FDA to Tighten Standards for Generic Antiepileptic Drugs

Allison Shelley

December 05, 2011

December 5, 2011 (Baltimore, Maryland) — The US Food and Drug Administration told the epilepsy community Friday night that regulators are taking a closer look at the divisive issue of generic antiepileptic drugs.

Barbara Davit, PhD, JD, acting director of the Division of Bioequivalence II of the FDA's Office of Generic Drugs, said here at the American Epilepsy Society (AES) 65th Annual Meeting that her team is considering tightening controls on certain drugs.

An advisory committee weighing in on the issue agrees that new criteria are called for, and plans are underway to establish drugs that have a narrow therapeutic index. Not all antiepileptic drugs are being considered, but the ones that qualify on the basis of efficacy and toxicity profiles would have to meet tighter restrictions.

Speaking at the town hall meeting, Brien Smith, MD, from the Epilepsy Foundation, said he is amazed by the progress. "A couple of years ago I couldn't envision us reaching this point, but I welcome this open discussion."

Many neurologists are voicing concern about clinically significant changes, with generic alternatives leading to unexpected seizures and serious adverse events.

Breakthrough Seizures

Most popular brand name products for epilepsy currently have generic equivalents, and some drugs have dozens. The agency says these alternatives are safe, but many have not been getting good reviews from patients and their physicians.

The AES opposes antiepileptic drug substitution without physician consent; its position is backed by the American Academy of Neurology.

"A single seizure represents a serious therapeutic failure," said town hall moderator Michael Privitera, MD, from the University of Cincinnati College of Medicine in Ohio.

Dr. Privitera told Medscape Medical News that he is encouraged by the FDA's response to these concerns, but he acknowledges that more work remains. "I'm eager to see the definition of a narrow therapeutic index drug and how new data are interpreted by regulators," he said.

Dr. Privitera is currently working on a new clinical trial comparing brand-name antiepileptic drugs with generics. "There are no adequately designed prospective studies, so we're looking to address that," he said. He is teaming up with investigators from the Johns Hopkins University School of Medicine in Baltimore, Maryland, and the University of Rochester School of Medicine and Dentistry in New York.

Prospective Clinical Trials

Tricia Ting, MD, from the University of Maryland School of Medicine in Baltimore, is also working to prospectively study this issue. "We're designing a test model to assess brand-name and generic antiepileptic drugs in epilepsy patients, not just healthy controls," she said at the meeting. This is a limitation of current studies.

As it stands now, the FDA looks at a small number of healthy people to establish bioequivalence. Dr. Davit says these studies typically include 24 to 36 people.

Measures of drug absorption or the area under the curve (AUC) are taken along with peak drug plasma concentrations (C-max). According to present standards, these values must fall within 80% to 125%.

All approved generic antiepileptic drugs currently on the market are well within current bioequivalence limits. The rows of data in Table 1, presented by Dr. Davit at the town hall meeting, demonstrate the highest and lowest point estimates and, in parentheses, the 90% confidence intervals.

Table 1. Bioequivalence Measures for Approved Generic Antiepileptics

Drug AUC Ratio C-max Ratio
Phenytoin 0.99 (0.95 - 1.02) 1.09 (0.99 - 1.20)
0.88 (0.85 - 0.92) 0.88 (0.83 - 0.94)
Carbamazepine 1.18 (1.14 - 1.22) 1.14 (1.10 - 1.19)
0.97 (0.90 - 1.00) 0.90 (0.87 - 0.94)
Lamotrigine 1.07 (1.02 - 1.12) 1.10 (1.05 - 1.15)
1.00 (0.94 - 1.04) 0.91 (0.85 - 0.98)
Levetiracetam 1.02 (0.97 - 1.04) 1.06 (1.02 - 1.12)
0.97 (0.95 - 1.0) 0.92 (0.85 - 1.00)
Zonisamide 1.08 (0.99 - 1.19) 1.08 (1.01 - 1.15)
0.96 (0.89 - 1.03) 0.96 (0.88 - 1.05)
Topiramate 1.05 (1.00 - 1.10) 1.09 (1.03 - 1.15)
0.95 (0.93 - 0.98) 0.92 (0.82 - 1.03)
Valproic acid 0.99 (0.96 - 1.03) 0.97 (0.90 - 1.04)
Insufficient data Insufficient data
Divalproex 1.04 (0.96 - 1.11) 1.13 (1.06 - 1.19)
0.94 (0.86 - 1.03) 0.88 (0.83 - 0.93)
Oxcarbazepine 1.03 (0.98 - 1.08) 1.04 (0.90 - 1.19)
0.94 (0.91 - 0.97) 0.88 (0.81 - 0.95)

"We know you have concerns," Lawrence Yu, PhD, deputy director for science and chemistry at the FDA's Office of Generic Drugs, said at the meeting. "Tonight I want to assure you of the purity of these drugs."

Reporting this summer in an article published in the August 2011 issue of the Annals of Neurology, Gregory Krauss, MD, from the Johns Hopkins University School of Medicine, agreed that most generic antiepileptic drugs (AEDs) provide total drug delivery similar to reference products.

"[D]ifferences in peak concentrations between formulations are more common," his team reported. "Switches between generic AED products may cause greater changes in plasma drug concentrations than generic substitutions of reference products."

This may explain in part the results of another study presented here at the town hall meeting. Investigators looked at close to 2 million prescriptions from the prescribing system of the Marshfield Clinic of Wisconsin. Of these, 80,000 were for patients with epilepsy.

Patients receiving levetiracetam, lamotrigine, or divalproex had the highest switchback rate from generic to brand-name products. Nearly half of all patients who switched did so for clinically significant reasons such as increased seizure or change in adverse reactions.

Table 2. Switchback Rate From Generic to Brand-Name Drugs (n = 313)

Reason Levetiracetam (n = 84) Lamotrigine (n = 81) Divalproex (n = 79) Carbamazepine (n = 45) Topiramate (n = 24)
Breakthrough seizure 11 5 1 4 2
Increase in seizure frequency 23 18 16 9 4
Change in adverse reactions 18 18 18 1 7
No clinical reason indicated 7 14 14 5 5
Physician preference 19 17 15 14 5
Patient preference 6 6 8 2 0

"Based on these study findings, close monitoring and evaluation during a switch from brand to generic is warranted," concluded the authors Luanne Malsin, PharmD, and Evan Sandok, MD, from the Marshfield Clinic.

"If you see anything, please inform the FDA so we can investigate it," Dr. Yu emphasized. He recommended clinicians notify MedWatch, the agency's safety information and adverse event reporting program.

"Generics are not necessarily bad," Dr. Sandok added. "In some patients, they work really well and make sense. We just have to be careful about who we switch and why."

The next step, Dr. Malsin pointed out, will be to address problems with formularies. Insurance companies often prevent physicians from prescribing the best drug for their patients, she said. "Lots of patients don't have the freedom to say no, and in some cases this can be the difference between paying a $1000 bill or a $6 copay. It can really matter."

Dr. Davit, Dr. Smith, Dr. Privitera, Dr. Ting, Dr. Yu, Dr. Krauss, Dr. Malsin, and Dr. Sandok have disclosed no relevant financial relationships.

American Epilepsy Society (AES) 65th Annual Meeting: FDA town hall meeting. Presented December 2, 2011.


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