Antiepileptic drugs (AEDs) have an important role in treating seizure disorders, as there are few non-pharmacological alternatives for most patients. These drugs are often described as narrow therapeutic index drugs (NTIs) because many patients require tight control of drug levels to balance therapeutic effects against adverse effects. For many patients on AEDs (both older and newer agents) common complicating factors include pharmacokinetic variability and/or interactions. Substitution of “equivalent” drugs has long been a concern of both patients and health care providers.
The FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations1 (aka the Orange Book) considers drug products to be pharmaceutical equivalents if “they contain the same active ingredient(s), are of the same dosage form and route of administration and are identical in strength or concentration.” The FDA has two categories in the consideration of whether multisource drugs are therapeutically equivalent to other pharmaceutically equivalent products, i.e., drug products for which: (1) there are no known or suspected bioequivalence problems; or (2) actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence. Members of the first group are designated AA, AN, AO, AP, or AT, depending on the dosage form; the second group’s members are designated AB. While this sounds as if the products that are considered equivalent are truly equivalent, the allowances can create clinically significant variations in some patients. For these and other NTIs, some states have created registries or have specific requirements for generic substitution.
Three recent case-control studies from large databases on antiepileptic drug (AED) substitutions tell us something that most knowledgeable clinicians already "knew" but did not have the data to back up. Hansen, Rascati and Zachry and their colleagues each reported separately that switching A-rated AED drugs from brand to generic, generic to brand and from generic to generic frequently resulted in an acute seizure event. Each of these papers report case-control analyses using large healthcare claims databases. Each study used adult patients with a diagnosis of epilepsy using ICD-9 codes (excluding infantile spasms), had to be insured for six months surrounding the index event, previously stable (no acute events in the prior 180 days) and had to have an adherence rate of >80% based on prescription refill records. An index event was defined as a seizure event requiring ambulance service, emergency department visit or hospitalization. Patients on any AED were included.2-4
Using the Rascati paper as an example, nearly 40,000 patients were screened for inclusion and 991 acute epilepsy cases (index events) were found and 109 (~11%) had a drug substitution. These were matched at a 3:1 ratio for age, diagnosis and gender. The control group had a drug substitution only 6.3% of the time (OR 1.84, CI 1.44-2.36). The Hansen and Zachry studies showed similar odds ratios (1.78 and 1.81, respectively).
Again, using the Rascati paper as the example, the greatest number of the switches in the case group was generic to generic (53/109; ~49%); with 35 of 109 (~32%) ...