Congress To FDA: Review Generic Epilepsy Meds
13 CommentsBy Ed Silverman // November 17th, 2009 // 7:50 am
Those who take meds to cope with epilepsy will be interested to know that Congress has asked the FDA to examine epileptic drugs the agency considers to be therapeutically equivalent to other products. The disclosure was made in a conference report pertaining to an appropriations bill for the agency (see page 86).
As the FDA Law Blog posits, the move is presumably related to questions about any “increased risk of seizures or toxic side effects when patients are switched from a brand name to a generic.” The issue has been raised before by the Epilepsy Foundation, the Washington Legal Foundation and a 2008 article in Neurology that changing from a brand to generic may result in seizures.
Pfizer, you may recall, encountered similar concerns last year. That’s when the drugmaker began marketing a new version of its age-old Dilantin med for treating epilepsy. Citing a need to upgrade manufacturing, Pfizer stopped selling Dilantin Kapseals and began selling Dilantin capsules. But some epileptics were complaining that the new product was causing seizures (background). The agency, meanwhile, is supposedly working on studies to address the problem (see here).
Hat tip to the FDA Law Blog
Concerned Pharmacy Director
Breakthrough seizures upon switching from a branded epileptic med to a generic version (and vice versa) is an important issue and should be studied. That is because many of these drugs require a precise blood level in the system to exert the right efficacy and/or avoid side effects. We call it a “narrow therapeutic index”. Breakthrough seizures can be a result of too much switching.
However, let’s not use sight of the fact that the majority of prescriptions for these drugs are for behavioral health uses (often off-label) as well as other syndromes such as pain. These uses more often than not do not require blood levels to estabslish efficacy. And since the patients taking these for such uses are not epileptic, they do not experience breakthrough seizures when switching versions.
I believe that most of this hysteria regarding this issue is promoted by PHARMA to state and federal politicians/legislators that do not understand the clinical intricacies of this situation. We are seeing many anti-generic substitution laws across the country, and PHARMA bankrolled lobbying is the cause of it……
Ex-FDA Reviewer
Part of the problem is the companies and the FDA itself. A few years ago if a company wanted to change the formulation on these medications they were reviewed by clinical pharmacologists and chemists in the New Drug Divisions that review neurology and psychiatry drugs. These reviewers not only looked at the manufacturing changes but also did look at the changes in the blood levels and evaluated the clinical implications utilizing their clinical knowledge, what they knew from years of experience looking at the data on these drugs, and based on the FDA files. We also worked closely with and could involve the medical staff as needed. Companies often did not like the results as they wanted to simply make whatever manufacturing changes were most economical to them.
In response to several companies who didn’t like negative decisions on manufacturing processes that had significant clinical implications Steve Galson stripped the review staff of reviewing these changes and created an entirely new review group.
This group was composed of the very worst and incompetent chemists and eventually one extremely incompetent pharmacokineticist who no one trusted and was often just put in charge of cupcake parties. They would sign off on changes based on promises to one day submit data (with no requirements that they even be bioequivalent. Plus they would sign off on changes to to drugs that were in the middle of programs to study new indications and they had no clue as to the clinical importance of the blood levels and they wouldn’t even tell the medical of new drug review staff.
We fought these changes but big pharma companies saving money on their manufacturing changes were more important.
JaT
Hysteria, Concerned Pharmacy Director?
People should be somewhat hysterical if a lack of efficacy is the result of changing between “bioequivalent” products. If clinical effectiveness no longer matters in the drug approval process.
Drug companies surely did participate in the drive to allow consumers their branded drugs. That, in itself, doesn’t necessarily mean they are wrong.
Where they are wrong and even hypocritical is where they change their own products and create the exact same scenario they are campaigning against. As happened with Pfizer’s Dilantin.
Todays new almost sounds like they are giving branded drug makers a pass. I haven’t read everything yet though so hopefully I missed something.
You think you’re concerned…
I don’t know whether to be elated or terrified. It is a ‘Be Careful What You Wish For’ moment for me. Not that I have any doubt that the cause is worthy. Do they really get it? Will they change their approval for the med I had to switch to?
Maybe they will insist that bioequivalent products are not close enough to the innovator now that the innovator was dramatically changed. I wondered aloud about that here months ago. Innovator ruins their product for a percentage of the people it is indicated for and the generic makers may have to follow suit?
Will FDA be objective when they have a horse in the race? Pfizer claims FDA told them to do it. The pilot scale CRADA for Quality by Design (naming Dilantin) appears to support their claim.
When I first came here today I thought YES FINALLY.
Immediately followed by the fear that they will use this opportunity to disprove the problem. You would not believe some of the stunts pulled. I have a hard time taking things at face value as a result.
“Breakthrough seizures can be a result of too much switching.”
Breakthrough seizures can be the result of ANY switching. They can be deadly. They can cause brain damage. They can result in broken bones. Financial ruin. Etc..
I’m rambling.
Much appreciated Ed.
Justice in Michigan
Fascinating. Many will recall that, back in the 90s, Warner-Lambert (now Pfizer) had to recall several batches of Dilantin because of manufacturing defects.
At that time, Sid Wolfe/Public Citizen noted that it was one of the worst examples of repeat offending and systemmic irresponsibility he had ever seen. He suggested then that, given W-L’s attacks on generics, W-L ought to “look in the mirror”
http://www.citizen.org/publications/release.cfm?ID=5555
Plus ca change?
M Helm, MD
Medications used to control seizures may or may not have a narrow therapeutic window, and may or may not have peculiar pharmacokinetic properties.
I’ve reviewed a few cases where after changing to a generic from a brand a patient was alleged to have worsened seizure control. In all cases, I noticed that the patient’s use of the medication was less consistent after the change. If a patient only takes the generic half of the time, and previously took the brand more than 80% of the time, the results aren’t surprising.
Seizures are bad. But, poor adherence to medications which may reduce their occurence is not a fault of the FDA or the manufacturers (brand or generic). Unfortunately, for some patients, adherence routinely falls over time, until another event occurs.
JaT
You’re kidding, right?
Someone has taken a drug and maintained good seizure control for a decade or two, and all of a sudden because he was switched to a generic, he has forgotten his dosing schedule?
Medications do not have NTIs, people do.
I think I may have seen you once or twice along the way, Doc.
JaT
That was uncalled for, sorry. Maybe the loss of diligence was the result of poor results and increased symptoms? Diligence just doesn’t generally decrease when seizures are the alternative.
M Helm, MD
JaT, You would surely think that your last statement would be true.
Evidence (and experience) show otherwise…
See the following as a starting point:
Epilepsia. 2008 Mar;49(3):446-54. Epub 2007 Nov 21.
Prevalence and cost of nonadherence with antiepileptic drugs in an adult managed care population.
Epilepsia. 2009 Mar;50(3):501-9. Epub 2008 Oct 3.
Impact of nonadherence to antiepileptic drugs on health care utilization and costs: findings from the RANSOM study.
I can’t explain why this occurs, but I can tell you that many times in the ER I saw children actively seizing who had no (or impossibly low) measurable levels of their antiepileptic medications in their blood, given that their parent/guardian swore that they received their medicines on the prescribed schedule.
For a time after the adverse event (seizure) the patient and family will be adherent, but the adherence behavior in some patients seems to decay over time. It is a phenomenon without a name as far as I know - maybe “event-generating adherence decline syndrome.” How about EGADS for short? (This is also common in diabetes, asthma, and a number of other costly conditions)
In my opinion the Dilantin issues were real, though some may have had seizures for reasons other than the pharmacokinetics changes. The older seizure meds seem particularly vulnerable to variability in delivery and seem to need blood/CSF levels nearer the levels associated with toxicity for effect.
My perception is that most of the newer meds have longer half-lives, better availability, and generally less toxicity than the older meds. Some still have weird and troubling interaction profiles. The new ones are also much more likely to be used off-label. (Some seem to generate more than 75% of their revenue from conditions which are not associated with seizures - and where there is not good evidence supporting effectiveness. For those uses, what’s wrong with the generic?)
As the newer ones were going generic, there seemed to have been a lot of money thrown around to the AAN and other interests to fight (or at least cloud the issues) on behalf of PhRMA.
Another possibility if increased seizures are perceived is that physician’s instill a belief in their patient that the generic is inferior. This could affect adherence - particularly if a physician is insistent that the patient should only be treated with the brand which has become much more costly to the patient. (Or if they take the generic a sense of fatalism about the poor control outcome may lead to hopelessness and apathy.)
Sadly, as a physician, I can say that we are not that good at actually determining (scientifically) WHY something happened. We often let our biases color our conclusions about an observation. If we think generics are inferior, and a patient has a seizure we blame the generic, when in fact there may be another cause.
As always, more study IS needed. I would not want anyone to suffer poor seizure control due to a difference in manufacturing - though the variations there (if any are significant) are probably much less than the variations that occur with co-adminstration of food/beverages, other med interactions, stress, sleep, infection, etc. in a single patient over time.
However, I (and all of us really) have a problem when the study hypotheses are poorly formulated because of particular biases we can’t see around.
Lisa Van Syckel
M Helm, MD,… I personally would like to have seen more safety data on antiseizure drugs in the elderly (ie toxicity.) My mother suffered from a seizure disorder in 2007 shortly after having a small stroke and was prescribed keppra at 1000 mg. This past february she was suffering from gastrointestinal issues. Unfortunately, her blood levels were never monitored, which was partly my mother’s fault because she canceled Dr. appts. In May of this year her keppra was slowly tapered down to 250 mg. Unfortunately a new Physician prescribed Lyrica, on May 28th my mother passed away due to hypovolemic shock from severe GI bleeding.
Do I plan to sue anyone, absolutely not..
Too many misteps along the way. I blame the healthcare system, my mother never rcved the appropriate medical tests,.. Thats the medicaid system for you.
Anne PME
1.Many states have authorized generic substitution w/out notification. The patient can be automatically switched w/out notification from brand to generic. Also, the patient can be automatically switched w/out notification from one generic brand to a second generic brand. There are also antedotal reports of break through seizure occurance with the automatic substitution of one generic AED for a second that do not appear to be addressed here.
If a patient is stable and seizure free on one generic brand, it can be difficult for the prescriber and/or pharmacist to ensure that the patient remains on that specific generic brand.
2. As I understand it, AED ANDA testing only tests blood levels on healthy humans, not on epileptic patients. It would likely not be ethical to test on epileptic patients. Is this correct, and if so, does this change things?
Question:
Can any of the medical/FDA professionals tell us if it is possible for an AED equivalent to to have bioequivalent blood levels but a different CNS penetration level than the originator and/or a different generic brand of an EAD drug?
3. Between outsourcing and increased mail order dispenses, it seems as though many prescription medicines are in shipping and handling channels for longer peroids of time. Would the additional potential for tampering and exposure to adulterating elements be a variable that might be precipitating increases in break through seizures?
Anne PME
Lisa,
I know that all of us here at Pharmalot are very sorry for your loss and hope that you are able to find comfort and good memories with your family and friends.
Lisa Van Syckel
Anne PME,… Thank You.
JaT
I am so sorry for your loss, Lisa. My mom is in a nursing home after her 3rd stroke. It is such a difficult thing.
Dr. Helm,
I don’t have the energy. It really would require a novel. I will say that so many long term doctor/patient relationships were ruined because of the change in that old product, the nay-saying, the patient blaming. We not only had to quickly find something to titrate to while trying to avoid epilepticus, toxicities, and allergic reactions- We also had to find doctors that were willing to listen to us over the stats and drug company and do some research of their own.
We did find them.