I have posted the full abstract so that you can judge. My headline would be generic-brand doses varied excessively in 13 to 23%.
I would offer other take home points: Do you want to take an antiseizure medicine with this variability? Do you want to offer meds with such variation to your child?
The article does not address generic-generic changes. Brand-generic equivalencies have to be within - 20% and +25% of the parent compound. Your pharmacist can switch you form one generic to another. You can go from a -10 to a +20 with an absolute change of 30% if you are switched.
My recommendation....stick to one generic.
JR
Some Generic Epilepsy Treatment More Equal than Others
SAN DIEGO -- Generic slow-release drugs for seizure disorders appear equivalent to branded versions, researchers said here, unlike earlier findings with immediate-release formulations.
Bioequivalence data from 53 studies submitted to the FDA for 25 generic modified-release drugs for epilepsy -- including phenytoin, carbamazepine, levetiracetam, and divalproex -- were reviewed. Despite considerable variability in the upper and lower bounds of the 90% confidence intervals for maximal concentrations (Cmax) and total drug exposure over time (area under the curve, AUC), the products could be interchanged without danger to patients, reported Ravi Juluru, MD, of Oak Ridge Institute for Science and Education in Nashville, and colleagues at the American Epilepsy Society's annual meeting.
In contrast, an earlier study involving immediate-release anti-epilepsy drugs -- led by Gregory Krauss, MD, of Johns Hopkins University in Baltimore, who was also senior investigator for the current work -- had found that patients switching among generic versions of the same drug ran significant risk of potentially dangerous increases or decreases in drug exposure.
The researchers determined the modified-release products are sufficiently equivalent to allow patients to "switch from brand to generic formulations with little or no changes in drug plasma concentrations and thus no apparent compromise in the safety and efficacy."
The FDA requires that makers of generic drugs show, through clinical pharmacokinetic studies, that blood levels of their products are close to those of the original branded forms.
Specifically, the upper bounds of the 90% CI for a generic drug's Cmax and AUC cannot exceed 1.25 of the means for the branded version, and the lower bounds cannot be less than 0.8 of the branded form's means.
For most drug classes, such variation is not a concern. But anti-epilepsy drugs have an unusually narrow therapeutic index. Particularly for immediate-release formulations, doses are usually titrated carefully to achieve seizure control without excessive side effects. If product blood levels in a given patient increase by 15%, adverse effects may result, whereas a 15% decrease may trigger onset of seizures.
Abstract Search
(Abst. 1.224 ), 2012
BIOEQUIVALENCE STUDIES AMONG GENERIC AND BRAND-NAME MODIFIED-RELEASE ANTIEPILEPTIC DRUGS SUPPORTS THERAPEUTIC EQUIVALENCE AND GENERIC SUBSTITUTION
Authors: R. K. Juluru, B. M. Davit, C. S. Chaurasia, Y. T. Chang, G. L. Krauss
Instit: Food and Drug Administration
Instit: Food and Drug Administration
Content:
RATIONALE:
Generic modified-release (MR) formulations of the antiepileptic drugs (AEDs) carbamazepine, phenytoin sodium, divalproex sodium, and levetiracetam are currently marketed in the US. MR formulations offer the advantages of less frequent dosing, improved maintenance of therapeutic drug plasma concentrations, and better patient compliance. In a previous study, we found that the smoother drug release provided by a MR AED formulation decreased serum fluctuations, leading to fewer breakthrough seizures. Thus, the objective of the present retrospective study is to evaluate the robustness of the bioequivalence (BE) measures determined in the pivotal clinical studies submitted to the FDA to support marketing approval of generic MR AEDs. BE studies, which determine whether a generic and corresponding brand drug provide the same rate and extent of absorption, are generally performed in healthy normal subjects given single doses of the drugs. The BE measures compared statistically are Cmax (peak drug plasma concentrations, to assess absorption rate), and AUC (total area under the drug plasma concentration versus sampling time profile, to assess absorption extent).
METHODS:
We collected Cmax and AUC data from the pivotal BE studies used to support the approvals of 25 generic AED MR formulations. Data were from BE studies under both fasting and fed conditions. We determined distributions of 90% confidence interval (CI) limits for generic/brand ratios of AUC and Cmax in the BE studies. We also obtained from the FDA-approved labeling information about the inactive ingredients in the generic and brand formulations.
RESULTS:
We evaluated 53 BE studies, including data from 1570 subjects. The 90% CIs of the generic/brand AUC and Cmax ratios differed by <15 125="125" 13.2="13.2" 15="15" 22.6="22.6" 25="25" 77.4="77.4" 80="80" 86.8="86.8" 90="90" acceptance="acceptance" aed="aed" aeds.="aeds." aeds="aeds" all="all" and="and" approved="approved" auc="auc" be="be" between="between" br="br" brand.="brand." brand="brand" by="by" cis="cis" cmax="cmax" compared="compared" demonstrated="demonstrated" did="did" differ="differ" differed="differed" drugs="drugs" for="for" formulation="formulation" formulations="formulations" general="general" generic="generic" higher="higher" however="however" immediate="immediate" in="in" intersubject="intersubject" irrespective="irrespective" limits="limits" measures="measures" moderate="moderate" more="more" mr="mr" nbsp="nbsp" not="not" observations="observations" of="of" or="or" our="our" poorly="poorly" previous="previous" products="products" rates="rates" ratios="ratios" release="release" respectively.="respectively." significantly="significantly" soluble="soluble" studies="studies" surveyed="surveyed" the="the" to="to" variability="variability" variable="variable" was="was" well="well" were="were" whether="whether" within="within">CONCLUSIONS:
Generic MR AED formulations provided total and peak drug delivery similar to that of brand products, ensuring therapeutic equivalence. Generic formulations were bioequivalent to the corresponding brand formulations despite differences in excipients and release mechanisms. This comparison of BE measures obtained in the pivotal studies supporting the approvals of generic MR AEDs suggests that patients can switch from brand to generic formulations with little or no changes in drug plasma concentrations and thus no apparent compromise in the safety and efficacy.
RATIONALE:
Generic modified-release (MR) formulations of the antiepileptic drugs (AEDs) carbamazepine, phenytoin sodium, divalproex sodium, and levetiracetam are currently marketed in the US. MR formulations offer the advantages of less frequent dosing, improved maintenance of therapeutic drug plasma concentrations, and better patient compliance. In a previous study, we found that the smoother drug release provided by a MR AED formulation decreased serum fluctuations, leading to fewer breakthrough seizures. Thus, the objective of the present retrospective study is to evaluate the robustness of the bioequivalence (BE) measures determined in the pivotal clinical studies submitted to the FDA to support marketing approval of generic MR AEDs. BE studies, which determine whether a generic and corresponding brand drug provide the same rate and extent of absorption, are generally performed in healthy normal subjects given single doses of the drugs. The BE measures compared statistically are Cmax (peak drug plasma concentrations, to assess absorption rate), and AUC (total area under the drug plasma concentration versus sampling time profile, to assess absorption extent).
METHODS:
We collected Cmax and AUC data from the pivotal BE studies used to support the approvals of 25 generic AED MR formulations. Data were from BE studies under both fasting and fed conditions. We determined distributions of 90% confidence interval (CI) limits for generic/brand ratios of AUC and Cmax in the BE studies. We also obtained from the FDA-approved labeling information about the inactive ingredients in the generic and brand formulations.
RESULTS:
We evaluated 53 BE studies, including data from 1570 subjects. The 90% CIs of the generic/brand AUC and Cmax ratios differed by <15 125="125" 13.2="13.2" 15="15" 22.6="22.6" 25="25" 77.4="77.4" 80="80" 86.8="86.8" 90="90" acceptance="acceptance" aed="aed" aeds.="aeds." aeds="aeds" all="all" and="and" approved="approved" auc="auc" be="be" between="between" br="br" brand.="brand." brand="brand" by="by" cis="cis" cmax="cmax" compared="compared" demonstrated="demonstrated" did="did" differ="differ" differed="differed" drugs="drugs" for="for" formulation="formulation" formulations="formulations" general="general" generic="generic" higher="higher" however="however" immediate="immediate" in="in" intersubject="intersubject" irrespective="irrespective" limits="limits" measures="measures" moderate="moderate" more="more" mr="mr" nbsp="nbsp" not="not" observations="observations" of="of" or="or" our="our" poorly="poorly" previous="previous" products="products" rates="rates" ratios="ratios" release="release" respectively.="respectively." significantly="significantly" soluble="soluble" studies="studies" surveyed="surveyed" the="the" to="to" variability="variability" variable="variable" was="was" well="well" were="were" whether="whether" within="within">CONCLUSIONS:
Generic MR AED formulations provided total and peak drug delivery similar to that of brand products, ensuring therapeutic equivalence. Generic formulations were bioequivalent to the corresponding brand formulations despite differences in excipients and release mechanisms. This comparison of BE measures obtained in the pivotal studies supporting the approvals of generic MR AEDs suggests that patients can switch from brand to generic formulations with little or no changes in drug plasma concentrations and thus no apparent compromise in the safety and efficacy.
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