Most generic formulations of antiepilepsy drugs (AEDs) deliver blood levels similar to their brand-name counterparts, but there is more variability in bioequivalence when like generics are compared against each other, according to a new study.
Patients taking generic drugs often are switched from one manufacturer to another depending on what the pharmacy happens to dispense. In addition, switches from one generic to another also frequently occur when insurance pharmacy benefits managers renegotiate costs with manufacturers.
This latest study from Johns Hopkins University suggests that physicians and patients need to be aware that switching among generics could cause changes in blood levels that could potentially cause side effects or even seizures.
The study, published in the online edition of the Annals of Neurology, did not look at the actual experience of patients with epilepsy, but rather involved a statistical analysis of pharmacokinetic data submitted by manufacturers to the FDA when the generic drugs went through the approval process.
The investigators reported that in 39 percent of cases, switching from one generic to another would cause a difference of 15 percent or more in peak serum concentration of the drug. (See “Data on Generic Antiepileptics.”)
Gregory L. Krauss, MD, professor of neurology at Johns Hopkins University and lead author for the study, said the research findings are not intended to be an indictment of generic products. “Most patients should be OK when switching to generics,” Dr. Krauss told Neurology Today. “The question is: Are there subgroups of patients that might have problems with a switch?”
He said subgroups that could be sensitive to switches might include “patients who require high doses for seizure control, are near toxic thresholds, or who have trouble tolerating their AEDs.” While more study is needed of the issue, he said, this new study “suggests that patients should try to remain on the same generic product.”
Some research and anecdotal feedback have suggested that some patients experience seizures or side effects such as dizziness, drowsiness, and blurred vision after switching from a brand-name drug to a generic, but researchers say the final word on the issue is not in. Patients who take generics often get pills from different manufacturers from one refill to the next because the pharmacy may get a better price from certain suppliers.
To conduct the analysis, the Johns Hopkins team used the Freedom of Information Act to obtain bioequivalence data on generic drugs from the FDA Center for Drug Evaluation and Research Office of Generic Drugs. The Abbreviated New Drug Application process allows a generic to go to market if the plasma concentration is similar to the brand-name product. Bioequivalence (BE) is established using single-dose crossover studies in healthy subjects to compare peak concentrations (Cmax) and total drug exposure — concentration measured over time: AUC — of the generic and brand product, according to background in the Annals of Neurology study. The generic must meet a bioequivalence standard of 80 percent to 125 percent (90 percent CI) when compared to the brand drug.
GENERICS SAVE MONEY
The study noted that more than 150 generic AEDs have been approved by the FDA in the last several years, which has resulted in sizable savings for patients. The quarterly cost of drugs for epilepsy patients in the US in 2008-2009 declined from $800 to $400 million, according to the study.
“Although generic-generic switches are common, current regulations do not require generic-generic BE comparison, and there are few data showing how similar generics are to each other,” the study noted.
AEDs with low bioavailability and solubility, drugs such as oxcarbazepine, had the most variability in bioequivalence, the researchers noted.
“These estimates require confirmation but nonetheless suggest that some generic-to-generic product switches could potentially produce larger differences… than reference-to-generic product substitutions,” the researchers wrote.
Dr. Krauss told Neurology Today that an FDA advisory committee last year heard discussion on whether generic AEDs should be classified as “critical dose drugs” that require a narrower range of variability in total drug deliverability, but he said there has been no action taken on the matter. His research team noted in its report that in Denmark, AEDs other than benzodiazepines are designated as “narrow therapeutic index” drugs, thus requiring that generic formulations meet a 90 percent to 111 percent bioequivalence standard, compared to the standard of 80 percent to 125 percent used in the US.
“Our model of the BE results showed that many switches between generic formulations would be likely to produce shifts in blood levels outside the range” of variation allowed by the FDA for generics compared to their brand counterparts, Dr. Krauss said.
STATE LAWS ON GENERICS
State laws determine the requirements for the substitution of a generic for a brand-name drug, but typically pharmacists are allowed to make a substitution unless the physician specifically indicates not to. Some state legislatures, including Maryland, have considered proposals that would require the pharmacist to circle back to the prescribing doctor before making a substitution, Dr. Krauss said. He said he is opposed to such an approach because it would be cumbersome for physicians and would add another layer to patients getting their medications in a timely fashion.
“I do not support regulations notifying physicians about generic conversions,” Dr. Krauss explained in an e-mail to Neurology Today. “I prefer that the prescribing system be optimized for a continued supply of single formulations. Physicians can currently require [pharmacists to]'dispense as written' to maintain patients on brand-name medications.”
In a 2007 position paper, the AAN stated its opposition to policies that would result in arbitrary switching among anticonvulsants. More specifically, the Academy said it opposes generic substitution of anticonvulsants for patients with epilepsy at the point of sale (for example, in the pharmacy), without prior consent of the physician and the patient.
Kore Liow, MD, clinical professor of neurology at the University of Hawaii, told Neurology Today that the current study touches on an important issue. A variation in drug coverage due to switching could potentially land a patient in the ER or hospital or result in a loss of a driver's license because of a seizure, he noted. He said he is particularly worried about drug switch-ups for patients whose seizures are not well controlled by medication or who are taking a maximum dose of a drug. There might also be a concern for patients taking multiple epilepsy drugs, he said.
“We really need to listen to what patients have to say when they make a switch,” said Dr. Liow, who was not involved with the study. “If they say they are dizzy or feeling tired, we need to listen to that.”
Carl W. Bazil, MD, PhD, professor of clinical neurology at Columbia University and coauthor of the AAN position paper, told Neurology Today that the Johns Hopkins study was somewhat limited because it couldn't say whether the statistical differences “are clinically significant.”
“It doesn't quantify the risk” in making a switch, he noted “but does prove some difference between generic and brand in peak — and by inference, trough — levels.”
Still, he believes “that it's better to keep someone with epilepsy on a brand-name drug because there is more consistency.” If a switch needs to be made because of cost or because of a patient's insurance company's formulary, he said it's wise for a clinician to get a baseline blood level so a comparison can be made later on if needed.
John W. Miller, MD, professor of neurology at the University of Washington at Seattle, said physicians should evaluate the wisdom of switching drugs “on a case by case basis.” Cost can't be taken out of the equation because cost is a determining factor for some patients in whether they adhere to a medication regimen, he added.
“Most patients are looking for ways to reduce the cost of their care,” he noted, and the availability of generic drugs can help them do that.
Dr. Krauss said the FDA is planning some studies to further examine the issue of blood concentration variations in patients with epilepsy.
DATA ON GENERIC ANTIEPILEPTICS
* The researchers analyzed data for 141 generic AED products that were evaluated in 258 BE studies.
* In head-to-head comparisons of a generic to a brand-name product, there were few differences in BE. The total drug delivery differed more than 15 percent in just about 1 percent of the studies. Cmax for the generic and brand-name drug differed by more than 15 percent in about 11 percent of the studies. There was more variability with Cmax in non-fasting studies as compared to studies in which study subjects were fed.
* The researchers evaluated switches among like generic formulations — in all, 595 potential pairs of generic AED products. The researchers found that differences in total drug delivery of more than 15 percent occurred with 17 percent of the matched pairs. CMax differed by more than 15 percent for 39 percent of the pairs.