[PHNUTR-L] Wellbutrin: Generic Drug May Not Equal Original

[Kathrynne Holden]

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Drug Tests: Wellbutrin vs. Generic Bupropion
Initial Posting: 10/12/07
http://www.consumerlab.com/results/wellbutrin-bupropion.asp?

Concerns about Generic Wellbutrin:
Background:

Generic drugs can make prescription medication much more affordable. But 
in early 2007, ConsumerLab.com became aware of reports by consumers 
experiencing problems when switching from Wellbutrin to its generic form 
(bupropion HCl). Wellbutrin is among the most popular anti-depressants. 
U.S. sales in 2006 were in excess of $1.8 billion according to Wolters 
Kluwer Health. The majority of these sales were of the XL (once-a-day) 
300 mg product. Most consumer complaints were about a generic version of 
the XL 300 mg product launched in December 2006 as Budeprion XL 300 mg 
by Teva Pharmaceutical Industries.

Consumer Complaints:
Early this year, The People's Pharmacy, a syndicated radio program and 
newspaper column, began collecting and reporting consumer complaints 
about generic Wellbutrin, many of which can be viewed on its website at 
www.peoplespharmacy.org. The personal accounts generally indicated that 
while taking the brand name Wellbutrin XL 300 for months or years, 
people felt well and their psychological symptoms of depression were 
successfully controlled. After switching to the generic formulation, 
Budeprion XL 300, many reported symptoms such as headaches, 
irritability, nausea and insomnia — known side-effects of bupropion. 
Others shared stories of becoming easily upset or aggressive, crying, 
gaining weight or experiencing a return of depressive symptoms. Some 
reported thoughts of suicide while taking the generic form of 
Wellbutrin. A large number of accounts note that returning to the 
original product brought symptoms under control. These reports prompted 
ConsumerLab.com to investigate whether extended-release (XL) and 
sustained-released (SR) bupropion generics were truly equivalent to 
original Wellbutrin and to each other.

Different Pills — But Called Equivalent:
The active ingredient in Wellbutrin is off-patent while the method for 
delivering it in time-released tablets is still patent protected. As a 
result, companies wishing to market their own time-released bupropion 
generics have had to use or develop types of tablets different from 
those sold as Wellbutrin XL or SR or obtain a license from the 
originator. In fact, as of September 2007, many of the time-released 
generics of Wellbutrin on the market used different tablet technologies.

Different types of tablets can release active ingredient at different 
rates. This can affect a drug's performance. But the safety and efficacy 
of generic drugs, unlike original drugs, is not clinically tested. 
Instead, the FDA relies on data from each manufacturer showing that 
their generic contains the same ingredient as the original, dissolves at 
approximately the same rate, and appears in people's blood at about the 
same levels as with the original product. If the results are within the 
FDA's limits, the generic is deemed "bioequivalent" to the original drug 
and can be approved for sale.

However, reviewing the FDA's test requirements, ConsumerLab.com found 
that generic products are allowed to vary from one another by a fairly 
wide range. For example, a twice-a-day (SR) version of bupropion is 
permitted to release anywhere from 60% to 85% of its ingredient after 
four hours into a dissolution test. At the completion of such a test 
(which only runs eight hours), a product could be as little as 80% 
dissolved or over 100% dissolved and still be considered bioequivalent. 
ConsumerLab also discovered that the acceptable limits for once-a-day 
(XL) versions have been blacked-out or deleted in documents on the FDA 
website.

For a list of other popular time-released generic drugs, see Extended 
Release Generics — Are They the Same as the Original?

Potential for Side-Effects:
A particular concern with Wellbutrin has been the potential for 
side-effects, including seizures if a high dose is provided too quickly. 
For this reason, instructions for Wellbutrin SR 150 mg (twice-a-day) 
state that doses should be given at least eight hours apart. It is, 
therefore, important that any version of bupropion release ingredient 
slowly enough to avoid delivering a large amount too quickly.

How the Products Were Tested:
ConsumerLab.com purchased the original Wellbutrin XL 300 mg product sold 
by GlaxoSmithKline as well as generic Budeprion XL 300 mg sold by Teva 
Pharmaceuticals. ConsumerLab.com also purchased two generic bupropion SR 
products. One, a SR 150 mg product from Watson Pharmaceuticals, is 
actually supplied to Watson by GlaxoSmithKline, the maker of Wellbutrin 
SR, and, aside from markings on the pills, is identical to 150 mg 
Wellbutrin SR. The other SR product was a 200 mg SR bupropion 
distributed by Global Pharmaceuticals that uses a different tablet 
technology.

All products were first tested to establish that they contained the 
correct amount of bupropion hydrochloride. The tablets then underwent 
dissolution testing — to determine the rates at which the tablets 
released active ingredient over specific periods of time. Dissolution 
testing of the XL products followed the method specified by the FDA in 
its approval of both Wellbutrin XL and the generic version sold by Teva. 
The two SR products were tested using a method developed by the United 
States Pharmacopeia (USP) specifically for SR products. See How Products 
Were Evaluated for more information about the testing.

What ConsumerLab.com Found:
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.

XL (Once-a-Day) Versions:

     * Wellbutrin XL 300 mg
     * Teva Budeprion XL 300 mg (Generic Bupropion)


Even before testing began, it was clear that these two products were not 
alike. Teva's XL 300 mg is a much larger pill than Wellbutrin XL 300 mg 
and found to weigh three times as much. These differences are due to the 
fact that these products use very different drug delivery technology. 
The Teva pill, made by IMPAX Laboratories, uses a matrix of materials 
that expands when wet and then breaks apart to release the ingredient. 
Wellbutrin XL, made by Biovail Corporation for GlaxoSmithKline, consists 
of a membrane through which the ingredient is slowly released while the 
membrane stays intact.


As seen in the graph above, the 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.

What This Could Mean to You:
Consumer complaints about Teva Budeprion XL 300 mg suggest that, at 
least for some people, it acts differently than the original. And it is 
clear that the two products behaved differently in the dissolution test. 
Do the test differences explain the reported problems? It's difficult to 
know. By dissolving more rapidly than Wellbutrin within the first few 
hours, it is possible that blood levels of the generic drug might at 
first rise higher than with Wellbutrin, potentially increasing the risk 
of side-effects. As much of this early burst of drug is eliminated over 
the rest of the day, the amount of drug in the blood might then fall 
lower than with Wellbutrin, potentially making the Teva product 
relatively less effective later on.

SR (Twice-a-Day) Versions:

     * Global Generic Bupropion SR 200 mg
     * Watson Generic Bupropion SR 150 mg


These two SR (twice-a-day) products were compared because, even though 
their strengths are slightly different (200 mg vs. 150 mg), they should 
release their ingredients at approximately the same rate. However, like 
the XL products, these two SR (twice-a-day) products are made with 
different tablet technologies from different companies. The Watson 
generic product is actually identical to Wellbutrin SR 150 mg. It is 
supplied by GlaxoSmithKline to Watson to sell as an "authorized 
generic." It is made with tablet technology from Biovail Corporation, 
like Wellbutrin SR. Global Pharmaceutical's SR 200 mg, however, is made 
with different technology and is manufactured by IMPAX Laboratories. 
(IMPAX is the same company that makes Teva's 300 mg XL product described 
above.)


As shown in the graph above, the Global SR 200 mg yielded a smaller 
percentage of its claimed amount of bupropion than the Watson SR 150 mg 
product at every point in time. In fact, at two hours, Watson released 
65% of its ingredient, while Global released only 45%. At four and six 
hours, Watson also released more of its ingredient — eighteen percentage 
points more. At eight hours, Watson had released 102% of its expected 
ingredient versus only 90% for Global.

The test results for both SR products fall within the FDA's acceptable 
range established by the United States Pharmacopeia (USP) (see How 
Products Were Evaluated for more information). However, Watson was near 
the upper limits for dissolution while Global was close to the lower 
limits. The Watson SR provided more of its total ingredient and released 
it faster.

What This Could Mean to You:
To date, ConsumerLab.com is not aware of consumer complaints about the 
Global SR product. But differences between it and the Watson product 
should be kept in mind.

Watson's bupropion SR products (which include the 150 mg tested, as well 
as 100 mg and 200 mg tablets) are supplied to it by GlaxoSmithKline and 
should, therefore, be identical to the corresponding Wellbutrin SR 
products. These SR products are all made with technology from Biovail 
Corporation and it is likely that they dissolve in a manner similar to 
one another.

Since the Global SR 200 mg product released less of its active 
ingredient than the Watson product during the eight hour dissolution 
test, it is possible that the Global SR 200 mg may also provide somewhat 
less drug if tested against Watson's SR 200 mg or Wellbutrin SR 200 mg, 
potentially making it less potent early on. It is also possible, 
however, that the Global product eventually releases the same amount of 
ingredient as these drugs, just taking a little longer, which could 
actually sustain its effectiveness later in the day.

Summary of Wellbutrin/Bupropion Tablet Dissolution Tests:
Drug Name (Original or Generic)

Distributor
	
Type and Strength
	
Different from Original?

Manufacturer
	
Test Results
	
What This Could Mean to You!
XL (Once-a-Day):
Wellbutrin
(Original)

GlaxoSmithKline 	
XL 300 mg
	Original.

Mfd. by Biovail Corporation for GlaxoSmithKline. 	Releases slowly during 
first few hours; more rapidly between 4 and 8 hours; slowing thereafter.
	The original product.
Budeprion
(Branded Generic)

TEVA Pharmaceuticals 	
XL 300 mg
	Different type of pill and delivery technology. Pill is three times 
heavier than original.

Mfd. by IMPAX Laboratories. 	Releases rapidly in first few hours, but 
less over rest of time period.
	Rapid initial release of drug may increase risk of side-effects; a 
lower level later in day might provide a less effective level of drug. 
Consumer complaints reported.
SR (Twice-a-Day):
Bupropion
(Generic)

GLOBAL Pharmaceuticals (a Division of IMPAX Laboratories) 	
SR 200 mg
	Different type of pill and delivery technology.

Mfd. by IMPAX Laboratories. 	Releases slightly lower percentage of its 
drug than other SR product during eight-hour test.
	Meets FDA requirement. May release slightly less ingredient initially, 
but no problems known to be reported.
Bupropion
(Generic)

Watson Laboratories 	
SR 150 mg
	Same as Wellbutrin 150 SR— but sold as an "authorized generic."

Mfd. by Penn Labs, Inc., a GlaxoSmithKline company, or DSM 
Pharmaceuticals. 	Releases full amount of ingredient over time.
	Same as original product. Releases full amount of ingredient.
Note:
These tests were performed on products purchased in May 2007 and may not 
reflect products currently on the market.


A Look at Other FDA Approved Bupropion Generics:
Additional bupropion products have been approved by the FDA and many are 
on the market. However, they are not necessarily identical to the 
comparable version of Wellbutrin — often differing in their tablet 
technology (i.e., the way in which drug is released). Be aware that the 
generic market is fast-changing: Products and their availability may 
change. Brands carried will also vary by pharmacy.

Other Generic Buproprion Hydrochloride Products (Not Tested by 
ConsumerLab.com)
Drug and Distributor
	
Type and Strength
	
Different from Original?

Manufacturer
	
What This Could Mean to You!
XL (Once-a-Day):
Bupropion

Anchen Pharmaceuticals 	
XL 300 mg
(Launched mid-2007)
	Different type of pill and delivery technology.

Mfd. by Anchen Pharmaceuticals 	Not identical to Wellbutrin or other 
generic versions. Some difference in performance possible.
Bupropion

Watson Laboratories 	
XL 300 mg
(Launched June 2007)
	Different type of pill and delivery technology

Mfd. by Andrx Corporation, a division of Watson Pharmaceuticals. 	Not 
identical to Wellbutrin or other generic versions. Some difference in 
performance possible.
Budeprion
(Branded Generic)

TEVA Pharmaceuticals 	
XL 150 mg
Expected to be launched in early 2008 or slightly before
	Different type of pill and delivery technology

Mfd. by Anchen Pharmaceuticals. 	Not identical to Wellbutrin or other 
generic versions. Some difference in performance possible.

Later in 2008, Teva may continue to market this product or market a 
different 150 mg XL made by IMPAX (see entry below)
Budeprion
(Branded Generic)

GLOBAL Pharmaceuticals or TEVA Pharmaceuticals 	
XL 150 mg
Expected to be launched in mid-2008 by either GLOBAL or TEVA.
	Different type of pill and delivery technology

Mfd. by IMPAX Laboratories.

(May be similar to the TEVA 300 XL tested in this report.) 	If similar 
to Teva's 300 mg tested in this report, may release differently than 
original.
SR (Twice-a-Day):
Bupropion

Sandoz 	
200 mg SR
	Different type of pill and delivery technology.

Mfd. by Sandoz 	Not identical to Wellbutrin or other generic versions. 
Some difference in performance possible.
Bupropion

Watson Laboratories 	
200 mg SR
	Same as Wellbutrin 200 SR — but sold as an "authorized generic."

Mfd. by division of GlaxoSmithKline. 	Same as original product.
Bupropion

TEVA Pharmaceuticals 	
150 mg SR
	Different type of pill and delivery technology.

Mfd. by IMPAX Laboratories. 	Not identical to Wellbutrin or other 
generic versions. Some difference in performance possible.
Bupropion

Watson Laboratories 	
150 mg SR
	Same as Wellbutrin 150 SR — but sold as an "authorized generic."

Mfd. by division of GlaxoSmithKline 	Same as original product.
Bupropion
(Generic)

Sandoz 	
100 mg SR
	Different type of pill and delivery technology.

Mfd. by Sandoz 	Not identical to Wellbutrin or other generic versions. 
Some difference in performance possible.
Budeprion
(Branded Generic)

TEVA Pharmaceuticals 	
100 mg SR
	Different type of pill and delivery technology.

Mfd. by IMPAX Laboratories. 	Not identical to Wellbutrin or other 
generic versions. Some difference in performance possible.
Bupropion

Watson Laboratories 	
100 mg SR
	Same as Wellbutrin 100 SR— but sold as an "authorized generic."

Mfd. by a division of GlaxoSmithKline. 	Same as original product.
Immediate release tablets: The original 3 times-a-day version of generic 
bupropion is available in 75 mg and 100 mg strengths. The FDA has 
approved such products from Teva, Mylan, Sandoz and Apotex. Because 
immediate release tablets do not normally involve specialized drug 
delivery technololgy, these products are likely to behave similarly — 
although pills may vary in design.


Strategies for Getting the Right Drug:

Request Generics by Name: If your current generic version is working but 
others have not, make note of the distributor and the manufacturer on 
the label and try to stick with that exact product. Ask your pharmacist 
to fill your prescriptions with that specific version. Call around if 
you need to — different pharmacies often carry different generic brands. 
Be aware though that occasionally a generic brand may change its product 
due to new licensing or manufacturing arrangements.

If you find that a generic version of Wellbutrin is not working, 
consider the following:

     * Dispense as Written: Have your doctor prescribe the brand-name 
version and indicate "Dispense as Written" or "Do Not Substitute." If 
your insurance will not cover it, ask your doctor to make a special 
request from your insurance company.
     * If your insurance still won't cover the original, you have other 
options:
           o Try a Different Generic: See if there is a different 
generic equivalent — preferably one made by the same company that makes 
the original drug, as this is likely to be identical to the original. 
(See Other Generic Bupropion Products above)
           o Get the Original at Low Cost: Pay out of pocket for the 
original, but try to save money by purchasing the drug from a discount 
pharmacy or a licensed Canadian or other non-US pharmacy. You can often 
save 50% or more over U.S. retail pharmacy prices. A three-month supply 
(90 tablets) of Wellbutrin XL 300 mg, for example, costs about $550 from 
a U.S. chain drug store but can be found for under $125 outside the U.S. 
— a 78% savings. A good place to compare low prices from licensed 
pharmacies is www.PharmacyChecker.com, a site started by ConsumerLab.com 
in 2002.
     * Switch Versions: Consider a different version of the drug. If a 
once-a-day generic is not working, consider a twice-a-day (SR) or 
three-times-a-day version that will yield the same total daily dose. You 
will have to remember to take the medication on schedule.
-- 
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
"Ask the Parkinson Dietitian"  http://www.parkinson.org/
"Eat well, stay well with Parkinson's disease"
"Parkinson's disease: Guidelines for Medical Nutrition Therapy"
http://www.nutritionucanlivewith.com/