Carisbamate Shows Antiepileptic Efficacy
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12 Epilepsy C LINICAL N EUROLOGY N EWS • January 2008 Michael Berg, director of the epilepsy center at Strong Dr. Gidal also cited data reported in 2007 by Canadian Separate, Not Equal? Memorial Hospital in Rochester, N.Y. “For most drugs researchers on the rates at which patients switched from Epilepsy from page 1 and diseases, a range [of bioequivalence] doesn’t matter, a generic to a brand formulation, a step that was pre- but we think it might matter for epilepsy and that’s why sumably triggered by problems with the generic drug. responded differently when a generic formulation was a study is important.” Switching rates were high, about 20%, for patients on substituted for a brand name formulation. Last April, the American Academy of Neurology issued antiepileptic drugs such as valproic acid (Depakene) and “In my practice, [formulation switching] has a tremen- a statement that criticized the practice of generic substi- clobazam (Frisium), while the switch rates were much dous impact. We now regularly ask patients who have a tution of epilepsy drugs. The academy called on pharma- lower, about 2%, for drugs for other disorders—drugs breakthrough seizure when they last filled their prescrip- cists to alert patients and prescribing physicians when such as fluoxetine (Prozac) and simvastatin (Zocor). tion” to check whether substitution occurred, he added. generic substitutions occur (Neurology 2007;68:1249-50). “Therapeutic equivalence and biopharmaceutical FDA representatives have said the agency will not The FDA’s standard for bioequivalence is that the 90% equivalence are not necessarily equivalent terms,” Dr. change its existing policy on how it assesses the bio- confidence interval for three key pharmacokinetic mea- Gidal said. “The overwhelming opinion is that generic equivalence of drug formulations for all indications, in- sures of the generic drug falls between 80% and 125% of substitution is a problem with the potential for break- cluding epilepsy, based on anecdotal reports like these, Dr. the values for the brand formulation, said Barry E. Gidal, through seizures or adverse events.” Privitera said. As a result, officials of the American Pharm.D., in a talk at the meeting. “While statistically A different take was presented in another talk by Dr. Tor- Epilepsy Society have decided to sponsor a study aimed valid, does this really answer the important clinical ques- björn Tomson, a neurologist at the Karolinska Institute in at testing the hypothesis that existing bioequivalence stan- tion?” asked Dr. Gidal. Stockholm. He cited a 2006 report in which FDA re- dards are inadequate for antiepileptic drugs. “Bioequivalence studies are performed in young, healthy searchers failed to document any cases of therapeutic fail- “The AES is in discussions with the FDA to design a adults. Can these data always be generalized to young chil- ure following substitution with an FDA-designated, ther- study that, if positive, will change the FDA’s policy,” he said dren or elderly patients?” asked Dr. Gidal, professor of apeutically equivalent generic drug. He also cited a 1997 at the press conference. Until results are available, it’s im- pharmacy and neurology at the University of Wisconsin, report that failed to find a difference among tested brand portant that pharmacists do not switch the formulation of Madison. and generic formulations of antiepileptic drugs. an epilepsy patient’s drug without first alerting the patient Additional problems have been uncovered for specific Dr. Tomson thinks it makes sense to start newly diag- and the prescribing physician, he added. antiepileptic drugs. Generic formulations of carba- nosed patients on a generic formulation when it’s available, “We just don’t know if the FDA’s bioequivalence reg- mazepine have shown substantial differences, he said. In and to use generics when a patient is not fully controlled. ulations are correct. Some anecdotal evidence suggests addition, methods for testing bioequivalence are probably It did not make sense to do a generic switch on a patient that different formulations are not equivalent,” said Dr. flawed for assessing a “nonlinear” drug like phenytoin. who is fully controlled on a stable regimen, he said. ■ Carisbamate Shows Antiepileptic Generic Substitution Boosts Efficacy; Phase III Studies Planned Total Cost of Epilepsy Care BY MITCHEL L. ZOLER contrast, the switch rate for drugs BY MITCHEL L. ZOLER phase of 4 weeks until they reached their target Philadelphia Bureau for other disorders, such as the β- Philadelphia Bureau dosage. They remained on a stable dose for 12 blocker carvedilol and the lipid drug weeks, when their response rate was assessed. P HILADELPHIA — Generic sub- simvastatin, ranged from 8% to 9%, P HILADELPHIA — Carisbamate, a new The three highest carisbamate dosages all led stitutions were linked with signif- reported Dr. LeLorier, a professor antiepileptic drug, showed safety and efficacy in to significant reductions in seizure frequency, icantly increased medical care cost of medicine and pharmacology at a phase II study with more than 500 patients. versus placebo. The reductions in these groups and total health care cost in a ret- the University of Montreal. Overall, Carisbamate’s ability to cut seizure frequency were 21%-29%, compared with a 6% drop in rospective study of more than 600 patients treated with a generic and boost the response rate, compared with seizure frequency in the placebo patients, re- epilepsy patients. antiepileptic drug were about 2.5- placebo, was notable because the study involved ported Dr. Faught, director of the epilepsy cen- Even though a year’s worth of fold more likely to switch to a brand very refractory patients with a history of nu- ter at the University of Alabama, Birmingham. treatment with the brand-name formulation than were patients merous partial seizures at entry, despite ongoing Patients in the 100 mg/day group had an average drug Lamictal costs an average of who had other disorders. treatment with as many as three antiepileptic 15% cut in seizure frequency, but this was not sig- about $360 (Canadian dollars) more A follow-up analysis in a second drugs, said Dr. R. Edward Faught Jr. in a poster nificantly different from the placebo group. than a year’s worth of generic lam- poster at the meeting attempted to presentation at the annual meeting of the Amer- The percentage of responding patients (those otrigine, this excess was more than convert the observed economic ef- ican Epilepsy Society. with at least a 50% decrease in their seizure rate) offset by an average 56% increased fects seen in Quebec into equiva- Carisbamate will be assessed in a phase III study was 24% in the 300 mg/day group and 25% in the cost for in-patient hospitalization lent costs in the United States. Two for preventing seizures in patients with epilepsy. 1,600 mg/day group. Both rates of lessening among those on the generic, as different conversion formulas were The drug is also undergoing testing in addition- seizure frequency were significantly higher than well as increased costs for drugs used; each formula took into ac- al phase III studies in patients with diabetic pe- the 10% rate among placebo patients. The preva- that were not antiepileptics. count economic factors that dif- ripheral neuropathy, essential tremor, and pos- lence of responders was 12% in the 100 mg/day Total health care costs averaged fered between the United States therpetic neuralgia. The drug’s mechanisms of group and 19% in the 800 mg/day group; neither $1,482 (Canadian dollars)/patient- and Canada during the study peri- action for all of these indications are not known. was significantly higher than that of placebo. year higher in patients treated with od, including currency exchange The phase II seizure study enrolled patients The incidence of adverse events was similar to generic lamotrigine, compared rates, purchasing power, and med- aged 8-70 years who had been diagnosed with placebo in the three lowest carisbamate dosage with those on Lamictal, a 23% rel- ication and health care costs. epilepsy for at least 1 year, had an established pat- groups. Patients on the 1,600 mg/day dosage ative increase that was statistically The extrapolation to U.S. costs tern of at least three partial-onset seizures per had significantly more adverse events, compared significant, Dr. Jacques LeLorier showed a much larger cost differ- month, and had failed treatment with at least with placebo patients. The most frequent ad- and his associates reported in a ence between generic lamotrigine three drugs. At enrollment, patients had to be on verse events were headache, somnolence, na- poster at the annual meeting of the and Lamictal. In one cost-conver- treatment with one to three antiepileptic drugs at sopharyngitis, and nausea. Adverse events led to American Epilepsy Society. sion model this difference meant stable dosages for at least 4 weeks. study discontinuation in 8% of the placebo pa- The study was sponsored by that treatment with Lamictal cost The patients who actually entered the study tients, and in 5%-12% of patients in the three GlaxoSmithKline, which markets an extra $1,175 (U.S. dollars) more had a history of epilepsy for an average of 19- lowest-dosage carisbamate groups. (The dis- Lamictal. Dr. LeLorier has received than generic lamotrigine per pa- 25 years, and experienced an average of 9-11 continuation rate was 19% in the highest-dosage consultation fees and research sup- tient-year. The second model cal- seizures per month. About 15% were treated group.) The rate of serious adverse events was port from GlaxoSmithKline. culated an excess cost for Lamictal with antiepileptic monotherapy, about 50% were similar in the placebo and carisbamate groups. The study used data obtained by of $1,926 (U.S. dollars) per patient- on two drugs, and about 35% were on three Clinically significant elevation of liver enzymes the medical and pharmacy health year, reported Mei Sheng Duh, drugs.