Are Generic Drugs Safe?

These money-saving alternatives may not always be as effective as brand names, according to an alarming new study. Prevention's exclusive, must-read report will give you all the facts you need to protect your health.

Read our exclusive interview with Tod Cooperman, MD, founder of, and learn how to take generic drugs safely.

Antidepressants have helped Holly Smith-West weather some very rough times. When she was diagnosed with hepatitis C, they kept her going during her chemotherapy regimen. Then they helped her cope with the death of her husband, who had type 1 diabetes and died on Christmas Eve 2003, while awaiting a kidney transplant. With Wellbutrin, she says, "I found joy again." That is, until early last year, when Medicare required her to switch to Budeprion, a generic form of the drug.

"I slowly felt my depression start to return," says Smith-West, 54. "I would get up in the morning and think, I have a whole day ahead of me of things I can't deal with. I didn't want to die. I just didn't want to be alive the way I was."

Smith-West had no idea why her medication suddenly stopped relieving her symptoms. But one evening, she was talking to her sister, who took Wellbutrin to manage the symptoms of chronic fatigue syndrome. Her prescription, too, had been changed to Budeprion--and her CFS symptoms had started to return.

That night, Smith-West went online. With a few clicks, she found the People's Pharmacy Web site and read dozens of postings from others who'd had problems with a generic form of Wellbutrin. "They all sounded just like me!" she says. "I called my doctor and went back on Wellbutrin--and I started to feel better right away."

For years, insurance companies have been working hard to get people to switch to generics. Medicare, too, has been coaxing its clients toward these cheaper drugs. And those efforts are succeeding: Americans fill 1 billion prescriptions for generics yearly and count on them to work as well as brand-name medications. But at the People's Pharmacy, we've worried about generics for years now. At our Web site, we've heard from hundreds of people who've had difficulties with some of these substitutes. They've told us, for example, that their normally manageable blood pressure spiked when they switched to a generic drug, or that the pain of bone cancer was made bearable by a prescription painkiller--but became excruciating when they had to rely on a generic. Or that their depression returned with a vengeance when they were moved to a generic antidepressant--as Smith-West experienced.

Reports like hers concerned us so much that last summer we approached, an independent company that since its founding in 1999 has tested more than 2,000 products, such as herbal supplements, vitamins, and functional foods. We asked for help: Would the firm compare long-acting Wellbutrin with generic versions of the drug? Tod Cooperman, MD,'s president, agreed.

Now the results are in--and a long-simmering worry has broken into open debate. The study shows that some generics performed respectably: Two generic versions of Wellbutrin (Global Pharmaceuticals bupropion SR 200 and Watson Pharmaceuticals bupropion SR 150) were roughly comparable to the brand. But a common Wellbutrin XL 300 substitute, Budeprion XL 300, behaved very differently in the test tube from the brand-name drug. And that suggests a problem we believe goes far beyond a single misbehaving antidepressant.

In this exclusive Prevention report, we'll tell you what the results mean to you and your medications. With details and interviews you won't read elsewhere, we explore the important questions the study raises. Can you trust your prescriptions? Most important, how can you protect your health and still take the medicine you need?

We want to be clear: We love the idea of generics. They're much more affordable than brand-name drugs--costing between 30 and 80% as much, on average--while the FDA requires that they have the same active ingredient as the brand-name drug. And although other components, such as fillers, can differ from those in the drug they replace, FDA regulations are supposed to ensure that the generic is equally safe and effective. So even before 1984, when Congress made it easier to bring plain-wrap substitutes to market, we saw these drugs as a great advance.



These days, 63% of all US prescriptions are for the no-frill versions. But our feelings have changed. The reason: Over the past 6 or 7 years, we've heard hundreds of complaints from people who've had bad experiences with generic drugs. And although we're in fairly frequent contact with FDA officials, their responses have left us more concerned, not less.

One of the first stories that caught our attention came from a mother who told us that Ritalin normally controlled her son's ADHD, but when she gave him a generic pill, his teachers--unaware of the drug switch--would complain about his behavior. (She noticed a difference, as well.) And pharmacists told us they'd been fielding similar complaints from parents.

Comments like these were scattershot--a dozen or so complaints about the generic version of the antidepressant Zoloft, a half dozen from people whose heartburn started acting up after they switched from Prilosec to its generic counterpart, omeprazole. But early last year, we began getting a lot of questions and complaints about a new generic drug: Budeprion XL 300, distributed by Teva Pharmaceutical Industries. It's used in place of GlaxoSmithKline's Wellbutrin XL 300. (XL indicates that these are extended-release formulations--you take just one pill a day, whereas other forms of Wellbutrin and its generics require two or even three pills a day.) We've received more than 250 letters, e-mails, and postings to our Web site about this pill, and they share a shocking similarity. The writers were all doing fine on Wellbutrin XL 300. But when they switched to Budeprion XL 300, many felt like they had fallen off a cliff.

They experienced the classic symptoms of depression--some even said they felt suicidal. Others reported common antidepressant side effects, including anxiety, irritability, nausea, headaches, dizziness, and trouble sleeping. Page 2 of 11 On March 20, 2007, we contacted the FDA with our concerns; both Robert J. Temple, MD, director of the Office of Medical Policy at the Center for Drug Evaluation and Research, and Gary J. Buehler, RPh, director of the Office of Generic Drugs, told us that the agency would look into it. But the FDA moves slowly, and we were anxious to get to the bottom of this, so we teamed up with to take a close look at Wellbutrin XL 300 and its equivalent, Budeprion XL 300, as well as two generics for sustained-release Wellbutrin. (Most generics go by the name of the active ingredient--in this case, bupropion hydrochloride. But some, like Budeprion, are given distinctive names.) bought samples of each drug to test, using two labs to double-check the results.


Budeprion XL 300 contained the right amount of the active ingredient, bupropion--but released it at a substantially different rate than the brand-name drug did. In the laboratories' test tubes, Wellbutrin XL 300 released the chemical slowly for the first few hours, while Budeprion XL 300 released the drug far more quickly. In fact, within the first 2 hours, Budeprion delivered more than four times as much drug as Wellbutrin--34% of Budeprion's active ingredient, compared with just 8% of Wellbutrin's. Within 4 hours, the generic pill had released about half of the crucial chemical, while the brand name had given up only one-quarter.

Granted, the pills were in a test tube, not a person. But the findings suggest that people on generic Budeprion XL 300 get hit fast with a big dose of the antidepressant--perhaps enough to raise the risk of known side effects such as nausea and anxiety. Even more important, the results raise the possibility that hours later, there may be too little of the drug in the bloodstream to prevent depression from returning. That pattern, of course, is exactly what our readers have described to us.

Teva Pharmaceuticals, the company behind Budeprion XL 300, says it followed the government's testing guidelines. "All of our products meet the FDA's regulations governing the review and approval of generic pharmaceuticals," said Denise Bradley, director of communications and community relations, in an e-mail. Bradley also said that's testing methodology isn't "currently approved by the FDA for comparisons of generic products and is, therefore, inappropriate."

However, says's Cooperman, used the method the FDA required when GlaxoSmithKline tested the original Wellbutrin XL 300--and that the FDA required when Budeprion XL 300 was approved, according to publicly available documents. "The results for the two products were shockingly different," Cooperman says. "And if the drug is releasing so much faster in the dissolution test, it's hard to imagine that it wouldn't be doing the same in the gut--the test is designed to simulate the gut."

It's impossible for us to know what's responsible for the way Budeprion dissolved. But experts say it can be tricky for a drug manufacturer to get a pill to release its active ingredient at the right time and at the right speed--especially for extended-release formulations. In Wellbutrin XL 300, the drug is released gradually through a membrane over the course of the day. This design is still under patent, however, and it wasn't used in Budeprion XL 300. Instead, that drug depends on something called a matrix technology, which means that the active ingredient is released as the pill gradually disintegrates. Some researchers worry that this kind of system is inherently less predictable. Food may affect the way the pill behaves in the stomach, and in some cases, this could lead to "dose dumping"--too much active ingredient getting into the bloodstream too fast.



The results are worrisome, says Ray Woosley, MD, PhD. Woosley, once a candidate for the position of FDA commissioner, is president and chairman of the board of the nonprofit Critical Path Institute, which partners with the FDA and the pharmaceutical industry to speed development of safe drugs. "That's a huge difference for a drug like this, and could make switching from one formulation to the other a problem," he says. "It could well explain the adverse events people have described."

Meanwhile, the FDA is paying attention, though progress is still hard to discern. Whereas Buehler's earlier e-mails told us, "We are investigating," his message on November 8, 2007, said, "This is a high priority for FDA and we are working diligently on it."

There's little research comparing generics with their brand-name counterparts. But a few studies indicate problems with specific types of drugs. In a 2000 survey of 130 cardiologists, for instance, the doctors reported 60 patients who'd gotten into trouble on a generic version of a drug meant to prevent cardiac arrhythmia, a potentially lethal heart rhythm disturbance (three of the patients died). And in Minnesota a few years ago, there was a statewide "experiment" with the anti-seizure drug Dilantin and its generic, phenytoin. In the late 1990s, the state began requiring pharmacists to use generic phenytoin to fill Dilantin prescriptions whenever possible. Neurologists in the state began to see patients who'd done well for years on Dilantin, but who suddenly were having more frequent and severe seizures. When researchers at the University of Minnesota did blood tests, they discovered that blood levels of the active ingredient were 30% lower in people taking a generic than in patients on Dilantin. The finding prompted Minnesota to exempt Dilantin from its push to encourage generics.

Finally, thyroid specialists say that using generics can be tricky for a patient on thyroid replacement hormone. "Each of the generics is fine--but you shouldn't switch from one to the other," says Jeffrey R. Garber, MD, author of The Harvard Medical School Guide to Overcoming Thyroid Problems and vice president of the American Association of Clinical Endocrinologists.

Unfortunately, Garber says, if a prescription doesn't say something like do not substitute, the pharmacist can fill it with any generic at all, jumping from one to the other depending on what's in stock. "That's the way the system works," he says.

For the full report (by subscription), go to



9 Ways to Take Generics Safely

If your doctor or pharmacy switches you to a generic, this checklist will help you stay safe and ensure that you're getting the correct dose

1. Ask if your drug has a "narrow therapeutic index" (NTI)
This means the dose needed for the medicine to work isn't much lower than the dose that can cause side effects. If your doctor says this is true of your drug, ask him to specify do not substitute or dispense as written on your prescription. Find out if your drug has a NTI.

 2. Track your progress
If you're on blood pressure meds, buy a home BP monitor, take readings a couple of times a day for a while, and write them down. Do the same with your blood sugar checks if you're diabetic. Also, keep results of lab tests. Bring these records to your doctor if you suspect that your drugs aren't doing their jobs.

3. Pay attention to how you feel
This is especially important if your meds are for a condition with no lab tests, such as depression.

4. "Challenge" your generic
If you suspect it isn't up to snuff, ask your doctor to put you on the brand-name drug for a month; then try the generic again. (Researchers call this a drug challenge.) The exercise may help convince your insurance company to charge you the generic co-pay for your brand-name drug.

5. Be prepared to appeal

If your insurance company has decreed that it will cover only the generic version of your medication, you may need your doctor to go to bat for you. This can be a drawn-out procedure, but it's often worth the effort.

6. Pay out of pocket, but shop around
Insurance company won't budge? If you decide to pony up for the brand, a discount pharmacy can save you money.'s sister site,, searches out the best prices from pharmacies that meet rigorous, posted standards.

7. Ask the pharmacist for the name of the manufacturer
Not all generics behave the same way--and if you keep track, you may find that you have better results with a drug from a particular manufacturer. However, because your drugstore can switch makers whenever it finds a better deal, you may have to call around to find the particular generic you want.

8. Switch versions
If a once-a-day formulation isn't working for you, a drug designed to be taken two or three times daily might be better.

9. Report problems to the FDA
The agency is supposed to investigate drugs with a pattern of problems reported to watch--though budget shortfalls mean that many reports go nowhere. Or tell us at We continue to press this issue with the FDA.



Where is the safety net? Why some bad generics might make it to market

When we began to investigate the safety and efficacy of generics, we were shocked to find that generic drugs get minimal monitoring. We quizzed FDA officials on their system in 2002. (When we recently asked for an update, we were told that the process hadn't changed, though the numbers vary from year to year.) That year, the FDA selected 50 or 60 different drugs--brand-name and generic--for a spot test. The agency got two or three batches of bottles for each of those drugs and sent them Page 4 of 11 to a lab for analysis. That's not a typo: The agency tested 50 or 60 drugs. Yet in 2006, people filled more than 3.3 billion brand-name and generic prescriptions.

The FDA is also supposed to send inspectors to each drug manufacturing plant every 2 years. However, Nicholas Buhay, director of the Division of Manufacturing and Product Quality at the FDA, acknowledged that the agency doesn't have enough inspectors to meet that goal; some companies are inspected only every 3 or 4 years. And the agency generally doesn't have authority to inspect overseas manufacturing facilities at all.

That's a major hole in the safety net, because 80% of the raw materials for prescription drugs now comes from outside the United States, according to Congressman Bart Stupak, who chairs a committee on the safety of these imports. India and China supply almost half the imports. In other words, when it comes to what's on pharmacy shelves, drug companies are on the honor system. That's true even though generic manufacturers have a powerful incentive to cut costs, because price is their major selling point.

The recent study by raises the question of whether the FDA's approval process ensures that generics truly act the same as their brand-name counterparts. To get a new brand-name drug approved, it's typically tested in hundreds or sometimes thousands of people. Development costs run into the hundreds of millions of dollars, and the company is rewarded with a period of patent protection: 20 years from the time the patent is submitted.

The generic manufacturer doesn't have to prove all over again that the drug works. In fact, drug testing is generally required only on 24 to 36 people for a brief period of time. As long as the pills contain the same active ingredient as the brand-name version, in roughly the same amount, and it gets into the bloodstream in a comparable manner, the meds are good to go.


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