For seven years Linda Douglas has been treating her depression with the antidepressant Wellbutrin, first with a twice-a-day version and then later with a more convenient once-a-day pill called Wellbutrin XL. The drug, she says, "renewed my joy for living."
All that changed earlier this year when she switched to a generic version of Wellbutrin XL 300 milligrams to save money. Instead of paying $250 for a three-month supply of the brand drug, she was paying just $53. The cost savings were welcome, but Douglas, 48, a telecommunications project manager in Columbia, Md., says the depression returned during the six months she took the generic antidepressant.
"I was questioning, did I take my medication today? Something's not right," she remembers. Occasionally she'd experience symptoms of a panic attack, or worse. "The suicidal thoughts came back," she says. At that point, Douglas started to suspect there was something wrong with her medication, and in August asked her doctor to switch her back to the brand-name version. She says she felt better within days.
New test findings by ConsumerLab.com that were released to MSNBC.com showed that one of a few generic versions of Wellbutrin XL 300 mg, sold as Budeprion XL 300 mg, didn't perform the same as the brand-name pill in the lab. The results offer a possible explanation for the experience of Douglas and reportedly hundreds of other people who wrote to a syndicated newspaper column called The People's Pharmacy with related complaints, says Dr. Tod Cooperman, president of ConsumerLab.com, a Westchester, N.Y.-based provider of independent evaluations of health and nutrition products.
Though experts agree the majority of generic drugs perform the same as their pricier brands, some say the results raise questions about whether that is always the case.
"When we saw the results we were shocked," says Cooperman.
Marc Goshko, executive director of legal affairs at Teva Pharmaceutical Industries, which sells Budeprion XL 300 mg, says the drug met all requirements of the Food and Drug Administration, including showing that the drug performed similarly to the brand in the lab and also was released into the bloodstream of healthy volunteers at the same rate. He did not cite specifics of that research.
In an e-mail response, FDA spokesperson Sandy Walsh said, "We are investigating the complaints regarding generic Wellbutrin, but cannot offer specifics at this time."
The FDA does not require generic drugmakers seeking approval to do clinical trials of their drugs on hundreds or thousands of people as is required for brand drugs. Instead, the agency requires lab data and "bioequivalence" testing in about 24 to 36 healthy volunteers showing that the drug appears in the bloodstream in a similar manner to the brand, says Walsh.
Dr. Sidney Weissman, a member of the board of trustees of the American Psychiatric Association and a professor of psychiatry at Northwestern University in Chicago, says that while he hasn't heard complaints about generic Wellbutrin XL himself, the findings are cause for additional investigation. "Is the FDA method for approving these different methodologies adequate?" he says.
"I, for one, am concerned," Weissman adds. "This raises questions for me on the reliability of FDA testing for these types of drugs."
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ConsumerLab.com began investigating after Joe and Terry Graedon, authors of The People's Pharmacy column, approached them with the consumer complaints. "In almost all cases people were saying their depression returned," says Joe Graedon, a pharmacologist. While the Graedons had received complaints from readers about generic drugs before, "we had never received this volume of response," he says.
For the testing, ConsumerLab.com purchased both the original Wellbutrin XL 300 mg sold by GlaxoSmithKline and the generic version sold by Teva, the same one that Douglas took and that many other readers complained about, and had six samples of each drug analyzed. While both drugs contained the stated amount of the active ingredient, bupropion, "dissolution testing" showed that the generic drug, which has a different time-release mechanism, released the active ingredient into a solution at a quicker rate.
"The Teva product released nearly half of its ingredients in the first four hours," says Cooperman. "The original Wellbutrin released 25 percent."
Within the first two hours, 8 percent of the original Wellbutrin had dissolved, compared with 34 percent of the Teva product, according to Cooperman. By 16 hours, both drugs had released all the medicine.
If the active ingredient is released more quickly into a patient's bloodstream, that could mean there is less medication available to the patient later, which may explain why people like Douglas experienced a return of their depression, Cooperman says. It also may explain why some readers who wrote in complained of more side effects, such as headache, irritability and nausea, given they may have received a higher dosage of the medicine upfront, he says. "Too much Wellbutrin can cause side effects, even the potential for seizure," he says.
Andrea Hofelich, a spokesperson for the Generic Pharmaceutical Association in Arlington, Va., called into question the validity of the ConsumerLab.com findings, saying the company's testing was "inadequate" compared to what the FDA requires for a generic drug to hit the market.
"The FDA is the world's gold standard for reviewing brand and generic medicines," she says.
Teva's Goshko also took issue with ConsumerLab.com's conclusions: "How the product dissolves in you is really the correct question here, not how it dissolves in a test tube."
But Mark Boesen, a pharmacist in Phoenix and a spokesperson for the American Pharmacists Association, says the findings offer "a reason for pause." Since the research was only done in the lab, not in real patients, the findings aren't conclusive, he says. Still, "the combination of anecdotal evidence and the conclusions of the in vitro study would lead one to believe that patients might receive a different therapeutic outcome from the two medications."
ConsumerLab.com also tested two generic versions of a twice-a-day Wellbutrin SR and found that variations were within FDA limits of acceptability.
Cooperman says he could not determine what the FDA variation limits are for the once-a-day extended release products. "We haven't seen anything published stating what's acceptable," he says. The FDA declined to comment specifically on the ConsumerLab.com report.
But given that the generic drug was approved by the FDA, "it appears that they are giving a lot of leeway in how the drugs are released," Cooperman says. "It would seem very difficult to imagine that the results we saw would be acceptable results."
The FDA's Walsh says the agency "cannot offer any examples where generics have been shown to not perform as expected" and that "health professionals and consumers can be assured that FDA-approved generic drugs have met the same rigid standards as the pioneer (brand name) drug."
Call for monitoring
But as the FDA plans to speed up approval of generic drugs , Cooperman and Graedon say they're concerned about safety. Graedon says the FDA should do more monitoring of generic drugs once they hit the market and are taken by thousands of people.
Other experts interviewed for this story say that in the majority of cases, switching from a brand drug to a generic poses no problem and offers an important cost savings. But some have concerns about certain medications, especially those used to treat heart conditions and epilepsy, where being properly medicated is critical.
While generics are required to have the same active ingredients as the brand drugs, the FDA allows for some variability in the amount of the active drug. Usually that variability is no big deal, says Boesen. However, "there is a small number of medications that we do worry about switching back and forth," he says.
Doctors and pharmacists refer to these drugs as having a "narrow therapeutic index." Translation: "If you get too much you can get sick. If you get too little you don't get any benefit," says Boesen.
Heart specialist Dr. Peter Kowey, a professor of medicine and clinical pharmacology at Jefferson Medical College in Philadelphia, says cardiologists are well aware that some patients don't do well when, for instance, they go from the blood-thinner Coumadin to the generic warfarin or from the arrhythmia drug Cordarone to the generic amiodarone. Likewise, though, patients may have trouble when they go from the generic to the brand drug, he says.
"But there has been precious little research done on this," says Kowey, who says he tried unsuccessfully to get government and pharmaceutical funding for a study that would compare brand and generic versions of amiodarone. "Nobody wanted to do the study."
Cardiologists worry about certain drugs where "relatively small changes in [blood] concentrations can have dire effects," Kowey says. Not being properly treated with blood-thinners can lead to dangerous blood clots, for instance, while not controlling irregular heartbeats could lead to cardiac arrest.
'Hesitant to rock the boat'
Some doctors also are concerned about anti-seizure drugs, such as phenytoin (brand name Dilantin), carbamazepine (brand name Tegretol) and gabapentin (brand name Neurontin), which are used to treat people with epilepsy.
While the brand drugs and their various generics are "probably reasonably equivalent," small differences may add up to bigger problems in patients with such a serious condition, says Dr. Michel Berg, an associate professor of neurology at the University of Rochester Medical Center in New York.
"If somebody has achieved a seizure-free state, which is our goal, I am very hesitant to rock the boat," he says. And that goes for switching patients from a generic drug they are doing well on to the brand-name version.
Berg says he is trying to get funding to do a scientific study exploring whether patients respond differently to brand and generic anti-seizure drugs.
Other drugs with a narrow therapeutic index include thyroid replacement medications and lithium, used to treat bipolar disorder, Boesen notes.
Hofelich, of the Generic Pharmaceutical Association, says the FDA does "rigorous" testing of generics to show they are the same as the brand drugs. She says the anecdotal reports of people experiencing differences when they switch from a brand to a generic may be the result of the patient simply being "more aware of how your body is feeling and acting because you're thinking more about it."
Dr. Sidney Wolfe, director of the Health Research Group at Public Citizen, a consumer advocacy organization in Washington, D.C., also says that FDA testing of generics is sufficient to show they work the same as costlier brand drugs.
"I do not have concerns about generic drugs other than why more people aren't using them," he says.
Meanwhile, Joe Graedon says readers of his People's Pharmacy column also have written in with complaints about other generics, including those for treating ADHD, diabetes, blood pressure and severe pain.
But without more research, it's impossible to know if any of these complaints are truly valid, experts say.
That's why they advise patients to carefully monitor how they're feeling while on medication and to immediately report any issues to their doctor. And before ever taking a medicine, be sure to ask the doctor and pharmacist if switching to a generic poses any safety concerns.
"Ninety-eight percent of the time the answer is going to be 'no,'" Boesen says. "The only difference will be the price."
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