinical implications of switching from branded Lamictal to generic lamotrigine (LTG) and whether signals exist suggesting outcome worsening. By using a public-payer pharmacy-claims database from Ontario, Canada, switchback rates from generic to branded AEDs [Lamictal, Frisium (clobazam; CLB), and Depakene (VPA; divalproex)] were calculated and compared with non-AED long-term therapies, antihyperlipidemics and antidepressants, in January 2002 through March 2006. We then assessed pharmacy utilization and AED dosage among LTG patients switching back to branded Lamictal compared with those staying on generic formulation. The 1,354 patients (403 monotherapy, 951 polytherapy) were prescribed generic LTG, of whom 12.9% switched back to Lamictal (11.7% monotherapy, 13.4% polytherapy). Switchback rates of other AEDs were approximately 20% for CLB and VPA. The switchback rates for AEDs were substantially higher than for non-AEDs (1.5-2.9%). Significant increases in LTG doses were observed after generic substitution for those who did not switch back (6.2%; p<0.0001). The average number of codispensed AEDs and non-AED drugs significantly increased (p<0.0001) after LTG generic entry, especially in the generic group. These results reflect poor acceptance of switching AEDs to generic compounds. They may also indicate increased toxicity and/or loss of seizure control associated with generic AED use.

Sentinel is a program sponsored by the US Food and Drug Administration to monitor the safety of medical products. We conducted a cohort assessment to evaluate the ability of the Sentinel Propensity Score Matching Tool to reproduce in an expedited fashion the known association between glyburide (versus glipizide) and serious hypoglycemia. Thirteen data partners that contribute to the Sentinel Distributed Database participated in this analysis. A pre-tested and customizable analytic program was run at each individual site. De-identified summary results from each Data Partner were returned and aggregated at the Sentinel Operations Center. We identified a total of 198,550 and 379,507 new users of glyburide and glipizide, respectively. The incidence of emergency department visits and hospital admissions for serious hypoglycemia was 19 per 1,000 person-years (95% confidence interval, 17.9, 19.7) for glyburide users and 22 (21.6, 22.7) for glipizide users. In cohorts matched by propensity score based on predefined variables, the hazard ratio (HR) for glyburide was 1.36 (1.24, 1.49) vs. glipizide. In cohorts matched on a high-dimensional propensity score based on empirically selected variables, for which the program ran to completion in five data partners, the HR was 1.49 (1.31, 1.70). In cohorts matched on propensity scores based on both pre-defined and empirically selected variables via the high-dimensional propensity score algorithm (the same five data partners), the HR was 1.51 (1.32, 1.71). These findings are consistent with the literature, and demonstrate the ability of the Sentinel Propensity Score Matching Tool to reproduce this known association in an expedited fashion. 3