[Ip-health] WSJ: Inexact Copies: How Generics Differ From Brand Names

[Matt Price]

Inexact Copies: How Generics
Differ From Brand Names
April 22, 2008; Page D1

http://online.wsj.com/article_print/SB120882069010332969.html

Joe Zealberg, a psychiatrist in Charleston, S.C., prescribed generic
drugs to patients for years and rarely had problems -- until last
year. A number of patients who had done very well on brand-name
medications "crashed and burned" when they switched to generics, he
says.

One woman "went from being perfectly fine to crying inconsolably 24
hours a day" after she switched from one generic antidepressant to
another, Dr. Zealberg says. Another patient was sold a generic version
of his attention-deficit drug that contained no identifying markings
whatsoever -- a violation of federal rules.

Ten of his patients switched to a new generic version of the
antidepressant Wellbutrin, but eight of them changed back, saying they
felt anxious or shaky or their depression had returned. Several
complained that the generic drug had a bad smell, he says.

Generic medications have been a boon to consumers around the world,
allowing millions to buy lifesaving drugs for pennies a day. Some 65%
of all prescriptions dispensed in the U.S. are for generics, though
they account for only 20% of the dollars spent, according to the
Generic Pharmaceutical Association.

While there is no hard evidence of growing problems from generics,
consumers and physicians are increasingly concerned as cost pressures
push more patients away from brand-name drugs. At the same time, the
globalization of pharmaceutical manufacturing has revealed regulatory
lapses.

By law, generics must have the same active ingredient and the same
action as the brand-name version, which allows them to piggyback on
the original safety and efficacy trials. But generics do have
different inactive ingredients, which can affect how they are absorbed
into the body. Generics can produce blood levels as much as 20% below
or 25% above that of the original drug and still be considered
"bioequivalent," according to Food and Drug Administration guidelines.

Some patients are more sensitive to those differences than others, and
people who experience problems with medications are advised to contact
their doctors, the drug manufacturer and the FDA's MedWatch. But as an
FDA report last week on generic Wellbutrin revealed, consumers who
complain may not get much satisfaction.
Many patients switched from Wellbutrin XL 300 mg to Teva's Budeprion
(right); a few have gone back.

Wellbutrin, made by Biovail Corp. of Canada and marketed by
GlaxoSmithKline PLC, is one of the best-selling antidepressants in the
U.S., with sales of $1.8 billion in 2006. The FDA approved a generic
version of Wellbutrin XL 300, a long-acting once-daily version, in
December 2006. The generic, named Budeprion XL 300, soon accounted for
roughly 40% of the one million monthly prescriptions for the
antidepressant.

But patients soon started logging complaints about Budeprion at
PeoplesPharmacy.com, a Web site that has become a clearinghouse for
medication gripes. "We've received hundreds of complaints about
generic drugs in general. But with this one drug, all of a sudden --
kaboom -- right after it was approved," says Joe Graedon, a
pharmacologist who runs People's Pharmacy with his wife. Readers'
postings cite side effects such as tremors, headaches, anxiety and
sleep disturbances. Some consumers said their depression had returned,
in some cases bringing thoughts of suicide. Many reported that their
adverse effects stopped when they returned to the brand-name drug.

Mr. Graedon alerted the FDA. He also asked ConsumerLab.com, which
normally runs tests for dietary supplement manufacturers, to compare
Budeprion and Wellbutrin. Using a test-tube test that some industry
experts question, ConsumerLab found that Budeprion dissolves faster,
releasing 34% of the drug within the first two hours, compared with 8%
for Wellbutrin.

"If you get four times the drug in the first two hours, that's too
much drug in the beginning and not enough for the rest of the day,"
says Mr. Graedon, who worries that what he calls "dose dumping" could
cause seizures, a concern with the brand-name drug as well.

Complaints about Budeprion also were coming into the FDA -- at least
130 from December 2006 to January 2008, according to Andy Georgiades
of Dow Jones News Service, who filed a Freedom of Information Act
request. Only four complaints were filed about two rival generic
versions of Wellbutrin XL 300 that went on the market in June 2007.

FDA Investigates

The FDA conducted an investigation and reported last week that
although there were "small differences" between the two formulations,
"they are not outside the established boundaries for equivalence." The
generic did reach its maximum blood concentration in two to three
hours, compared to five to six hours for Wellbutrin, but the FDA said
those differences "were not considered clinically significant."

What accounted for the consumer complaints? The FDA cited "the natural
history of depression," in which some patients have a recurrence of
symptoms even while on medication.

Alarm Bells
HOW TO REPORT DRUG PROBLEMS
=95 If you have a bad reaction to a drug or concerns about quality, your
first stop should be your doctor, who can file a medical report with
the FDA.
=95 You can also submit a consumer report to the FDA's MedWatch program
at www.fda.gov/MedWatch3. You will be asked to describe the
medication, the adverse event and some brief medical history. Your
identity isn't requested. If you supply an email address, you will
receive confirmation that your report was received. You can also speak
to an FDA representative at 1-888-INFO-FDA .
=95 Contact the manufacturer or distributor. The FDA requires
prescription and over-the-counter drugs to list contact information on
the packaging.
=95 Return the medication to the pharmacist; use one you know and trust.
=95 www.PeoplesPharmacy.com4 also logs complaints about generic drugs,
but these aren't counted as official FDA adverse-event reports.

Some critics say the FDA, in effect, was saying, "it's all in their
heads." But they were more alarmed to read in the report that the FDA
relied on tests comparing a lower dose of Wellbutrin and Budeprion --
150 mg -- when it first approved the 300 mg version in 2006, and
didn't have specific bioequivalence data on the 300 mg dose that had
generated the complaints.

"Everybody involved in this whole chain -- pharmacists, physicians,
insurance companies, drug-store buyers -- assumes the FDA approves
every single generic formulation to prove that it isn't harmful," says
Mr. Graedon. "We learned last week that that's not the case."

The FDA explained that it didn't want to expose test subjects to the
risk of seizures with the 300 mg dose. Bioequivalence tests are
conducted on healthy people, not those who need the medication, and
each gets just a single dose, so there is no chance to work up to 300
mg slowly, as actual patients are advised to do. Sandy Walsh, an FDA
spokeswoman, says this is common procedure for testing antidepressants
and antipsychotics.

"If we see scientific evidence that a product is not performing as
expected, we will take action," Ms. Walsh says. "The FDA cannot offer
examples where generics have not performed as expected because there
have been none for the agency to report."

Bioequivalent

Deborah Jaskot, vice president for regulatory affairs at Teva
Pharmaceuticals USA, which distributes Budeprion, says the ConsumerLab
dissolution test was an invalid comparison, and that on all the
accepted tests, Budeprion performed within the range of bioequivalence
with Wellbutrin. Teva itself has received 101 reports of problems with
Budeprion -- out of 4.5 million prescriptions written -- and hasn't
heard reports of unusual smells, a spokeswoman says.

Ms. Jaskot also says Web sites that collect complaints about drugs
"are doing the public a disservice." If consumers have problems with
their medications they should "tell their physician, tell the
manufacturer, tell the pharmacists, tell the FDA -- that's the only
way these can get acted on and evaluated for veracity," she says.

But what if you complain to the FDA and are told, in effect, that your
concerns are insignificant? As with so many other areas in health
care, consumers have to be their own regulator and their own chief
advocate.

"Consumers need to know that there are variations between generic
drugs and brand-name drugs, and from one generic drug to another,"
says Wayne Pines, a former FDA spokesman who now consults for drug
companies. "This is an area in which the patient has to be really
self-protective, to be sure that they are getting the therapeutic
effect that is best for them."

If you are taking a medication for a long-term condition, Mr. Pines
advises staying with the version you are stabilized on. Some
pharmacies sell generic versions interchangeably; tell your pharmacist
you want to stay with the same one.

Monitor Symptoms

If you need to switch to a generic from a brand name for cost reasons,
monitor your symptoms and review them with your doctor. Assess whether
it's worth it to you to pay more. (There are some medications,
particularly for thyroid and blood conditions, in which substitutions
are never advised.)

The Graedons also recommend asking for copies of your lab reports, so
you can help your doctor monitor any changes in your condition.

Be alert to changes in smell or appearance of your medications. Tell
your doctor, pharmacist and the manufacturer if you notice anything
odd.

Dr. Zealberg, however, is still waiting to hear back from the pharmacy
that sold his patient blank pills.

Write to Melinda Beck at HealthJournal@wsj.com5
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   Hyperlinks in this Article:
 (1) http://forums.wsj.com/viewtopic.php? t=3D2229
(2) http://forums.wsj.com/viewtopic.php? t=3D2229
(3) http://www.fda.gov/MedWatch
(4) http://www.PeoplesPharmacy.com
(5) mailto:HealthJournal@wsj.com
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