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Supreme Court Rules Against Pharmaceutical Industry

Posted by medconsumers on March 5, 2009

New York Times, March 5, 2009: The Supreme Court, by a 6-to-3 vote, upheld a jury verdict of $6.7 million in favor of a musician from Vermont whose arm had to be amputated after she was injected with an anti-nausea drug. The drug’s manufacturer, Wyeth, had argued that its compliance with the Food and Drug Administration’s labeling requirements should immunize it from lawsuits. Days after the Supreme Court decision was announced, Democrats in Congress reintroduced a bill called the Medical Device Safety Act, which would permit lawsuits against companies that made medical devices that injure people.

As of May 13, 2009, H.R. 1346, sponsored by Frank Pallone, Jr. (D-NJ), has picked up 79 co-sponsors, and S.540, authored by Senator Ted Kennedy (D-MA) has 21 co-sponsors.

For context on this important issue, read this Center for Medical Consumers 2008 position statement.

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Fosamax-Induced Osteonecrosis of the Jaw More Common Than Previously Thought

Posted by medconsumers on March 1, 2009

Dentists have been in the forefront of identifying a severe complication of Fosamax, the osteoporosis drug widely prescribed to prevent fractures. The January issue of the Journal of the American Dental Association published a study describing a significant risk of osteonecrosis of the jaw from even oral use of Fosamax. Until this small study of 208 dental patients was published, jaw osteonecrosis was thought to be rare and limited to people with cancer who received large doses of Fosamax intravenously to treat bone metastases.

Dental School Patients Studied

In this study conducted at the University of Southern California School of Dentistry, 4% of the dental patients taking oral Fosamax had osteonecrosis of the jaw. All had suffered dental trauma—either a tooth extraction or ill-fitting dentures that resulted in jawbone exposure; all were women, average age 73 years, who had been taking the drug for 12 months or longer. Osteonecrosis is defined as “the presence of exposed bone in the mouth, which fails to heal after appropriate intervention over a period of six or eight weeks.”

Parish P. Sedghizadeh, DDS, and colleagues at the USC School of Dentistry found no cases of osteonecrosis of the jaw among their 4,384 dental patients not taking Fosamax who underwent tooth extraction. Fosamax was the first and most aggressively promoted of all drugs in a class called bisphosphonates, which also includes Actonel, Boniva, Aredia, Zometa and Bonefos.

4% Risk is Not Rare

Sedghizadeh and colleagues say their findings contradict Merck’s claim that jaw osteonecrosis is a rare side effect of its drug. “We have been told that the risk with oral bisphosphates is negligible, but 4% is not negligible,” said Dr. Sedghizadeh. (The benefit of Fosamax could also be described as rare because the drug reduces the risk of hip fracture from 2% to 1%, as demonstrated in premarketing trials.) Prior to receiving FDA approval, Fosamax was tested in trials that lasted only three to five years. Ever since this drug first came on the market in 1996, the unanswered question has been: How long can people safely take Fosamax—or any one of other bisphosphonates, which are known to suppress bone turnover.

Drugs Have a Long Half-Life

This warning came from the USC Dental School research team: Bisphosphonates have half-lives of ten years or more, and people taking the drug orally may ultimately reach the same high dose level as that given intravenously to treat bone metastases in cancer patients. Sedghizadeh and colleagues also explained that because bisphosphonates stay in the bone for a long time, the risk of osteonecrosis remains even after people go off the drugs. The half-life of a drug describes how long it takes for half of it to be eliminated from the bloodstream.

The USC study is not the last word on the frequency of osteonecrosis of the jaw in people taking bisphosphonates. A much larger study is needed; ideally, one that takes place in many dental schools. Researchers at other institutions are trying to determine the prevalence of osteonecrosis of the jaw in cancer patients treated with bisphosphonates for cancer metastases. In the journal Bone, Dr. I.R. Reid, University of Auckland, estimated that it is 5% among people with myeloma, breast cancer or prostate cancer.

What to do

Thirteen years after Fosamax was launched, severe adverse effects have been showing up that may not be as rare as the public has been led to believe. Last year, the FDA reported that all bisphosphonates carry the risk of severe and sometimes incapacitating musculoskeletal pain. And case reports in several medical journals describe an unusual type of severe fracture of the femur associated with bisphosphonate use. In 2007 an increase in serious cases of atrial fibrillation was reported in people given the relatively new once-a-year bisphosphonate injection for fracture prevention (Zometa).

Osteonecrosis Treatments

As for osteoporosis of the jaw, more information is needed about how to prevent and treat it successfully—if that’s possible. Sedghizadeh and colleagues at USC Dental School did not have too much to offer on this topic. They advise unnamed alternate treatment options be considered for “nonnecessary extractions;” reducing the amount of the bacteria with a chlorhexidine rinse for those who must undergo a procedure; and daily antibiotics for those with denture trauma. For the exposed bone that fails to heal, the researchers name a procedure called “mucosal coverage.”

University of New Zealand’s Dr. Reid put it more succinctly “Management focuses on prevention, treatment of infection and cessation of bisphosphonate. The role of surgery is unclear.”

For more information: Read my 2008 article about Fosamax and this 2008 article about Evista. For an overview of how the definition of osteoporosis was expanded by the pharmaceutical industry: read “The marketing of osteoporosis: how a risk factor became a disease,” which appeared in the April 2009 issue of the American Journal of Nursing.

Maryann Napoli, Center for Medical Consumers©

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Generic Heart Drugs Just As Good

Posted by medconsumers on February 1, 2009

Generic Heart Drugs Just as Good as Brand-Name Drugs

Buying prescription drugs under their generic names can save a substantial amount of money, but the perception lingers—among doctors and consumers alike—that brand-name drugs are superior. To determine the accuracy of this prevailing view, a team of reviewers assessed all the studies that compared generic and brand-name heart drugs and found a major contradictory force at work. Although the studies produced no evidence that generic drugs are inferior, many of the medical journal editorials that accompanied these studies urged against their use.

First, it must be said that the FDA requires all generic drugs to be proven bioequivalent to their brand-name counterparts before they are allowed on the market. This means that they must be chemically equivalent in terms of the active ingredients of the brand-name drugs. However, generic drugs may differ in terms of their inactive ingredients like color and shape of the pill, fillers and inert binders. Generic drug manufacturers are not required to replicate the original effectiveness trials. Brand-name drugs are expensive until their patents run out. Once that occurs, other companies are free to produce lower cost generic versions of the same product.

38 Trials in the Review
For their new review, Aaron S. Kesselheim, MD, and colleagues at Harvard Medical School, assessed 38 trials that had randomly assigned people to take either a brand-name heart drug or its generic equivalent. Nine different classes of cardiovascular drugs were studied, including drugs to lower cholesterol and blood pressure and drugs that stabilize heart rate.

Most of the studies (6) involved warfarin, the blood thinner that doctors identify as having a narrow therapeutic index, which describes the difficulty of calibrating the correct dose—too high can cause internal bleeding and too low can result in fatal blood clots.

The reviewers’ conclusion: “Whereas evidence does not support the notion that brand-name drugs used in cardiovascular disease are superior to generic drugs, a substantial number of editorials counsel against the interchangeability of generic drugs.”

Kesselheim and colleagues came up with two educated guesses about the contradictory advice from the doctors who wrote negative editorials. 1) “Physicians’ concerns are based on anecdotal experience;” 2) “The conclusions may be skewed by financial relationships of editorialists with brand-name pharmaceutical companies, which are not always disclosed. Approximately half of the trials in our sample and nearly all of the editorials and commentaries did not identify sources of funding.”

Dr. Kesselheim was asked by e-mail whether his results say anything about generic versions of other drugs. “Well, our study only looked at drugs used in cardiovascular disease, so anything I’d say about other fields of medicine would be outside of the bounds of what we specifically looked at.,” he responded. “Still, for nearly every other field of medicine, I would not expect the results to be substantially different, given the positive experience of millions and millions of patients over the years who take generic drugs for psychiatric, rheumatologic, endocrine, etc. reasons.”

This review was published in the December 3, 2008 issue of the Journal of the American Medical Association and was funded in part by the Attorney General Prescriber and Consumer Education Grant.

Maryann Napoli, Center for Medical Consumers©

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Peppermint Oil, Fiber and Antispasmodic Drugs for IBS

Posted by medconsumers on January 1, 2009

Three inexpensive treatments work well for many people with irritable bowel syndrome, according to a new review published in the British Medical Journal. While peppermint oil, fiber and antispasmodic drugs have long been known to be helpful, uncertainties surround the supporting evidence. After evaluating 30 years of published research, the reviewers verified the effectiveness of these three treatments in comparison to placebo and found that peppermint oil may provide the strongest benefit.

These findings are of special interest due to the serious harms caused by two widely advertised prescription drugs for irritable bowel syndrome—Lotronex (ischemic colitis, transfusions, surgery, death) and Zelnorm (heart attacks, strokes).

The Fiber Trials
The symptoms of irritable bowel syndrome can be chronic and varied, including diarrhea, bloating, constipation and abdominal pain. And the condition is difficult to treat. Starting with the old, stand-by—fiber—the international review team led by Alexander C. Ford, McMaster University, Hamilton, Ontario, Canada, found 12 trials that explored this treatment. Virtually all those that involved the insoluble fiber in wheat bran found that it was no better at easing symptoms than a low-fiber diet or placebo.

Soluble fiber is best, but the reviewers were careful to note that the beneficial effects seemed to be limited to ispaghula husk, also known as psyllium, which contains a high level of soluble dietary fiber. (This is the chief ingredient in many commonly used laxatives, such as Metamucil® and Serutan®.) Based on the six soluble fiber trials in this review, the reviewers estimated how many people experienced relief. For every six people on a diet high in ispaghula husk, one experienced symptom relief. Adverse effects were not mentioned by the authors of most of the 12 trials.

Peppermint Oil Trials
Peppermint oil was better than placebo at alleviating symptoms, though the trials did not use the same doses. (They ranged from 200 mg to 225 mg capsules of peppermint oil, taken two or three times daily.) While peppermint oil was the most effective of the three treatments, it had the least amount of supporting research. There were only four trials with 392 participants, altogether. Efficacy was high, though. For every two people who took peppermint oil, one experienced symptom relief. Adverse effects occurred in five people taking peppermint oil, compared to none for those taking placebo. The trial authors, however, did not elaborate on the nature of the adverse effects.

Anti-Spasmodic Trials
Antispasmodic drugs are generally seen as the first-line treatment, especially when pain and bloating are the predominant symptoms. The highest number of trials, 22 in all, compared antispasmodic drugs with placebo in 1,778 participants, altogether. Most followed participants for less than four months. Adverse effects were described as, “significantly more frequent in those taking antispasmodic drugs than in people taking placebo, but none was serious.” For every three or four people who took an antispasmodic drug, one experienced symptom relief. Of the five different antispasmodic drugs studied, only one drug, hyoscine, showed consistent evidence of efficacy. It is an inexpensive prescription drug that is available generically. This review of trials was funded by the American College of Gastroenterology.

Maryann Napoli, Center for Medical Consumers© January 2009

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The Healthy Skeptic

Posted by medconsumers on December 31, 2008

The Healthy Skeptic (University of California Press: 2008)

Sometimes it’s the opening anecdote that draws you into a book. In the introduction of The Healthy Skeptic: Cutting through the HYPE about your Health, author Robert J. Davis describes a youthful encounter that jump-started his own quest for truth. It was the early years of the low-fat-diet-for-all heart disease prevention message to the public. A college student at the time, Davis bragged to friends that his “highly enlightened family” (father a physician) shunned whole milk and drank only 2%, the type that is low in fat.

Another student challenged him saying, “2% milk is not really low in fat.” Incredulous, Davis cited the claim on the milk carton to support his contention. “Well, the carton lies; the fat content in 2% is closer to whole milk than to skim milk,” countered his challenger. “If you want low fat, you need to drink skim or 1%.” A trip to the library to consult a nutrition textbook led Davis to the conclusion that the other student was correct. “A glass of 2% milk has about five grams of fat, compared with eight grams of fat in whole milk and nearly zero in skim.”

Thus, the stage is set for the message of The Healthy Skeptic. Do your own searching for the evidence to support health claims. Davis, a health journalist and teacher at Emory University’s Rollins School of Public Health, makes a clear distinction between skepticism and cynicism. The former demands much more of us. He cites this quote from Marcia Angell, former editor-in-chief of The New England Journal of Medicine:

Cynicism is much easier than skepticism because it requires no distinctions. We needn’t distinguish between reliable evidence and unreliable evidence, between big dangers and small ones, between likely effects and unlikely ones, between the reasonable and the bizarre. Yielding to cynicism over skepticism is therefore an easy way out.

Thanks to the Internet, searching for reliable evidence is much easier today. The Healthy Skeptic does much of the research for you, taking on some of the most common health messages about foods, beverages, drugs, vitamins, herbal remedies, sunscreen and other products that bombard the public, mostly by way of the news media. Sometimes the hype is obvious; for example, the selling of yet-another exercise gadget in one of those middle-of-the-night infomercials.

Too often, however, it’s not so obvious that you are viewing a sales pitch. Exhibit A is the notorious video news releases, or VNRs, used for years by TV stations large and small. The VNR can look like an objective news item; for example, a reporter interviewing a physician who comes across as an independent expert about a new superfood or drug. VNRs are, in fact, what Davis calls “propaganda disguised as news,” bought and paid for by the company that makes the product. Sometimes that fact is mentioned briefly at the end of the VNR; sometimes it isn’t.

Celebrity pill-pushing can be mistaken for morning show chitchat. Years ago, actress Kathleen Turner did a round of TV and print interviews, discussing her “battle” with rheumatoid arthritis. Her mention of a helpful Web site in each interview came across as information-sharing—that is, until it was revealed in 2002 that Turner was a well-paid spokeswoman for Immunex, a bio-pharmaceutical company, which along with Wyeth, makes the RA drug Enbrel. The recommended Web site was theirs.

There was a backlash in the media after Turner was outed as an industry-funded shill. Now such financial arrangements are usually disclosed during the “interview,” but as The Healthy Skeptic notes, it can be acknowledged so quickly and offhand that the disclosure can go unnoticed.

In a section entitled, “Sunscreen Science,” we learn that sunscreens have become a $500 million-a-year business since these products were introduced in the early 1970s. But increased sunscreen use has not reduced the rate of melanoma, the deadliest form of skin cancer. In fact, studies have produced conflicting results about their most important protective benefit.

Some studies found sunscreen use decreases the rate of melanoma; some found usage increases the rate of melanoma; and others showed no effect either way. On the other hand, there is clear evidence that sunscreens protect against squamous cell carcinoma, which can be disfiguring but rarely fatal. As for basal cell carcinoma, the least dangerous and most common type of skin cancer, there is little solid evidence that sunscreens reduce its risk.

You are not likely to hear these uncertainties from your doctor. The leading supplier of information about sunscreens to the public as well as health professionals is the Skin Cancer Foundation. Despite its seemingly non-commercial name, Davis says the Foundation’s list of corporate benefactors reads like a “who’s who of sunscreen manufacturers”.

This small book does not simply expose such things as the “iffy assertions” of doctors who practice anti-aging medicine; the lack of definitive evidence about calcium’s benefit to bone health; the overselling of prevention and the exaggerated dangers of high cholesterol. It also provides a way of assessing public-health messages, their funding sources, and most important, the quality (or absence) of the supporting evidence.

(Disclosure: The Center for Medical Consumers is described as a “trustworthy source of information” in the chapter about cholesterol.)

Whether you choose to be a cynic or a skeptic is entirely up to you.

Maryann Napoli, Center for Medical Consumers© 2008

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Take a Closer Look at Statin’s Benefit

Posted by medconsumers on December 1, 2008

Going on Statin’s? Take a New Look at the Size of the Benefit

The current practice of advising healthy adults to go on prolonged drug therapy just got a big boost from a large international trial. It found that people with normal cholesterol can halve their risk for heart attack and stroke by taking the cholesterol-lowering statin drug Crestor (generic name: rosuvastatin). Although at low risk for heart disease, all the participants had high blood levels of C-reactive protein, or CRP, which indicates the presence of inflammation within the artery walls.

This trial, which is expected to greatly expand the market for Crestor, was funded by its maker, AstraZeneca. And it is the brainchild of the lead author Paul M. Ridker, MD, who co-owns the patent on the CRP test. The 17,802 participants—men 50 or older and women 60 or older—were randomly assigned to take either 20 mg Crestor or a placebo each day. Results were so definitively in favor of Crestor that the trial was stopped three years ahead of its five-year schedule. Millions more healthy Americans are now candidates for Crestor, and there is talk of including a CRP screening with the routine blood test for cholesterol.

The findings from this trial called JUPITER were first presented early last month at a meeting of the American Heart Association. The next day, they became freely accessible at the Web site of The New England Journal of Medicine days before the intended publication date—a move that signals the importance of new trial results.

Crestor’s 50% reduction in cardiac events was widely reported in the media, but few reporters explained that this statistic is actually far more modest than meets the eye. JUPITER’s finding is, in fact, no different from the results of other trials designed to test whether a drug can prevent a disease in healthy people—only a tiny minority will benefit from years of drug therapy.

If the small chance of benefit is important to you, so too is this critical look at JUPITER.

50% reduction explained:

JUPITER defined cardiac events as heart attack, stroke or confirmed death from cardiovascular causes. According to the editorial that accompanied JUPITER, at least one of these cardiac events occurred in 1.8% of the participants in the placebo group (157 of 8,901 participants) and 0.9% of those taking Crestor (83 of the 8901 participants). In short, over the nearly two-year duration of the trial, few of these low-risk people had a cardiac event whether they were taking Crestor or not. To single out cardiovascular deaths, there were 37 deaths in those taking placebos and 31 deaths in those on Crestor.

What it means to you:

If you fit the profile of the people who participated in JUPITER, your chance of benefiting from Crestor is also explained in the editorial that accompanied JUPITER: For every 120 people who take Crestor for nearly two years, one cardiac event will be avoided. Or, put another way: Out of every 120 people who take Crestor, 119 will receive no benefit.


Profile of the participants:

JUPITER excluded people with diabetes, high LDL cholesterol, uncontrolled hypertension, cancer diagnosed in the past five years, or inflammatory ailments, such as severe arthritis, lupus or inflammatory bowel disease—among other conditions too numerous to mention in this space.


Stopping JUPITER early:

All major trials have a Data and Safety Monitoring Board. For ethical reasons, JUPITER’s DSMB stopped the trial as a majority of participants neared the two-year mark when those on the placebo had nearly 1% more cardiac events than those on Crestor. The early stopping of trials, an increasingly common practice, has been criticized by researchers and consumer groups. It favors the drug company’s interest since more adverse effects are likely to be reported if the trial is allowed to continue. On the other hand, the benefit may also increase. Some of the JUPITER participants were tracked for nearly five years. The difference in favor of Crestor continued a steady increase as these participants neared the five-year point.


Adverse events:

There was a small increase in the diagnosis of type 2 diabetes in people taking Crestor. This increase comes close to the nearly1% benefit shown for Crestor. Newly diagnosed diabetes was reported in 3.0% of people on Crestor and 2.4% of people on placebos. The rate of any serious adverse event was the same whether participants were taking Crestor or a placebo. However, JUPITER followed participants for a median of 1.9 years, and people take statins for the rest of their lives.


Other long-term statin info:

Since 1995, nine primary prevention trials, comparing a statin drug with a placebo, have been published. They followed participants for about five years. Although all the trials collected serious adverse events, all have failed to make the complete data available to researchers. Thus, the safety of statins is unknown.

Interesting statistic:

25% of the participants in JUPITER who were assigned to take Crestor had stopped taking the drug when the trial was stopped at 1.9 years.

Noteworthy aspects of JUPITER:

This is the first trial to have a representative proportion of female, Hispanic, and African-American participants. Findings were separated out according to subgroups which showed that the reductions in cardiac events were roughly the same for all—50%.

Noteworthy previous research:

JUPITER is not the first trial to show that a statin drug can benefit people with no history of heart disease or high LDL cholesterol. Other statins—e.g., lovastatin (Mevacor), pravastatin (Pravachol)—produced similar, though slightly smaller, reductions in cardiac events. These studies, which date back to 1999, provided the first hints that the benefit of statins may be unrelated to their cholesterol-lowering effect (they are far better at lowering cholesterol than they are at lowering the risk for stroke, heart attack and death).


Cost:

Crestor is still under patent and is therefore not available generically. A month’s supply of Crestor is $105. The cost of statins, including generic versions, can vary considerably, according to Consumer Reports. A month’s supply of another statin, sold generically as simvastatin, can cost $30 at some retail pharmacies and as little as $6 at Costco.

Inflammation and heart disease:

The role of CRP and inflammation in heart disease is hotly debated, according to The New York Times, which quoted Paul M. Ridker, MD, the lead author of JUPITER, saying that he believes inflammation plays an important role, probably by causing plaque in the arteries to rupture. Dr. Ridker went on to say, “Screening for cholesterol alone is like having two passengers in a car but only one air bag. If we’re not screening for CRP, we don’t have the opportunity to save that person’s life.” Dr. Ridker, a cardiologist at Harvard Medical School, co-owns the patent on the test that measures CRP. He is expected to earn millions of dollars once it becomes part of the routine blood test for all adults.


Other conflicts of interests:

Dr. Ridker and most of his 13 JUPITER co-authors have received grants, lecture and consulting fees, and other funding from AstraZeneca and other drug companies, many of which make statin drugs. The list at the end of the JUPITER paper in The New England Journal of Medicine was so extensive that it took up six inches of tiny type.


Should you be tested?

Some say JUPITER calls into question the prevailing hypothesis that high cholesterol is a major risk factor for heart disease. This position is bolstered by the long-known, but oft-forgotten, fact that half of all heart attacks occur in people with normal cholesterol levels. Many assume that CRP testing will soon become routine.

In one of their excellent podcasts recorded at the University of British Columbia, Vancouver, (www.ti.ubc.ca), James McCormack, Pharm.D, and Michael Allan, MD, dismissed the obsession among some researchers who are trying to tease out whether statins work by lowering cholesterol, or reducing inflammation or some other mechanism. McCormack and Allan say that statins clearly reduce the risk for cardiac events, and this was shown to be 1% in low-risk people like the JUPITER participants. Other trials show the benefit is higher in high-risk people, e.g., the 2% benefit for those who have had a heart attack or stroke. If these benefit rates sound good to you, say McCormack and Allan, then just take the statin and forget about having your CRP or cholesterol measured—they add nothing to the decision.


For more information:

To read the JUPITER trial findings, click here.

Added April 2011: See this relatively new, doctor-authored website for the modest effectiveness of statins click here.

Maryann Napoli, Center for Medical Consumers ©

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Risks of Biologic Drugs

Posted by medconsumers on December 1, 2008

New Concerns About a Class of Drugs Called Biologics

The fastest growing class of new drugs in the U.S. is the so-called biologics. Although the first in this class of drugs was approved in 1982, most have been marketed for a decade or less and little information was available about their safety. A team of Dutch researchers set about to address this important knowledge gap and their findings were recently published in the Journal of The American Medical Association.

Their findings? Almost one in four new biologics approved in the US and/or the EU between 1995 and 2007 had safety problems serious enough to require regulatory action after their approval. The term biologics (also known as biologicals) refers to drugs derived from living material, which can be human, plant, animal or microorganism in origin. Production of biologics is considered to be much more complex than that of traditional drugs. According to the Dutch researchers, “small differences and changes in the production process can therefore have major [safety] implications.” Examples of popular biologics include Enbrel and Remicade for rheumatoid arthritis, Tysabri for multiple sclerosis and Avastin and Herceptin for cancer.

While no biologic has been withdrawn, 19 were found to have had safety problems severe enough for regulators to require black box warnings on the labeling. Adverse events include life-threatening infections, acute hypersensitivity reactions and worsening heart failure—among others. Most of the regulatory actions were taken between 3 ½ and 5 years after approval.

There are some important overall lessons to be learned from this study. First, the data lends supports to the advice that, if better-understood treatments are available, a newly approved drug should be used with extreme caution, if at all, for at least the first five years after marketing. Second, the Dutch researchers suggest that the mode of action and complexity of biologics should demand heightened safety scrutiny by regulatory authorities before approval. In addition, there is some evidence that biologics may have higher rates of safety problems than traditional drugs. This is especially worrisome since about one quarter of newly approved drugs are biologics and their numbers are expected to grow rapidly in the coming years.

One possible reform in the FDA approval process that I believe would address this concern, and which I strongly support, would be to create a new option for FDA to grant “conditional approval” of a new drug when there is any hint of serious safety problems. At present, the FDA can only approve or disapprove a new drug; there is no middle ground. A conditional approval option could constrain the use of a newly approved drug suspected of safety problems by imposing limits on its prescribing and distribution by requiring its makers to accept rigorous safety monitoring.

The pre-approval trials currently required by the FDA suffer from serious limitations. For example, there are often only a few patients in the trial and the trials are often too short to get a full picture of the drugs’ effects. As a result, safety problems often go undetected until the drug is in widespread use. By that time thousands of people may have been exposed to serious harm.

I believe that establishing a conditional approval option would be a win-win for patients. It would result in a better understanding of a new treatment’s safety and prevent harm. And it would provide access to new treatments for patients with life-threatening conditions that are unresponsive to other therapies.

Arthur A. Levin, MPH, Center for Medical Consumers ©

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Safe Drug Use: An Interview

Posted by medconsumers on November 1, 2008

Prescription Drug Use: New Podcast Dispels Many Myths

One of the many information sources used in preparing our articles is Therapeutics Initiative, which publishes a free online newsletter. This project was established in 1994 by the Department of Pharmacology and Therapeutics in cooperation with the Department of Family Practice at the University of British Columbia, Vancouver. According to this Web site, its purpose is “to provide physicians and pharmacists with up to date, evidence-based, practical information on rational drug therapy. The Initiative is an independent organization, which is at arms length from government, pharmaceutical industry and other vested interest groups.”

Last Spring, two professors affiliated with this program began podcasting on the Therapeutics Initiative Web site (www.ti.ubc.ca). One of them, James McCormack, Pharm.D, who is with UBC’s Faculty of Pharmaceutical Sciences, is interviewed by Maryann Napoli, Center for Medical Consumers.

MN: Your podcasts are unique. There is no show that I know of in the mainstream U.S. media that draws upon the evidence the way you do to dispel myths about drug treatment. You are addressing primary care physicians, but there is much to be learned by anyone who takes drugs.

JM: Thank you. My co-host, Dr. Mike Allan, who is a great family doc at the University of Alberta, Edmonton, and I have been doing these podcasts primarily because they are fun to do and hopefully the information is useful to the listeners.

MN: I’m going to touch on different subjects to give my readers an idea of the range of topics you address in your shows. I’ll start with dose. Whether you’re talking about drugs for high blood pressure or antibiotics for sinusitis or strep throat, you make the point that drug doses are often set arbitrarily and the high-end doses are usually too high for most people. Is there general advice you can give here?

JM: If the condition [for which you will be taking the drug] will kill you tomorrow, take a big dose just in case. If the condition is not life-threatening or urgent, then there is absolutely no reason to start with the dose that is typically recommended. Typically, those are the doses that have been shown to work in most people.

MN: Because there’s a range of responses.

JM: Yes. It has been established that the initially recommended doses, especially for new drugs are, on average, too high for many people. When you look at the dose-response curve from trials, you see that many people respond to lower doses, but there is absolutely no way you can predict in advance who will respond to what dose. If there’s no hurry, and given that many conditions get better on their own, start with a small dose. Typically, ¼ of the recommended dose is where to start.

MN: Now for the duration of drug treatment. In one show, you said something that sounded like heresy because the public is told to complete the 10- or 14-day antibiotics regimen or something horrible will happen. Yet you said that for respiratory infections like sinusitis, bronchitis, and even community-acquired pneumonia [as opposed to hospital-acquired pneumonia], people can stop taking their antibiotics when they feel better and have no fever for three days. Typically that would be a 5-day course for many people, but you also said it depends on how quickly they respond.

JM: Three-day courses of antibiotics have been shown in studies to be effective for bladder infections and there is even a study of 3-day treatment for pneumonia. For almost all upper respiratory tract infections the most you need is five days. The key is if you are not improving after 2-3 days, you need to be reassessed by the prescribing physician. Interestingly, there was no evidence to support that 10- to 14-day recommendation in the first place. However, there are a few infections that require taking antibiotics for a longer time—bone infections, prostate infections, cardiac infections, but for most non-life-threatening infections, shorter [until you have felt better for 3 days] is usually just as good.

MN: You often joke that “we [health care practitioners] don’t know what we’re doing.” You said it recently in one of your shows about upper respiratory illnesses. Why is it that doctors don’t know the correct dose or type of antibiotic to use for these common conditions?

JM: It ‘s not so much we don’t know what we are doing, but we don’t always have studies that look at the answers to the important day-to-day clinical questions. I want to know what is the best drug and how long must it be taken. Many of the antibiotics in use today came on the market way before we did lots of trials. Unfortunately, the research done by drug companies often doesn’t answer the questions we need to know the answers to. We do what we were taught and don’t question whether it’s the best way to do something. How can I predict whether you would need 10 or 5 days of an antibiotic?

MN: People on anti-hypertension drugs might be surprised to learn from your show that drugs reduce the risk of heart attack, cardiac death, stroke by only 1-2% over five years. You said that there is uncertainty about whether this is due to the mechanism of the drugs or the lowered blood pressure.

JM: We don’t know exactly, but we’re pretty convinced that some of the effect is from blood pressure lowering. But there are a number of studies that show drugs that equally lower blood pressure do not produce equal reductions in the rates of heart disease. For instance, atenolol* is a highly prescribed drug that lowers blood pressure. However in clinical trials lasting 5 years, the people taking atenolol had the same number of heart attacks or strokes as those taking a placebo. That tells you something else is going on. Either blood pressure reduction is not the major reason for that 1-2% benefit from anti-hypertensive drugs, or any potential benefit from atenolol’s blood pressure lowering effect was offset by the inherent toxicity of atenolol. Even though we don’t know exactly what is going on, we do know that patients who take atenolol for 5 years are not reducing their chance of heart disease, which is the only reason to take drugs for high blood pressure.

MN: Given your general advice about starting with a low drug dose and the lack of certainty that anti-hypertensives work by lowering blood pressure or some other mechanism, why is dose a guide here?

JM: Because the major reason to start with a low dose is to reduce side effects and the second is to reduce cost. You’re right, it’s a catch-22 situation here. The drugs are given to lower blood pressure. We know very well that lower doses typically produce most of the blood-pressure lowering effects and increasing doses rarely adds much more benefit. We also know from studies that even if you did nothing, many patients’ blood pressure would go down over time.

MN: Blood pressure goes down without drugs?

JM: We know from any anti-hypertensive trials about 50% of the people on placebo will have normal blood pressure within a year. So take low doses, see the doctor periodically to have blood pressure measured and every year or so, in conjunction with your physician, start slowly cutting back on your medications to see if you still need them. Don’t lose sleep over your blood pressure. It’s inappropriate to scare people by telling them it is a silent killer. Blood pressure of, say, 160/100 increases your risk of cardiovascular disease by 2-3 % over 5 years compared to someone who has a blood pressure of say 140/85. That’s what you need to know.

MN: Why give anti-hypertensive drugs if untreated blood pressure goes down in so many people?

JM: The 1-2% reduction in cardiovascular disease over five years we mentioned earlier. Hopefully, there will be more over a lifetime. Many people see this as an important difference [over a placebo—that is, no treatment]. However, and most importantly, if these drugs cause any side effects you are on the wrong drug.

MN: I liked something you said about osteoporosis: “If you’re not prepared to take one of the bone drugs like Fosamax or raloxifene, then don’t have a bone density test. That makes so much sense, but I doubt many women have had this explained.

JM: It’s in the Physician’s Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation; 2000. “Utilizing any procedure to measure bone density is not indicated unless the results will influence the patient’s treatment decision,” which is in agreement with the U.S. Preventive Service Task Force recommendations for postmenopausal women.

MN: In describing studies, you often show how small the benefit of drug treatment can be, demonstrating that most people with self-limiting conditions get better in time without treatment. For example, you cite a Cochrane Review of the best trials involving the use of steroid intra-nasal spray for sinusitis, which made 73% feel better, compared with 66% of those on placebo.

JM: People don’t know the questions they should ask about drugs. Most important is: What will happen if I do nothing? What’s my ballpark chance of death, heart attack, stroke, fracture, symptoms etc) over, say, the next 5-10 years if I don’t take drugs. Then get the doctor to give a rough idea of how much the drugs will reduce that chance. Then get a ballpark estimate about your chance of having severe side effects.

Based on that information, you decide whether or not to take the drug and whatever decision you make, your doctor should support that decision.

*Atenolol has been sold under brand names like Tenoretic, Tenormin and Apo-Atenolol for nearly 35 years. A 2004 analysis of four randomized trials, published in the British journal Lancet, challenged atenolol’s safety and efficacy.

Maryann Napoli, Center for Medical Consumers ©

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Why is Anyone Taking Zetia or Vytorin?

Posted by medconsumers on October 1, 2008

Vytorin and Zetia Continue to be Prescribed Despite Hints of Harms and No Proof of Benefit

There is no proof that Zetia can do anything beyond lowering cholesterol—no evidence that it can reduce heart attacks or cardiovascular disease, which, of course, is the ultimate goal. Once again, this blockbuster drug sold alone or as a combination medicine has produced negative clinical trial results. This time it failed to provide any benefit to people with heart-valve disease. Worse, there were more cancers and cancer deaths among the drug-treated participants than in those taking a placebo, though these findings are described as “due to chance.”

Release of preliminary results of this trial had generated so much interest in the media last summer that The New England Journal of Medicine allowed the final results to be available on its Web site in early September—well in advance of the planned publication date.

Zetia is a relatively new cholesterol-lowering drug that can be prescribed alone. Vytorin combines Zetia with the 22-year-old statin drug, called simvastatin (brand name Zocor), into a single pill. Last year this expensive, heavily promoted combination drug became what only can be described as a drug maker’s worst nightmare. Study results showed that Vytorin was no better at reducing atherosclerosis of the carotid (neck) arteries than the older, cheaper simvastatin alone. There was also a hint that Vytorin might actually worsen artery disease.

And if that’s not bad enough, Merck and Schering-Plough Corp., which jointly market Vytorin, had withheld these unfavorable study results for nearly two years. It was, of course, in the financial interest of both companies to do so because Vytorin and Zetia are among the top-selling drugs worldwide. Four years after both drugs went on the market, backed by an aggressive ad campaign that featured a “food and family” cholesterol theme, yearly sales reached $5.2 billion.

On its Web site last month, The New England Journal of Medicine also published an editorial and an analysis that addressed Vytorin’s possible cancer-causing effect. The analysis was based on all the people diagnosed during the new heart-valve study and two other, much larger ongoing Vytorin trials. It was conducted by an Oxford University, U.K, research team, which found no increase in cancer incidence, but did find an increase in cancer deaths among those taking Vytorin. This finding was described as due “entirely to the play of chance rather than to a true increase in cancer mortality.”

The New England Journal of Medicine editors, however, are not so sure. In an editorial, they described a plausible mechanism for a cancer-causing effect, “[Zetia] interferes with the gastrointestinal absorption not only of cholesterol, but also other molecular entities that could conceivably affect the growth of cancer cells.” Once the cancer concerns were made public again last month, the FDA announced that its own analysis is in the works.

What makes this Vytorin/Zetia story so appalling is the fact that Zetia’s only advantage over the older statin drugs is a 17% greater reduction in LDL cholesterol. Incredibly, Merck and Schering-Plough were able to sell doctors and the public on the idea that this is more important than proof that this drug can cut the risk of heart attack (which has been proven for statins prescribed to high-risk men and people with heart disease). Zetia was studied for only 12 weeks before it went on the market.

Despite their uncertain safety records, Zetia and Vytorin continue to be prescribed to people with high LDL cholesterol. After the initial bad publicity, sales of Vytorin and Zetia dropped 40% in the first six months of 2008. That’s encouraging. But the question remains: Why is anyone still taking these drugs?

Maryann Napoli, Center for Medical Consumers ©
October 2008

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Osteoporsis Drug: New Adverse Effects

Posted by medconsumers on August 1, 2008

More Bad News About Fosamax

An unusual type of severe fracture has been reported in people taking Fosamax for more than five years. Ironically, this drug is widely prescribed to prevent fractures in people with bone loss. The new finding came from a series of case reports published in the May/June Journal of Orthopaedic Trauma.

The fractures occurred in the femur, which is the large thighbone that connects to the hip. They are particularly alarming because of the unusual pattern described by many of the people whose cases were reported. Their thighbones had ached inexplicably for months or weeks and then broke spontaneously while walking or standing. Nineteen of the 20 people in the case series had been taking Fosamax for an average of nearly seven years.

These are not the first reports of what is called atypical low-energy fractures after long-term Fosamax (generic name: alendronate) therapy. In 2005, the Journal of Clinical Endocrinology & Metabolism published case reports of nine women who sustained spontaneous non-spinal fractures while on Fosamax, six of whom showed either delayed healing or no healing for three months to two years. And last year, the Journal of Bone and Joint Surgery reported that nine Fosamax-treated women in Singapore showed the same early warning signs prior to a spontaneous fracture.

These adverse effects are not unexpected. Ever since Fosamax first came on the market over a decade ago, some osteoporosis researchers have periodically expressed safety concerns about prolonged usage, mostly in letters to medical journals. The drug improves bone density, but it does so by suppressing the bone remodeling process by which microscopic parts of old bone are constantly being dissolved and new bone is added.

Here’s how bone physiologist Susan Ott, MD, describes Fosamax’s effect on this process, “The bisphosphonates get deposited in the bone and will accumulate for years. It is possible that many years of continuous medicine would make bone more brittle or impair the ability to repair damage. Bisphosphonates do reduce fractures and improve measurements of bone strength for the first five years in both animal studies and in women who have osteoporosis. After five years, the fracture rates are as high in the women who keep taking alendronate as in the women who quit (see http://courses.washington.edu/bonephys).”

Although Fosamax advertising has focused women and doctors on the importance of bone density, bone strength is now regarded by osteoporosis researchers as more important to fracture prevention (see HealthFacts, April 2008).

Atypical low-energy fractures did not appear in the clinical trials required of Merck, maker of Fosamax, for FDA approval because these trials lasted only three to five years. Although these fractures are considered to be a rare side effect at this time, some osteoporosis experts are now advising against taking the drug beyond five years.

The published case reports all involved Fosamax, which is one of a drug class called bisphosphonates. Others in the class include: Actonel, Boniva, Aredia and Didronel. That all the case reports are confined to Fosamax may be explained by the fact that Fosamax was the first bisphosphonate to be aggressively marketed for the treatment of osteoporosis, and many more women worldwide have been taking this particular bone drug and for a longer time.

It’s reasonable to assume that the spontaneous fracture risk is associated with prolonged use of any bisphosphonate until research proves otherwise. Read this March 15, 2010 notice from FDA, stating that the agency has reviewed the relevant data and “found no clear connection between bisphosphonate use and a risk of atyical subtrochanteric femur fractures.” Also, read this 2009 updates on this topic “Osteonecrosis of the jaw—more common than previously thought” and this article written for the American Journal of Nursing “The Marketing of Osteoporosis–How a risk factor became a disease.”

Maryann Napoli, Center for Medical Consumers ©

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