I must admit that I was given this drug 4 times in a five year span for persistent migraine headache. I am happy to report I have all my limbs. Why? because it was always through an IV drip and never through an IV push. I confess that on more than one occasion I asked why it wasn’t through a IV push as the drip seemed to take so long, “they” said it would be dangerous through a push, although it wasn’t indicated so clearly on the package insert ( I read everything…).

When you have suffered through a few days with a horrible migraine, you will seek any means that sounds reasonable. I can relate to Levine.

I wasn’t in the US when I received this drug through and IV drip.

Like I said before, this isn’t a great case for preemption and Levine should continue to look forward to what she was awarded.

I wouldn’t joke about this…

You are very kind to lend me an ear.

I think the VA’s confusion (if there is any)comes from Dilantin NMP being approved by the Office of Generics- according to an FDA spokesperson- which might have caused the sNDA to be considered a sANDA.

As for the fasting requirement for bioequivalency, that was not the only problem, just the only one that a simple AUC comparison might indicate.

Our pharmacists were instructed by our physicians to give us Dilantin (DAW) no matter what Dilantin was at the time. There was no additional warning for fed/fasted requirements on the packaging insert initially (not that I got anyway). The pharmacists in my area were oblivious to the change.
Epilepsy drugs often require weeks of careful titration. There is no way we would have put ourselves at risk if all it took to avoid those risks was to reschedule our meal/dosing times. We would not have gone through (often failed) attempts with other drugs. Switching is and has been dangerous.

We were told that the product was the same except for the appearance. Pfizer even called it “New Look” which implies just that.

Please read this article and take note of the statements made by the FDAs spokesperson about how it was approved:
http://www.pharmalot.com/2008/05/a-new-version-of-dilantin-is-giving-pfizer-fits/

I do hope our reports are still on record somewhere in the MedWatch system and that someone will take another look. New and increased instances of AEs in long time users deserves some sort of action.

FDA Reviewer, I do understand your explanation of changes in the agency, but where does that leave us? Pfizer blames the FDA saying that it was on FDA request that they changed their product. I could possibly accept taking a new drug and finding out it is harmful, but we had successfully taken Dilantin for many many years (some for decades) and were blindsided, along with our doctors and pharmacists. Left without our treatment to even go through a safe transition. These kinds of drugs need thorough evaluation for approval. Otherwise the agency is making the statement that our demise or loss of wellbeing is unimportant.

Thanks for your time.

For new drugs these issues really take a collaborative approach from medial reviewers, chemists, and clinical pharmacologists working together.

Management has been playing musical chairs with us with the move to the new campus. Now the medical reviewers are in one building, the chemists in another, and the clinical pharmacologists in another. So that it’s a 20 minute fast walk to collaborate. Forget it. With all the new inexperienced reviewers being hired they don’t even know what other review disciplines even do.

Plus the clinical pharmacologists have now been told to not even look at how changes in formulation and manufacturing during development of new drugs alter drug effects. Without this you can’t tell if you should even expect a possible problem with changes after approval.

The moves appear to be intentional or as one senior manager put it “divide and conquer”.

For example back the Clinical Pharmacology staff was moved last april first into a new building because they had just the right number of staff members and the Office of Generic Drugs who were supposed to move into this space were going to have too many based on the plans to higher more reviewers to review generic applications. Within days of the move into the new building the plans to hire all these new reviewers to review generic drugs was canceled. Not only that but the building that had been designed 10 years ago had special computer rooms for the new drug-disease modeling etc. under an ex-Pharma VP. Plus there were rooms for all these new fellows that Von Eschenbach just announced he was going to hire.

An FDA Reviewer

I have no personal information on this. I think the VA may simply be in error. Dilantin is the brandname of the innovator’s drug product and any changes would have to come from the innovator and would covered under an sNDA. ANDAs are only for generics.

Having said that I found comments on the epilepsy foundation website that the Dilantin produced under the new manufacturing process (NMP) is not bioequivalent when compared under fed conditions (only fasted).

There has been a lot of changes at FDA over the last few years. One is that the manufacturing changes for branded drugs like Dilantin has been removed from the review groups who have always handled them (i.e. the clinical pharmacologists and chemists who work on the original product) and has been handed off to a separate group of chemists who don’t even tell the reviewers who look at the clinical implications what is going on. It has been an incredible mess as they’ve stuck the worst people over there and they have been doing all kinds of things like signing off on changes based on promises by companies that they will show bioequivalency in the future. (I know this has been an issue with the groups who had been reviewing neuro drugs.)

Now the primary review teams are looking at clinical studies and finding out that the studies were done with a totally different formulation that behaves very differently than they thought.

All of these changes in FDA appear to be coming at the request of industry because they simply didn’t like it when FDA reviewers told them that there’s a potential issue with something they wanted to do. (The attitude from industry and even verbalized by upper FDA management is who are we to tell companies anything about what they want to do.) It also causes a lot of excessive work for the primary review team as they have to spend inordinate amounts of efforts trying to stop these problems before they occur. Unfortunately the staff reviewers have been losing these battles and they are just overruled.

An FDA Reviewer

I thought the most interesting comment was made By Chief Justice Roberts:

“So, as I understood your answer to be, all we have to do is simply look at the record, and if we think the FDA considered specifically IV push risks as opposed to general arterial exposure, then you lose, and if we determine that they did not, then they lose.”

That would seem to narrow the issue: However I realize just because Justice Roberts asked this question does not necessarily mean that he agrees with the premise.

The other comment by Justice Roberts that I found to be of interest was his comments on the fact that Statutory law includes a preemption for Medical Devices but does not include one for drugs.

I wonder if the fact that there is no express Statutory language favoring preemption will determine his decision?

The fact that Wyeth’s attorney referenced Riegel in his answer doesn’t help here; Riegel was decided on behalf of the Respondent because the Statutory Law did exist.

As to the question on whether Levine’s Attorney presented a good case on behalf of preemption; based upon the transcript I don’t think he did. I thought his answers to the Court’s questions seemed to lack a specific focus. I think his “what did they know and when did they know it argument” will not be relevant in this case as it was acknowledged that the risk was known for years by everyone including the FDA. He testified that Wyeth was aware of the problem as far back as the 70’s; I don’t think this particular testimony helps his case; if the problem goes back that far where are all of the other lawsuits? It just seems to me to reinforce the argument that the problem was with the provider and not the manufacturer.
The other fact is that he pointed to the broad powers granted to the FDA since 2000. Broader authority brings broader responsibility. I can’t help but think that this will favor the industry and bring us right back to Justice Roberts’ Question.

Maybe because it was the reference product that was changed there is a new application catagory? Does this change also change the rules for generic makers, to be virtually identical to the new product? Because if the generics we moved to are going to toss us into seizures and toxicities some day soon- it would be helpful to know in advance.

I’ll stop hijacking this thread now. Sorry.

The reason I ask is because, according to the VA, Dilantin NMP was approved via sANDA.

If Dilantin NMP was not an ANDA or a sNDA, then what exactly was it? I understand that Dilantin NMP was not approved under the usual circumstances of an ANDA.
So based on Kneedler’s comment, it seems reasonable that anyone privy to post-marketing information should do something. Otherwise we were not even being involuntarily harmed for the greater good.

I do wonder how it is that the agency thinks it can ensure proper warnings when testing is so limited that it does not exclude long time users with a NTI. This was a dramatic change that caused serious harm. A change such as this leaves us wondering how our doctors can ever know what they are prescribing. This approval also made the DAW pointless.

Thank you for your reply. I am curious about sANDAs if you have the time.

An sNDA would NOT include an ANDA. The labeling of an ANDA has to be virtually identical with the labeling of the holder of the reference product.

For others an ANDA is a generic drug.

Another comment. I disagree with Formet Commissioner Kessler’s comment the other day that labeling is fully revealing at initial approval because the company is told that they are not allowed to change any wording or the drug will be misbranded. At approval the labeling is a product of negotiation and FDA often doesn’t get everything it wants. The warning is really to tell the sponsor to not try to pull a fast one and change the negotiated wording to make it more sales friendly, and thus this a warning that this is the bare minimum we will accept.

I’ve seen too many times where sponsor send us back mockups of supposedly negotiated labeling and it’s been changed. Or in supplements things get changed and we’re not told so if might approve some change we’re not even aware the company did.

One of the most surprising things I ever heard is when one of the biggest companies around told me during labeling negotiations, “but if we put that in the labeling it’ll decrease our sales by 10%”.

Isn’t it up to the patient and the physician to have an informed opinion so they can decide the risk vs. benefit of use.

(This wasn’t as surprising as when a company representative yelled at us in a meeting, “But we paid for an approval!”)

An FDA Reviewer

Which gets me to my next point. The fact that the FDA did not say DO NOT GIVE BY IV PUSH means that they cannot be expected to handle every detail related to prescription drugs, especially since their staff is being hounded to approve drugs as soon as possible, via pharma pressure. I think this is the BEST argument against preemption of state law by FDA approval.