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1.  You’re all a Bunch of Nutjobs, so Shut the F#¢« Up and Take Your Meds

The case that brought the differences between branded and generic medications into the public and media spotlight (but not, unfortunately, congress) was Teva’s Budeprion XL. Teva and its subsidiaries manufacturer a hell of a lot of generics, and they rarely have any problems. Like many of my fellow nutjobs I request Teva’s topiramate and lamotrigine from my pharmacist, as I’ve yet to have a form of topiramate from anyone else that’s acceptable and I prefer their generic lamotrigine to GSK’s brand-name Lamictal.1 So, what happened with Budeprion XL? Impax (the actual manufacturer) used a matrix system to delaying the release of bupropion HCl, while GSK had originally designed Wellbutrin XL to use a reservoir system. You’ll need to read the article, as I can’t explain it any better.

Teva’s once-a-day XL version was acting more like the twice-a-day SR version, some people even reported it working like the three-times-a-day immediate-release version. The nature of side effects and specific lack of efficacy all centered around one simple fact: it wasn’t a true once-a-day pill. So, how did the FDA respond to the complaints? Here are the key points:
First up, Budeprion XL passed the required tests, so there absolutely can not be a problem.

The basis for approval of Teva’s bupropion XL was that there was no significant difference in the rate and extent of absorption as measured by the plasma bupropion concentrations between 150 mg of the Teva XL product and 150 mg of Wellbutrin XL. Because of the potential risk of seizures at higher doses, the 300 mg strength was not studied. This practice is used when evaluating the pharmacokinetic profile of a drug in normal volunteers, especially when a drug’s adverse effects increase with dose. The pharmacokinetic profile is not expected to differ between 300 mg and 150 mg doses of bupropion.

The area under the drug plasma concentration over time curve (AUC) is a graphical and statistical representation of the total amount of drug absorbed. The average bupropion AUC from the volunteers receiving the Teva generic product under fasting conditions was 98% (90% CI, 91.9%−104.4%) of the average AUC from all of the same volunteers after receiving the Wellbutrin XL under fasting conditions. Under fed conditions the average bupropion AUC for the Teva product was 108% (90% CI 101.4% −115.4%) of that for the Wellbutrin XL product.

The average maximum bupropion plasma concentration (Cmax) produced by the Teva product was 89% (90% CI, 80.3% – 98.2%) of that produced in the same volunteers by Wellbutrin XL under fasting conditions and 110% (90% CI, 103.2% - 118.0%) under fed conditions.

The established bioequivalence limits provide that the entire 90% confidence interval (CI) for the generic/reference comparison of both AUC and Cmax be within 80% to 125%.2 Thus, the small differences observed in AUC and Cmax, with no consistent direction, are within the established limits for bioequivalence between brand name products and generic versions, and are not considered clinically relevant.

The major active metabolite, hydroxybupropion, which is responsible for much of bupropion’s effect, also met the AUC and Cmax bioequivalence limits. Review of Therapeutic Equivalence Generic Bupropion XL 300 mg and Wellbutrin XL 300 mg 3

I highlighted the two areas in this section I have a problem with. It was a sub-therapeutic dosage4, and they didn’t provide any data for the active metabolite. Who is hiding what?

Fortunately the FDA has finally updated its standard for crazy meds.

Next we see why Cmax and AUC by themselves are pointless

The time to maximum drug plasma concentration (Tmax) was examined but is not required to be within any specified limits. The bupropion Tmax was faster for Teva’s XL product (2–3 hours) than Wellbutrin XL (5–6 hours). The median Tmax values for hydroxybupropion (the active metabolite) with Teva’s product was 10 hours while Wellbutrin’s hydroxybupropion Tmax was 12 hours (in both fasting and fed subjects). These differences in Tmax for both bupropion and its active metabolite, however, were not considered clinically significant. The somewhat more rapid times to maximum concentration, with no differences in the plasma bupropion concentrations (including the lowest levels, known as trough levels) throughout the day, would not lead to decreased effectiveness. This is supported by the fact that the bupropion Tmax of Teva’s XL product was similar to that of the marketed Wellbutrin SR and was, in fact, slower than that of Wellbutrin IR, a dosage form shown in clinical trials to be effective. The pharmacokinetic profiles of the generic and branded products do not support a conclusion that the reported lack of antidepressant effect and new onset side effects are the result of differences between the two products. ibid

This is a remarkable new level of willful ignorance. I’ve been writing that bureaucracy is the antithesis of logic for years, but this takes it to a new low. The FDA spells out the problem, that Budeprion XL is bioequivalent to Wellbutrin SR, not Wellbutrin XL, and choose to ignore it none the less. They even include it as a graph in the document they use to tell everyone that there is no problem!:

If there’s no difference in efficacy between the IR, SR, and XL forms, why should GSK bother making SR and XL forms in the first place? Why is only the XL form approved seasonal affective disorder? Why is Zyban (bupropion SR) the only form approved for smoking cessation?

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Once again, don’t just take my word for it:

[N]umerous postmarketing reports have cited loss of antidepressant effect and/or emergence of side effects when patients were switched from a proprietary formulation of bupropion XL (using a reservoir system) to an approved generic formulation (using a matrix system). Evaluation of the bioequivalence data revealed small PK differences that were within the equivalence boundaries and an earlier Tmax that was similar to that of bupropion SR. A Horse of a Different Color: How Formulation Influences Medication Effects Meghan M. Grady and Stephen M. Stahl

That’s right bitches, no less than Stephen freaking Stahl wrote the exact same thing I’ve had on this site for over three years, including using the FDA’s own graph to show how wrong they are about Budeprion XL being equivalent to Wellbutrin XL.

So, what caused the problem? According to the FDA: it’s all in your head - the so-called nocebo effect - or it was just a coincidence and you were going to have a relapse of symptoms anyway. From their response:

The recurrent nature of MDD offers a scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product. The adverse effects (e.g., headache, GI disorder, fatigue and anxiety) reported following a switch were relatively few in number and typical of adverse drug events reported in drug and placebo groups in most clinical trials (i.e., including, but not specifically for, bupropion). Although many of these adverse effects are seen soon after drug therapy is initiated, adverse effects are known to occur throughout the course of a patient’s therapy, as well as among patients on a stable dose of medicine or in patients receiving placebo.ibid

Are the people at the FDA in charge of this complete idiots, criminals, or both?

1.1  We Were Never Slightly Wrong, and We’re Going to Change How We Do Things. But Probably Not.

As of 3 October 2012 the FDA decided that they got it a little bit wrong by calling Teva’s 300mg Budeprion XL bioequivalent to 300mg Wellbutrin XL, and asked Teva to voluntarily pull it from the market. 150mg Budeprion XL is still rated as bioequivalent in spite of the fact that IT’S NOT! I go into great detail about the FDA’s announcement and why Budeprion XL is not bioequivalent to Wellbutrin XL in any dosage on the Expanded Wellbutrin Comments page.

Amazingly enough, prior to that bullshit admission of being sorta kinda not all that wrong about it, the FDA had decided to change things a little when drugs have complex PK like Wellbutrin Ambien CR. These two documents explain it:
Minutes from the FDA meeting on new bioequivalence standards for drugs with complex PK
The slides from the presentation referenced in the minutes.
What does it all mean? In English: it explains, in dense PK terms, why the FDA totally fucked up approving Teva’s once-a-day Budeprion XL when it’s, at best, twice-a-day SR; and how the new method they will now use more-or-less works with something like Ambien CR, but there could still be problems.
Why will there still be problems? Because all they’re going to do is add a couple more useless PK parameters to their tests. As a great exemplar of my maxim “bureaucracy is the antithesis of logic” these tests are as pointless as they are expensive.

1.2  Oh, We Were SO RONG!!! Please Don’t Tell Anyone How RONG We Were. Please?

I don’t know when they did it, but the FDA quietly released the long-awaited study they conducted comparing Impax/Teva’s Budeprion XL with Wellbutrin XL. You can find it here. I’ve kept a copy in case they move it or remove it, which they often do with documents that embarrass the FDA, drug companies, or, as in this case, both5. Here’s the most important part:

The Test columns are the numbers for Budeprion XL, Reference are the numbers for Wellbutrin XL.

To me the only numbers that matter are the three easy-to-grasp ones: Cmax - the maximum amount of the substance in your blood, Tmax - how many hours it takes to reach Cmax, and Thalf - the substance’s half-life. Based on those numbers Budeprion XL is so not bioequivalent to Wellbutrin XL. The FDA likes the obtuse AUC6 and Cmax. To qualify as bioequivalent the last column, Ratio of Test to Reference as to be in the range of .90 to 1.10, which is the standard for drugs with a narrow therapeutic index, or are otherwise dosage critical. And the FDA now considers crazy meds to be dosage critical. Took them long enough to understand that the brain is a delicate organ.

Using my metric Budeprion XL is nowhere near bioequivalent to Wellbutrin XL. Cmax sucks for Impax’s version of bupropion and all three of its active metabolites, and that alone fails the med as far as I’m concerned. It may as well have less than 90% of the bupropion than regular Wellbutrin. The half-lives are good, but Tmax is way too short for the bupropion, and way too long for its active metabolites. Combine the lousy Cmaxes with the irregular Tmaxes and the side effects reported make a hell of a lot of sense.

As far as the FDA is concerned, the bupropion was a total fail, the second active metabolite, erythrobupropion, is bioequivalent, while hydroxybupropion, the first active metabolite and real workhorse of Wellbutrin, barely failed. The third active metabolite, threobupropion, also barely failed. As it may or may not do anything at all, and I’m too lazy to copy its numbers in a way that would look good, you’ll have to look them up yourself on the above link if you want to see them.

How the fuck did that drug get approved in the first place? You really want to know the answer to that question?

First of all it was done using the old 80–125% BA/BE standard for drugs without a narrow therapeutic index or ratio, aren’t dosage critical, whatever you want to call them. Secondly, the FDA rarely checks the generic companies’ analyses, and just accepts their numbers on faith7. Rather, they rarely check the analyses after the second or third generic for a med is approved. As long as the paperwork is correctly filled out, it’s good to go. This seems a bit of an aberration as Budeprion XL was the first generic XL form of bupropion approved, but there were so many generic versions of Wellbutrin and Wellbutrin SR on the market the FDA may have become as lazy as I am. Or they’re short-staffed and chronically overworked. Or they don’t give a rat’s ass about crazy people.

2.  What the FDA has done:

After a bunch of bullshit like:

Then they came up with their new standard of the AUC and Cmax having to be within a 90–110% ratio in addition to their 80–125% BA/BE range. Whoopee shit. It’s still total bullshit. Why? Because I think the AUC is a bullshit number they use to try to force the pharmacokinetics of a single dose of a med which, unlike the Budeprion XL in this test, may need to be taken more than once a day. And they give to healthy volunteers, fit the profile of people who are not healthy! That’s why it’s a bullshit number. So it doesn’t make a damn bit of difference if one bullshit number matches another bullshit number.

And that’s still for the first couple of new generics for any given med, crazy or otherwise. My money is on their still letting most of them get by on paperwork alone and no actual BA/BE testing.

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‹|Back to Brand vs. Generic Meds

1 Teva's lamotrigine tablets are, easier to split, don't dissolve so quickly, and aren't a weird shape, so they're a lot easier to take in addition to being less expensive. Anyone who has a problem with the differences between brand and generic meds shouldn't be splitting their pills in the first place, but I'm not as sensitive to the differences in Lamictal as I am with those in Topamax. Plus I don't need to split them at all now, and when I do a split pill would be just part of my daily dosage.

2 THAT is the +/- 25% standard a generic drug has to meet, NOT the amount of the active ingredient.

3 For some mysterious reason the FDA keeps moving this document all over their site, and sometimes it completely vanishes. Fortunately I made of copy of it. The links to parts of the FDA's site and other documents don't work, but all the salient data are on that page.

4 While I'm the world's biggest advocate of starting and staying at sub-therapeutic dosages that work, most people taking most meds will be doing so at the typical target/therapeutic dosages. In Wellbutrin's case that's 300mg a day.

5 Another way to tell how embarrassed the FDA is about this entire mess: that .pdf file is a collection of images. I can't copy and paste the embarrassing numbers. It's type them in manually, copy pictures, or direct you to URLs the FDA will, in all likelihood, change if there is too much traffic. Oh well, they just asked for the file name…

6 Remember when you were in statistics and/or calculus class and you or someone else asked your teacher, "What good is this going to do us in real life?"? Well, now you know. Especially AUC in calc class. I could extrapolate uses for a lot of it, even if I wasn't going into that particular field. But the area under the curve? What the hell use could that have?

7 Whether or not this qualifies as a faith-based government program is up to someone more qualified than I am to judge.

FDA vs. Teva/Impax vs. Reality on Budeprion XL by Jerod Poore is copyright © 2014 Jerod Poore

Last modified on Monday, 18 April, 2016 at 00:16:22 by JerodPoorePage Author: Jerod PooreDate created: 21 March 2014

All drug names are the trademarks of someone else. Look on the appropriate PI sheets or ask Google who the owners are. The way pharmaceutical companies buy each other and swap products like Monopoly™ real estate, the ownership of any trademarks may have changed without my noticing.

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1 While there are plenty of books to help you with hypochondria, for some reason there’s not much in the way of websites. Then again, staying off of the Internet is a large part of curing/managing the disorder.

2 Remember kids, Microsloth operating systems are like TOS Star Trek movies with in that every other one sucks way, way more. With TOS Star Trek movies you don’t want to bother watching the odd-numbered ones. With Microsloth OS you don’t want to buy and install the even-numbered ones. Anyone who remembers ME and Vista knows what I mean.

3 Have I mentioned how open source operating systems for commercial applications is one of the dumbest ideas in the history of dumb ideas?* I don’t even need my big-ass rant any more. Heartbleed has made my case for me. And that’s just the one that got all the media attention. The very nature of an open source operating system makes security as much of an illusion as anonymity on teh Intergoogles. Before you flip out too much: the domain Crazymeds is hosted on uses a version of SSL that is not affected by the Heartbleed bug. That’s one of the many reasons why I pay a lot of money and keep this site on Lunarpages.

* Yes, I know I’m using open source browsers. I also test the site using the now-defunct IE and Safari browsers. Their popularity - and superiority - killed IE and Safari, so that’s why I rely on the open source browsers. It’s like brand vs. generic meds. Sometimes the generic is better than the brand.

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