BETHESDA, MD 11 Jan 2017—Research results presented at the November 18, 2016, workshop "Substitutability of Generic Drugs: Perceptions and Reality" put to rest the issue of FDA's requirements for bioequivalence of antiepileptics but raised concern about the actions of pharmacists when dispensing the products.
FDA and the Johns Hopkins Center of Excellence in Regulatory Science and Innovation hosted the workshop, which was held at the agency's campus in Silver Spring, Maryland.
Appearances matter. Harvard Medical School's Ameet Sarpatwari, reporting on an FDA-supported survey of pharmacists who practice in traditional community pharmacy settings, said those practitioners, for the most part, "really don't have much of a preference" with regard to the appearance of generic drug products. Some 53% of 719 pharmacists who completed the survey in early 2016 indicated they had "no preference" with regard to dispensing generics with the same appearance as the corresponding brand-name products.
"Interestingly, it's those pharmacists who have been in practice longer who have a preference [for patients to receive] generics with the same appearance," he said, adding, "I'm not sure what to make of that."
Patients, however, clearly have a preference, Sarpatwari said.
About 40% of 1006 older adults who participated in the Harvard Medical School phone survey in early 2016 indicated that they would "definitely" prefer for their refill prescription's tablets or capsules to look like the brand-name product, he said. "Probably" was the answer selected by 22% of the participants.
The FDA-supported study involved adults 50 years of age or older who had received generic drug products for the treatment of epilepsy, diabetes mellitus, hypertension, hyperlipidemia, depression, or HIV infection.
Patients want to know. When tablet or capsule colors are changed, "patients notice" and may not take the medication as prescribed, Sarpatwari said after briefly describing research conducted several years ago by colleagues.
Those researchers found that the odds of patients failing to refill a prescription for carbamazepine, ethosuximide, lamotrigine, phenytoin sodium, valproic acid, or zonisamide within five days of the expected date of supply depletion significantly increased if the most recently acquired supply was colored differently from an earlier supply.
"[A]s more widely used brand-name drugs face generic competition, . . . pharmacists might take greater care to alert patients when changes in suppliers lead to new pill characteristics," the research team wrote in an article in JAMA Internal Medicine in 2013.
Sarpatwari reported at the workshop that 29% of the patients in his study said they initially thought they had received the wrong tablets or capsules when the appearance of a refill supply differed from that of a previously obtained supply.
Further, the patients indicated a desire to be notified if a new batch of tablets or capsules differed from a previous supply in color, shape, size, or markings.
"A large proportion of patients are relying on pill appearance to make sure that they are taking the correct medication," he said.
Bioequivalence confirmed in patients. Specialty medical and patient support groups a decade ago questioned whether FDA's standard criteria for bioequivalence—based on drug levels in healthy people—were sufficient for drugs whose purpose is to prevent seizures in patients with epilepsy.
The American Academy of Neurology and the American Epilepsy Society in the mid-2000s separately issued position statements opposing generic substitution of antiepileptics without the prescriber's and patient's prior consent. The Epilepsy Foundation recommended "extreme caution" when switching among versions of an antiepileptic.
FDA, with prompting from the American Epilepsy Society and the Epilepsy Foundation, funded two studies whose results were summarized at the workshop: the BioEquivalence in Epilepsy Patients (BEEP) study and the Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) study.
Both studies focused on lamotrigine, the subject of some of the anecdotal reports of breakthrough seizures after generic substitution.
BEEP study researcher James E. Polli of the University of Maryland reported that brand-name lamotrigine and a generic lamotrigine product met FDA's criteria for bioequivalence when tested in 34 adults already taking lamotrigine to treat focal or generalized epilepsy who were "generic brittle" (i.e., had a history of exacerbation of seizures or adverse effects after a change in antiepileptic formulation, intolerable adverse effects from an antiepileptic in the year preceding the study, or refractory seizures in that year).
EQUIGEN study researcher Timothy E. Welty of Drake University in Iowa reported that testing of two generic products from different manufacturers indicated no significant difference in exposure or clinical response among 33 adults who were already taking lamotrigine for epilepsy.
As for the EQUIGEN single-dose study, which involved six distinct exposure periods, Welty said the bioavailability of the brand-name product and two generic 25-mg products did not differ significantly when the medications were administered to 46 adults with epilepsy who were not already taking lamotrigine.
Education still needed. Amen I. Ogunmekan, clinical lead pharmacist for behavioral health at Truman Medical Center in Kansas City, Missouri, did not attend the workshop but had already concluded from the American Epilepsy Society's statement in the May–June issue of Epilepsy Currents that the controversy about generic substitution of antiepileptics was mostly over.
At the height of the controversy, Ogunmekan said, she had just graduated pharmacy school. Her reaction was "OK, well, this is just the drug company talking" in an attempt to protect its brand-name product's market share from competition from generic equivalents that were entering the market. She speculated that the drug maker had sent representatives with talking points to physician offices to fuel the controversy.
Because of the rigorous tests that generic drug products must pass to gain FDA approval, Ogunmekan said, she had found it hard to believe that the generic antiepileptic products were causing patients to have more seizures.
But she has encountered patients who have had problems after generic substitution of their antiepileptic, although patients' anxiety and stress about the substitution might have been factors, she said.
"The biggest thing is [pharmacists] knowing the difference in formulations," Ogunmekan said.
She named Depakote and Depakote ER, from AbbVie Inc., in particular and pointed to the potential for mistakes to be made during medication reconciliation.
Both products have divalproex sodium as the active ingredient. Depakote, however, is a delayed-release formulation, is given twice a day, and has several generic versions. Depakote ER is an extended-release formulation, is given once a day, and has no FDA-approved generic version.
Pharmacists unfamiliar with Depakote and Depakote ER, Ogunmekan said, may not realize that switching from one formulation to the other is not simply a matter of totaling the day's dose in milligrams and dividing by the number of times the formulation is to be given.
The FDA-approved labeling for Depakote ER states that the extended-release formulation, when given at doses 8–20% higher than the total daily dose of Depakote, is bioequivalent to the delayed-release formulation.
Improperly converting the dose when switching from the delayed-release formulation to the extended-release formulation—in order to, for example, reduce the number of dose administrations by the nursing staff—may result in patients having a seizure, Ogunmekan said.