Pharmalot... Pharmalittle... Good Morning

While I have not looked at and would not be qualified to look at this data, does anyone else think that the FDA panel rejected in part b/c of issues with other Forest medicines?

Would FDA issues involving other medicines make the FDA panel members more inclined to take a closer look at the Forest data that this panel looked at?

This in response to the PhRMA "transition" appointment. I don't know what is typical, but perhaps PhRMA may want to see which way the wind is blowing after the November elections before making a more defining choice.

I'd like to know how the FDA would allow a pharmaceutical company to extrapolate clinical trial data from an Asian population to a Western population given the well known interethnic pharmacogenomic differences. Anyone have any thoughts? On the other hand, I wouldn't have a problem if Asian data were only used for Asian approval, but we know that will not be the case with Pfizer, or any other Pharma company for that matter.

http://www.sbfte.org.br/editorialGSKPharmacogen.pdf

Please, I need a translation. Can someone look at this and see how USP has revised their criteria for phenytoin products? So many of us are so sensitive to this product that any change is a bit terrifying.

http://www.usp.org/pdf/EN/USPNF/extendedPhenytoinSodiumCapsules.pdf

I don't have a clue how dissolution rates translate to absorption rates, but if it would be helpful I have the Cmax, AUCo, Tmax, & T-1/2 for two different phenytoin products- as compared to the innovator. Though the innovator numbers are different in each comparison.

Thanks

More specifically- I have the Cmax, AUCo, Tmax, & T-1/2 for two different 100mg phenytoin products- as compared to the innovator. 100mg being my personal concern.

Post the data with means, sd, cv, range, and medians, and sample sizes for each product. I'm assuming this is from a crossover study. I also need the geometric means, and the geometric mean ratios with their 90% confidence intervals. Sometimes geometric means are listed as LSMeans. Also if there's a tlag I'd like to see it. I assume by AUCo you mean 0-infinity.

If you have the data for both fasted and fed conditions and the type of meal used that would be useful.

There's a lot of other info I would need to verify things but if an approved product I'll assume it's all been checked.

Salmon

Hi Salmon,

I don't begin to have all that you are requesting.

CapsulesNMP is Pfizer's reformulated Dilantin. My big concern all along is that, when Dilantin was reformulated, as the innovator, the generics would have to follow suit.

Pfizer, sent their NMP numbers to a pharmachologist right after the reformulation-comparing the new CapsulesNMP to the Old Dilantin Kapseals. The Mylan numbers were in the magazine, Neurology, 2001, 57, pgs. 582-589.

The type of meal Pfizer described was a very high fat, high calorie, high protein, breakfast- bacon, eggs, and a several other items. Incidentally, there were no fasted or fed requirements for the old Kapseals, as food made very little difference. Pfizer then said that effectiveness was improved by taking the NMP fasted. __________________________

So my info has these listed as fed:

Cmax: CapsulesNMP 1.19 vs Kapseals 1.26, Ratio 94.8, 90% Confidence interval, 81.95 to 109.62

Mylan100mg: 1.18 vs. Kapseals 1.36, Ratio 87.0, 90% Confidence interval 80.6 to 93.8 _______________ AUCo: CapsulesNMP 33.5 vs. Kapseals 31.8, Ratio 105, 90% Confidence interval, 99.29 to 111.47

Mylan100mg: 29.4 vs. Kapseals 33.9, Ratio 86.7, 90% Confidence interval 81.4 to 92.4 _______________ Tmax: CapsulesNMP 5.04 hrs. vs. Kapseals 6.01 hrs.

Mylan100mg: 6.50 hrs. vs. Kapseals 7.48 hrs. _______________ T-1/2: CapsulesNMP 13.7 hrs. vs. Kapseals 12.8 hrs.

Mylan100mg: 15.1 hrs. vs. Kapseals 15.5 hrs.

Here is a link to Taro's info- where they might have all you are looking for: http://www.freepatentsonline.com/y2007/0185180.html

You are a little over my head. I'm obviously not in the field, but any info would be greatly appreciated. Can you get anything from this or should I do some better research?

Forget what I said before. It's useful for the dissolution test changes. I've now had a chance to go back and look at the dissolution tests and first I can't even figure out what's changed as I don't have the old version. Second the dissolution test and criteria for this is pretty bad. You need to look at different parts of the curve early (~ 20 - 25% dissolved) middle (~50% dissolved) and late (~85% dissolved). The values used are too close together to be very useful as they really wouldn't be able to differentiate changes in dissolution rates. You can also see between test 1 and test 2 that even though you increase the degree of agitation the change in the criteria is minimal as it's only a minor change in the middle value.

Salmon

Thanks for giving it a look.

As for the BE values. The drugs are barely passing the tests, meaning that there's a lot of variability. It's likely that they used a lot of subjects just to get the passing values.

It's not surprising since a major assumption is that clearance does not change between dosing yet with phenytoin we know that even minor changes in absorption alters clearance. This makes the differences in the numbers kind of screwy and difficult to interpret.

The comment about food is concerning. Since with NMP Cmax is lower and Tmax is shorter but AUC is higher this may mean food is delaying absorption initially but there's more absorbed later. Also since they say efficacy is improved by taking it fasted this may also imply food slows absorption and you'll get higher peaks if taken fasted. This could result in peak related toxicity in some people and either way possibly higher overall exposures and greater accumulation on multiple dosing.

On the other hand the NMP data suggests there's less peak-trough fluctuation when taken with a heavy meal which is better for maintaining consistent levels and minimizing toxicities. The problem is we don't know what less heavy meals will do. The types of meals used are designed to maximally stress the absorption characteristics but unless you're eating Denny's grand slam breakfast or MacDonald's all the time may not be relevant to the real world.

Overall the Mylan product seems to be somewhat less bioavailable than the kapseals.

This is based on what you posted and I don't have time to go through everything. In any event I would want to look and each individual's data.

This is based on the numbers. It's a difficult product and since clearance is so finicky things could be different if the exact same experiment was redone with the same products. In other words I could be reading too much into 1 experiment.

Another question is whether any data was thrown out due to vomitting. That would really confuse things and even having partial data would help.

The way things are it's likely that most people won't have problems but as it's a narrow therapeutic range drug, which varies with the individual, some people who are very sensitive to changes will have problems with even minor changes. All in all the manufacturing changes may be reasonable but some people will have problems with even reasonable changes and minor differences.

The best things is to just get stabilized on a single product and don't change.

You hit the nail on the head, Salmon. To get on one thing and stay with it would be a blessing- if they would just stop making changes to stuff. I wonder if the powers that be have any concept how important consistency is. Maybe they flat don't care. This is why the revision worries me. I won't get into what led me to stumble on it. "They" all need to leave this product alone- ugly as it may be. Some of us have no options. I'm a little peeved that any revision, as with the prior reformulation, went off without letting anyone know. It is dangerous. It is such a hassle that consumers have to constantly dig for what might happen next. I am not getting caught off guard again- though we can't do anything about what we are offered.

Thank you again.

Some people do have an idea. However even under the best circumstances there are going to be changes. Equipment gets old and needs to be changed. The buildings get old and things are consolodated to a different plant. The manufacturers of the ingredients stop making things or changes or there are other changes in the source ingredients. Sometimes manufacturers decide it isn't worth it and to just let the generics have it.

With most drugs it doesn't matter. With a few, minor differences may make problems. Even then it's a subset of the patients who really have problems and most who don't.

Companies make changes for a variety of reasons, try to match up dissolution characteristics as best as possible.

(Which is problematic since as in this case the rapidity of the dissolution compared to the Tmax indicates that someone just wanted to set something up that would be fast so they maybe they could be done by lunch. Yet these things have to be developed and tweaked as the drug is developed and so if there's no thought and communication between the formulation chemists the lab techs, the clinical pharmacologists and the clinicians it's done independently with no thought to consequences and at the end of development you're stuck.)

So when you make changes to the formulation later you try to make it so that the clinical implications are minimized for the vast majority of people. Even so you know that some people won't tolerate things and you hope that they will be able to readjust to something new without too much problems. Then you put it out there, the company and the pharmacies should tell patients changes have been made and you watch and listen to people. There will always be some unlucky ones with drugs like dilantin.

Unless there's huge problems and even if there are you're probably already committed and can't go back.

One of the problems I see is that if people don't have trust in the companies and the FDA then even if you do the best you can (which I don't think is what's happening currently) then patients are not going to believe that anything the companies and FDA say regarding the changes and the process used.

As for yourself. Try to find a clinical pharmacist who specializes in neuro. Make a daily log of specific product that you take and how you respond over the course of each day (efficacy and toxicity) along with diet info. Then have them look at your lab values on the current vs. old product and try to figure out which product's bioavailability and characteristics are, and integrating it with how you respond and your personal concentration effect profile, figure out how dosing and how you take things can be tweaked. That's the best that I can offer.

Here's a drastic idea for phenytoin, but one that is grounded in my professional experience. The FDA should regard any reformulated Narrow Therapeutic Index (NTI)drug as a New Drug, requiring some form of NDA. I go back in time with Boots Pharmaceuticals, which inherited Synthroid from Flint Laboratories. Synthroid had been grandfathered as a pre-1962 drug, thereby not requiring an NDA. Over the years, Synthroid had undergone several reformulations, but since it was not an NDA'd drug, these changes did not have to be submitted to FDA. Periodically these formulation changes would result in sub-potency significant to produce clinical symptoms.

Finally, in 1997, the FDA, aware of these problems put out a notice in the Federal Register declaring all Levothyroxine products to be classified as New Drugs, and required that NDA'S be submitted and approved by Year 2000, lest the products be taken off the market.

Although the FDA's intention was good, the unintended consequence was a confusing matrix of innovator and generic products, some of which were or not AB rated to others, depending which LT4 compound was used as the comparator.

Perhaps FDA can apply lessons learned to future NDA's for NTI drugs.

I could go with that, pharmavet, but there still needs to be room for titration periods. Hmmm, well, then again, they'd still alter them- which will still present problems. But it's better than an ANDA for sure. I was on Kapseals for well over a decade- some were on it for a few decades. Ability to maintain a quality product can't be that difficult. _________________

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm142591.htm FDA-Pfizer CRADA: Quality by Design and Process Monitoring of Pharmaceutical Manufacturing at Pilot-Scale

"There is a need within the regulatory community and the pharmaceutical industry for case studies that put these principles into action and test these approaches.

Research Approach: This research project has focused on pilot-scale manufacturing of Dilantin capsules as a CRADA with Pfizer."

This Is Only a Test (beeeeep beeeeep beeeeep)

J.Q. CaseStudy

On face it appears to make sense as it clearly does in the Synthoid case (I remember that one too). However ideally it requires changing the name of the 'new dilantin' to something else as they are not the same product. In any case changes to the innovator product can make the innovator product inappropriate to use as the reference product for newer generics. Consequently the Mylan product although equivalent to the old Dilantin, may not be equivalent to the new dilantin. But this is always the case. One generic may have greater bioavailability than the innovator product yet still meet bioequivalence criteria, while at the same time a second generic will have lower bioavailability than the innovator and also meet bioequivalence criteria. Yet generic 1 will not be bioequivalent to generic 2.

Even drugs that are not NTI can have issues with formulation changes such that 10% of patients may have either little or super absorption with a new product (I've seen this with oral hypoglycemics and it causing hypoglycemia in studies.) Even though overall bioequivalence was met. Practicing physicians and pharmacists haven't a clue. Right after I saw this I was in a pharmacy and heard a patient telling the pharmacist the generic was causing her problems and the pharmacist not being aware of this told her they were approved and there weren't any differences. Levodopa is another problem rapid absorption results in vomitting yet the data is excluded so it biases the results as you're cherry picking the data.

As much as people argue about generics, it starts with the innovator product. I've seen a number that had batch to batch problems. In some cases the company was lazy or didn't want to rework the batches (i.e. extract the drug and start over).

Salmon

It shouldn't have had the same name. "New Look" Dilantin is not the same product. It rendered the DAW completely pointless. New Look was not the extent of the changes and our docs thought we were nuts until we proved to them the differences. They had no idea what they were prescribing. Our pharmacists didn't know what was on their shelves. I do see your point about the implications for generics though. Still, there must be a better solution.

Hey Salmon,

Your explanation about food and the possible reactions described well why we all probably handled the NMP as differently as we did. Sadly though, the varied reactions also made people doubt that the reformulation was the cause of our new or increased AEs. Our blood serum levels were all over the place. Myself and others have made every attempt to try to make people understand. We've exhausted every resource on every level. I just don't know what else can be said or who else to say it to. If there are people in regulatory positions that understand then why are we beating our heads against the wall. ______________

The CDER report that I posted suggests that Dilantin was chosen for the purpose of trying a new process. Nothing has ever made me feel more insignificant (and then angry, scared, angry, determined, scared). This of all drugs- epileptics of all people. When other medications would be less likely to cause such awful results. It is shameful. Some of the stories that resulted would make any decent person hurt to the soul. DoJ is supposed to protect us. They have proven to be about as good an advocate as the ~drug company funded~ Epilepsy Foundation that was removing our posts, our discovery. _______________

You said (above) "There’s a lot of other info I would need to verify things but if an approved product I’ll assume it’s all been checked."

This is from Ed's article: "However, the criteria Pfizer used was not requested by the FDA to show bioequivalence and was different from the FDA criteria, according to an FDA spokeswoman. She adds that the FDA was unable to review the study protocols before Pfizer proceeded and the agency doesn’t know why Pfizer chose different acceptance criteria. Nonetheless, the agency did approve the new Dilantin." http://www.pharmalot.com/2008/05/a-new-version-of-dilantin-is-giving-pfizer-fits/ _______________ Anywho- I couldn't find the USP requirements before the revision. All I can do is wait for my next refill and see what comes of it. I'm giving up this pointless battle. I'm exhausted by it all. I only wish that I knew for sure that I could quit this crap without going into status- and I don't want to succumb to seizures at all. I have developed drug induced lupus. I made the decision yesterday to suffer that and not risk the dangers of seizures. Crappy trade off. ______________ ______________

You are all such a decent people to have allowed me to try to work this stuff out here. It's been an honor. I'm just gonna put on my dark shades and enjoy my days in the sun. Maybe take up painting or poetry or some such shit. ;)

Ed, you are possibly the kindest person I have come to virtually know. Endless Thanks.