Generics may not be the bargain they appear, at least not when it comes to antiepileptic drugs (AEDs). So suggests a study in the December Epilepsy & Behavior in which more than two thirds of neurologists reported patients experiencing breakthrough seizures—and more than half of whom observed increased side effects in their patients—due to generic substitution of brand-name AEDs. The direct and indirect costs associated with additional seizures and side effects must be weighed against potential cost savings of generic AEDs, believes study author Andrew N. Wilner, MD.

“The only justification for generic substitution is cost savings. No one has ever suggested that generics are superior in any other way,” asserted Dr. Wilner. Although the substitution of generic AEDs for brand-name medication is common, both pharmacists and physicians share concern about its appropriateness. The uneasiness may stem from the FDA definition of bioequivalence for generics that allows a range of bioavailability of 80% to 125%. “Introducing this magnitude of variability in therapy just didn’t make sense to me in patients who were so hard to control and were taking narrow therapeutic index antiepileptic drugs. When I researched this further, I discovered that the range of 80% to 125% was not evidence based, but determined by ‘medical experts,’” Dr. Wilner recounted to Neurology Reviews. His belief was shared by more than 80% of neurologists who participated in his survey, who felt that the FDA standards for bioavailability are not sufficiently narrow.

A neurologist in private practice in Newport, Rhode Island, Dr. Wilner recalled one patient in particular whose seizures were controlled, but who would also have breakthrough seizures. “I couldn’t figure out why. It was only after several months when she finally brought in her medication bottle that it became apparent that she had started taking the generic carbamazepine for the brand-name Tegretol^®. Although this was not proof positive that the generic switch was responsible for her increased seizures, it highlighted the question for me, How often was a switch to generics responsible for breakthrough seizures and side effects in my patients?”

In a presentation at the 58th Annual Meeting of the American Epilepsy Society in New Orleans, Dr. Wilner outlined his study that sought to assess whether a switch from a brand-name AED to a generic AED, or from a generic AED to another generic AED, resulted in breakthrough seizures or side effects in patients with epilepsy. Dr. Wilner designed a 13-question survey for neurologists that concerned patients with epilepsy who had experienced a generic substitution in medication within the past year, and asked about consequences of breakthrough seizures or side effects. Three hundred one neurologists responded.

“SUBSTITUTION JUST DOESN’T MAKE SENSE”

The results surprised Dr. Wilner, who thought that “generics probably did cause some problems, but I never anticipated that 68% of neurologists would have seen breakthrough seizures due to generic substitution, and 56% would observe side effects. The problem appears much larger than I surmised,” he said.

Additionally, 94 neurologists (33%) reported breakthrough seizures and 76 (27%) reported increased side effects attributable to a switch from one generic to another generic AED. Six percent of neurologists reported one patient, 47% reported between two and four patients, and 28% reported five or more patients experiencing breakthrough seizures or increased side effects.

In order to treat the consequences of generic drug substitution, 188 neurologists reported the need for phone consultations, 166 extra office visits, 128 emergency room visits, and 46 hospital admissions. Seventy-seven neurologists reported that patients missed work, 25 indicated that the doctor-patient relationship was undermined, and 23 reported patient injury.

“Evidence is accumulating that generic substitution just doesn’t make sense for many patients with epilepsy,” said Dr. Wilner, citing a recent paper in Neurology by Burkhardt et al that demonstrated that generic phenytoin and Dilantin^® are not clinically equivalent.

A STEPWISE APPROACH

According to Dr. Wilner, there are a number of steps that should be taken by physicians, pharmacists, and patients to ensure that patients with epilepsy receive the most appropriate care possible:

• If pharmacists choose to substitute a generic antiepileptic drug for a brand-name preparation, they should inform not only the patient but the prescribing physician, as well. The prescribing physician should have the option of insisting on the brand name or other steps, such as follow-up blood levels after the switch. “As it stands, physicians are usually the last to know that their patients are not taking the drug they prescribed,” observed Dr. Wilner.

• Physicians have the option of writing “Brand name necessary” or a similar phrase to ensure that patients receive the brand-name drug. This does not always work, as there may be other factors, such as formulary restrictions, which limit patient choice. However, if the physician feels that the brand name is important, he or she should indicate this on the prescription.

• Patients with epilepsy need to be educated on the potential harm of generic substitution. Generics may be bioequivalent, as currently defined by the FDA, but they are not the same. Patients need to be vigilant when they receive their prescription and should check to see whether the shape or color of the pills has changed. If so, they need to ask the pharmacist if a generic has been substituted, and then inform their physician accordingly.

• There are currently no generic substitutes for long-acting carbamazepine preparations, although these may be in development. For now, if a physician prescribes one of these long-acting forms, there is no possibility of generic substitution.

UNNECESSARY SUFFERING

As evidenced by the findings in the survey, many patients have breakthrough seizures and side effects associated with generic substitution, Dr. Wilner pointed out. “These patients are suffering unnecessarily, and their seizures and symptoms are creating the need for extra office visits, lab work, emergency room visits, and hospitalizations—all at substantial expense.” As he described in his study, for these patients, generic medications may actually be costing the health care system more than they are saving.

“It may be that generic substitution for patients with epilepsy just doesn’t make medical or fiscal sense. If we are going to provide our patients with high-quality care and cost-effective care, we need to find out whether generic AEDs provide the same level of seizure control and similar side-effect profiles, and whether they actually save money in the big picture,” he explained.

The FDA needs to reconsider its definition of bioequivalence for patients with epilepsy, suggested Dr. Wilner, who suspects a range of 80% to 125% of plasma concentrations is just too wide a therapeutic range for patients with epilepsy or for a subgroup of patients with difficult-to-control epilepsy. “In this era of evidence-based medicine, ‘medical opinion’ really is not sufficient for bioequivalency guidelines,” he said, “particularly when there is so much evidence suggesting that generic drugs, while bioequivalent, are not clinically equivalent.”

A double-blind, crossover study of patients taking generic and brand-name AEDs would be worthwhile in an effort to document whether generic AEDs are clinically equivalent. It may be that generic substitution is suitable for some patients with easy-to-control epilepsy, Dr. Wilner allowed, but not for others with more difficult-to-control epilepsy.

NR

—Heidi W. Moore

Suggested Reading
Burkhardt RT, Leppik IE, Blesi K, et al. Lower phenytoin serum levels in persons switched from brand to generic phenytoin. Neurology. 2004;63:1494-1496.
Wilner AN. Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behav. 2004;5:995-998.

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