Terra Sigillata

This issue was brought up by my fellow blogger, Joseph at Corpus Callosum, following an article in yesterday’s LA Times.

For those not familiar with the concept or countries other than the US where laws may differ, generic drugs are those with the same active chemical as the originally-approved “brand name” drug. The original drug manufacturer is the one that conducts all of the preclinical and clinical safety and efficacy testing, natural product isolation and/or chemical synthesis, formulation with inactive ingredients to assure dissolution and reproducible release of the drug, etc. In return for all this work and an investment of about $800 million, the company produces a “brand name” drug for which they have a period of marketing exclusivity of roughly 17 years from the date the drug was first patented (in some cases this can now be extended another 5 years). While that sounds like a monopolistic proposition, many drugs take up to 12 years from patenting to be approved by the US FDA, meaning that the company has to recoup its investment in a rather compressed time period.

When a drug patent is about to expire, companies specializing in the manufacture of drug products compete to gain FDA approval to market a generic version of the drug without all of the huge investment made by the brand name developer of the drug. Hence, generic versions of brand name drugs are priced much lower. However, the generic company[ies] must demonstrate the so-called bioequivalence of their drug, meaning that the active component must be absorbed into the bloodstream within 80% to 125% that of the brand name drug, without any regard for the time course of that process. These studies rarely require more than a few dozen patients given a single dose of a drug. In many cases, this is adequate.

However, there are some situations in which generic drugs are not the same as brand name drugs, even when manufactured according to FDA tolerances. And while the initial approval process for generic drug manufacturers may be reasonably stringent, the follow-up monitoring of such companies is often less than ideal primarily because of short-staffing of this part of the FDA.

Joe and Teresa Graedon are consumer health advocates who write a syndicated drug-focused newspaper column called The People’s Pharmacy and air a NPR radio program of the same name. For over 30 years, they were strong supporters of generic drugs over brand name drugs until readers and listeners increasingly reported problems or lack of effectiveness when switching from a brand name drug to a generic formulation. While these were technically anecdotes, the volume of the case reports suggested that there may be more to the story than just patient perception (as has been reported recently in a study where a higher-priced placebo medication exhibited effects superior to that of a low-priced placebo).

Together with the independent testing laboratory, ConsumerLab.com, the Graedons commissioned an analysis of the Wellbutrin XL brand name version of the antidepressant bupropion versus three generic versions of the active component. From the ConsumerLab.com report:

Analyses of all four products showed that each contained its claimed amount of bupropion hydrochloride. However, the rates at which the products released their ingredient were quite different, raising concerns about their equivalency. A second laboratory repeated the dissolution tests on all of the products. Results from the second lab confirmed the major differences found in the first lab which are described below.

I have not yet requested permission to post their graphic results but here are some of the details:

[T]he Teva product released much of its drug earlier than Wellbutrin. Wellbutrin (shown in blue) released ingredient into solution slowly over the first several hours of the dissolution test, with only 8% dissolved at two hours and 25% at four hours. In contrast, Teva’s pill released ingredient rapidly at first — delivering over four times as much drug as Wellbutrin in the first two hours (34% vs. 8%). Within the first four hours, nearly half the drug in the Teva product had gone into solution, almost twice as much as Wellbutrin. At eight hours into the test, results for Teva and Wellbutrin began to even out, with each about three-quarters dissolved. By the end of the test, both products had fully released their expected amounts of drug.

As noted earlier, the FDA has hidden from online viewing the specific dissolution requirements for generic forms of Wellbutrin XL. So it’s not clear if the above results for Teva meet the FDA’s requirements for bioequivalency.

Drugs like antidepressants must be kept at a minimum threshold blood concentration over a long period of time and Wellbutrin has been formulated to release its active ingredient over an extended time frame. The generic version released much more of its drug earlier – how this relates to effectiveness is not yet clear since the ConsumerLab study was not a clinical efficacy trial.

However, the disturbing statement in their report was that FDA did not make available “the specific dissolution requirements for generic forms of Wellbutrin XL.” In fact, this difference would not have been publicly released if not for the joint People’s Pharmacy/ConsumerLab testing. From the update on the ConsumerLab website:

The Director of the Office of Medical Policy of the FDA’s Center for Drug Evaluation and Research, Dr. Robert Temple, has acknowledged that TEVA Budeprion XL 300 releases drug at a different rate than the brand name Wellbutrin XL 300, consistent with ConsumerLab.com’s findings in this report. Dr. Temple’s remarks were made during a radio broadcast on Southern California Public Radio station KPCC on December 19, 2007. He noted that the FDA was aware that bioequivalence studies in people showed the once-a-day generic to release drug sooner than its brand-name counterpart but that the FDA “thought that that wouldn’t make any difference.” He admitted that the once-a-day generic “had an early release pattern that was a little closer to the original [three-times-a-day] product” than to once-a-day Wellbutrin XL. The FDA approved the once-a-day generic without mention of this difference, further clinical testing or special follow up.

Two weeks prior to Dr. Temple’s remarks, on December 1, 2007, the United States Pharmacopeia (USP) officially released information indicating that the dissolution of the Budeprion XL 300 varied significantly from the original drug. According to the USP, tablets of Wellbutrin XL release only a small amount (less than 20%) of drug during the first two hours of dissolution. In contrast, the Budeprion XL releases at least 25% and as much as 50% of its drug in that period. These USP dissolution standards are based upon performance characteristics that the FDA approved for the original and generic drugs, respectively, and were provided to USP by the manufacturers.

The new information from the FDA and USP corroborate ConsumerLab.com’s findings for the Budeprion XL 300 product in this report which show it to release four times as much drug as the original Wellbutrin XL 300 — 34% versus 8%, respectively — in the first two hours of a dissolution test. The Generic Pharmaceutical Association questioned ConsumerLab.com’s findings. It is now clear that ConsumerLab.com’s findings were consistent with differences well known to both the manufacturer and the government but not disclosed publicly. [emphasis mine]

Generic drugs have great promise for reducing health care costs but should not be forced upon patients by insurers and/or the government if the drugs are substandard. Hiding this information undermines the public’s confidence in these products. FDA clearly needs to invest in more staff and laboratory resources to assess and monitor generic drug formulations as their use is now often required by insurers.

Comments

  1. #1 MattXIV
    March 18, 2008

    Wow, that’s pretty bad, especially given that pharmakinetics matters a lot for buproprion since it has a short halflife and the extent it lowers the seizure threshold increases non-linearlly with dose and becomes significant at doses not that much higher that the recommended ones.

  2. #2 Elisa
    March 18, 2008

    I had a less-than-wonderful experience with the generic Wellbutrin XL, and it took ages to get my doctor to believe me. My insurance company never did, and I couldn’t afford anything once the insurance was gone. I filed complaints everywhere I could find and did eventually receive a call about it, but, given that my ADD was uncontrolled at that point, I never did call them back.

    I got so sick of hearing “but it’s the same thing!”.

  3. #3 Chris
    March 18, 2008

    My wife has to use a name brand prescription medication instead of a generic because the generic produces stronger side effects, but of course the insurance company doesn’t care. They reimburse at the generic cost. Not only that she is restricted to the amount of medication she can get at one time, about half of what the doctor prescribes. So he has prescribe the same drug more often.

  4. #4 Pete
    March 18, 2008

    Switching to the generic “equivalent” of Wellbutrin XL seriously messed me up for about a month and a half. I had no idea what was going on with me, either, until I read an article about the People’s Pharmacy tests and realized that my mood swings could indeed be the result of the drug releasing too quickly. Fortunately, my doctor didn’t argue with me when I asked to go back on the brand-name drug.

  5. #5 chezjake
    March 18, 2008

    I can see where achieving and maintaining effective blood/tissue levels of a drug should be part of FDA’s requirements for generics. That really should be part of demonstrating bioequivalency.

    However, let’s not lose sight of the fact that there are many generic drugs in use that work perfectly well and do help reduce drug costs significantly for many users.

    When was the last time anyone actually got the original brand name versions of penicillin G, any of the thiazide diuretics, or many other older drugs? They are basically only available as generics now, and are obviously still effective since they are still prescribed.

    Let’s not let one bad example of generic equivalency color our entire perception of generic drugs.

  6. #6 PalMD
    March 18, 2008

    This is bad. Really bad. I have always been an advocate for generic drugs, and at least 3 large retailers in my area offer large lists of generic meds for $4.00/month.

    While I’m not about to change my prescribing habits, this is a cause for great concern.

    It is certainly possible that bupropion is uniqued, though. It has three different release formulations, so I’m guessing it must not be real easy to develop delivery systems.

  7. #7 coracle
    March 18, 2008

    That’s interesting but does anyone know under what conditions the solubility was tested? I don’t know a lot about solubility testing for pharmaceutical products, but unless it was close to physiological, would the results mean anything?

  8. #8 DuWayne
    March 18, 2008

    I have noticed a significant difference in the effectiveness of the dimenhydrinate I take on occasion, depending on the manufacturer. Oddly, I have had a better experience with the Equate version, over that of Dramamine, though not a huge difference. I did take some that I could get at the dollar store a few times, which was a little more effective than a sugar pill.

    My old HIV pos roomie, has had allergic reactions to generics that were not carried over to the brand name version of the same drug. Apparently the drugs he reacted to, all use a similar filler. His doctor, aware of the issue, has to do a little researching, before he prescribes anything to Craig.

  9. #9 Abel Pharmboy
    March 18, 2008

    The comment by chezjake is very well taken. This is just one case where a drug’s effect is highly dependent upon its pharmacokinetics; there are others whose effectiveness can tolerate wiggle room. So, yes, this case is not an indictment of the entire generics industry. Rather, it is a call to the FDA and the industry for greater vigilance toward this large classification of drugs that can provide great benefits in the face of rising pharmaceutical costs.

  10. #10 a girl
    March 18, 2008

    What I don’t understand is why the XL version is even necessary. I never even considered it because I can’t afford brand-names and my doc said the generics were iffy. I use a generic SR version and it seems to work just fine. Not that this isn’t still important, but so many people say they HAD to go back to branded XL… is it really that bad to take SR 2 or 3 times a day?

  11. #11 Smith
    March 19, 2008

    My pharmacy switched me to to generic birth-control pills and I started spotting after years of no problems on the real thing. I didn’t get pregnant, so I suppose the generics were doing their job, but it was scary to think they might not be.

  12. #12 N.B.
    March 19, 2008

    It took me long enough, but I finally threw in my two cents on this issue. I actually intended to write something about the Wellbutrin issue like a month ago, maybe more. Your post gave me the push I needed to get off the ground!

  13. #13 Matt
    March 28, 2008

    Has anybody had a negative experience with generic drugs? Im looking to speak with a Minnesota patient who has been switched from a brand name drug to a generic and who could share their experience. If you are interested, please email me at mdepoint@tunheim.com.

  14. #14 Janine
    September 5, 2008

    Yes, I am one who has had not one, but a repeated problem with generic drugs. I have an incurable, painful, bladder condition known as IC. I have maintained a fairly good quality of life with pain management. One drug I took was Ativan (the generic from Watson Pharm, luckily I knew this). I was forced to switch drugstores, when my ‘mom and pop’ DS went out of business; that is when the CVS gave me a different generic. It simply was not effective. It controls bladder spasms, and I was having severe spasms. I talked with my dr and CVS finally gave in and ordered me the Watson brand. Ok, now another nightmare has just begun. I picked up my usual generic of Phenazopyridine (Pyridium) and saw it was NOT my usual. Ok, I complained again, but said I will give it a go. It was horrid! I felt they had given me the placebo. So, back to the pharmacy and they ordered another brand. This brand is just as bad if not worse; if I take two I can get by…it just seems to be very weak. This began two weeks ago and now I am in a full-fledged flairup. My bladder lining must be bright red from inflamation, because I can’t even leave my bathroom, for more than a few minutes. Believe it or not, the pharmacy is trying to order me a third generic to try. When all this began, I begged my dr to get a pre-approval for the brand-name drug and the papers have not yet been signed and sent off. That was two weeks ago. I am appalled.

    To the guy or gal in Minnesota, I would be glad to write to you. Let me know. I pretty much did share my experience here, but still I am left hanging and in great pain and distress.

    Is there anything the consumer can do?

  15. #15 norma pratt
    October 10, 2008

    I used prinivil which worked for my high blood pressure. now I have to take linispril a generic. however I have had to increase the dosage. It is made by Ivax which has been O.K however my insuranse has now put me on linispril made by Lupin. It does not work for me at all. My blood preasure is still high. I believe that this Lupin manufacturer is inferior.

  16. #16 Joe
    May 1, 2009

    Since the spammer brought this post back …

    I encourage the readers to investigate the Graedon’s website (linked above). They are credulous promoters of nonsense. They mix good and dubious advice indiscriminately. Anecdotes suffice for data to them.

    Check this out “Such [ganglion] cysts often disappear on their own, so “watch and wait” is the first choice for treatment.” Followed by “We did hear about an unusual treatment for ganglion cysts from a young woman who applied frankincense oil to hers. It disappeared.” (!?) http://www.peoplespharmacy.com/archives/herb_home_remedy_qa/frankincense_as_aid_for_cysts.php Hello … didn’t they just note that the cysts go away without treatment?

    They, also, heavily promote putting a bar of soap under the bedclothes to prevent restless legs. I guess they heard a lot of anecdotes about that.

  17. #17 Dr. Bio-Med Sciences
    February 14, 2010

    In examining the comments combined with my professional research and opinions, I can’t deny that there may be some issues with some generic meds, in some people. The comments sound like it seems to have casued a slight paranoia concerning the entire generic medication market. I’d like to point out that only a small percentage of generics have had any issues and, in that, has only affected a very small percentage of patients. I’m a pharmaceutical scientist and, as a patient myself, I use generics on all 8 meds that I take everyday with no problems. After serveral years of taking them, I can tell a difference in the meds among the different generic manufacturers and have my pharmacist order the kind I prefer. Interestingly, I prefer a certain med made by Actavis, whereas I DO NOT prefer ANY of my other meds to come from Actavis. Bottom line… the vairables – each med, med manufacturer, and individual are inevitabley going to cause a different reaction within each set of variables.

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