Drug Injury Watch

Heart Failure Drug Natrecor Fails Efficacy Part Of "Off-label" Use Study

Safety Profile Of Natrecor Continues To Be Subject Of Controversy And Debate

(Posted by Tom Lamb at DrugInjuryWatch.com)

The results of a large study for Johnson & Johnson's heart failure drug Natrecor failed to prove that its out-patient use in people with severe disease in addition to the current standard treatment regimen was any more beneficial than the standard treatment alone.

According to a March 25, 2007 Reuters article about this Natrecor study:

The company-sponsored, 920-patient trial fell short of its primary goal of showing the drug, Natrecor, could reduce the risk of death or heart and kidney-related hospitalizations. Results were presented on Sunday at an American College of Cardiology meeting in New Orleans.

The trial failed to find a difference between a group of patients getting standard treatment and those getting standard treatment plus Natrecor, known generically as nesiritide and given by infusion....

"The take-home message is, giving (Natrecor) intermittently did not reduce patients' risk of death or hospitalization. The strategy didn't work," said Steven Nissen, chief of cardiology at the Cleveland Clinic and president of the American College of Cardiology.

Natrecor is sold by the Johnson & Johnson subsidiary Scios.  Natrecor is approved to treat patients with heart failure serious enough to have them admitted to a hospital.  In recent years there has been growing concern about its "off-label, or unapproved, use in patients outside the hospital, i.e., out-patient setting.  In addition, several studies have suggested that Natrecor may actually increase the risk of death and worsen kidney function.

There was some debate about whether this recent study did anything to alleviate those concerns about the safety profile of Natrecor.  From the March 25 Reuters article:

The study also found no difference in severe side effects between both patient groups. The drug's supporters hope that result will allay safety concerns among doctors about its use....

...Scios vice president for medical affairs Roger Mills said the study should reassure doctors who cut back on the drug's use when the negative studies came to light several years ago.

"There is no hint of a problem with renal function or mortality. I think for the most part physicians should find these data very reassuring," Mills said.

But doctors on a panel discussing the study disputed the claim that the drug can be declared safe as a result of the study, noting there were more drug-related side effects in the Natrecor group. And there was a trend toward more days alive outside the hospital in the placebo group.

"I'm a little perplexed about your conclusions that this drug is safe," one panel member said.

In response to inquiries about the results of this Natrecor study, Scios said it had not decided, yet, whether the company will continue to test the efficacy and safety of Natrecor use in any out-patient setting.

Sanofi-Aventis Sends "Dear Doctor" Letter Regarding Antibiotic Ketek In Late March 2007

The Letter Concerns Black-Box Warning, Prescribing Changes, And Patient Medication Guide Announced Back In Mid-February 2007

(Posted by Tom Lamb at DrugInjuryWatch.com)

On March 26, 2007 the FDA announced that a so-called "Dear Doctor" letter regarding the antibiotic Ketek (telithromycin) has been sent by Sanofi-Aventis to healthcare professionals alerting them to new safety information for Ketek.

As one may recall, in mid-February 2007 the FDA and Sanofi-Aventis announced some important new prescribing and safety information for Ketek.  This important information was to be disseminated by several means, including a new package insert, or label, for Ketek that would have a black-box warning and label changes regarding the new prescribing guidelines as well as some associated side effects; in addition, there was a detailed medication guide for patients.  A summary of those items follow:

• The black-box warning states that Ketek is contraindicated in patients with pre-existing myasthenia gravis, a disease that causes muscle weakness;
• The antibiotic Ketek should be prescribed for community-acquired pneumonia, only, and should no longer be used as treatment for acute bacterial exacerbation of chronic bronchitis nor acute bacterial sinusitis.
• As for the other label changes, warnings were strengthened for hepatotoxicity (liver injury), loss of consciousness, and visual disturbances associated with Ketek; and,
• The new Patient Medication Guide is intended to let patients know about the risks of Ketek and how to use this antibiotic safely.

To our knowledge, no explanation was issued by the FDA nor Sanofi-Aventis about why there was an apparent six-week delay in sending out this March 2007 Dear Doctor letter regarding the important Ketek safety information that was first raised by them back in February 2007.

March 2007 GAO Testimony On The Effectiveness Of FDA's Postmarket Drug Safety Monitoring

FDA's Current Initiatives May Or May Not Address Past Shortcomings -- Too Early To Tell, Still

(Posted by Tom Lamb at DrugInjuryWatch.com)

In March 2007 Marcia Crosse, a representative of the U.S. Government Accountability Office (GAO), gave testimony to Congress (the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, House of Representatives) about the current status of the FDA's ability to monitor and manage safety issues for prescription drugs that have been approved by agency and that are being used daily by patients.

According to a March 22, 2007 GAO publication entitled "DRUG SAFETY: FDA Needs to Further Address Shortcomings in Its Postmarket Decision-making Process", as Director of Health Care at GAO, Marcia Crosse was asked to testify on the effectiveness of the FDA’s ability to manage drug safety issues which emerged after the agency had approved a drug, also known as postmarket drug safety.  The GAO publication provides this background:

This testimony is based on Drug Safety: Improvement Needed in FDA’s Postmarket Decision-making and Oversight Process, GAO-06-402 (March 31, 2006). The report focused on the complex interaction between two offices within FDA that are involved in postmarket drug safety activities: the Office of New Drugs (OND), and the Office of Drug Safety (ODS). OND’s primary responsibility is to review new drug applications, but it is also involved in monitoring the safety of marketed drugs. ODS is focused primarily on postmarket drug safety issues. ODS is now called the Office of Surveillance and Epidemiology....

In its March 2006 report, GAO found that FDA lacked clear and effective processes for making decisions about, and providing management oversight of, postmarket drug safety issues. There was a lack of clarity about how decisions were made and about organizational roles, insufficient oversight by management, and data constraints. GAO observed that there was a lack of criteria for determining what safety actions to take and when to take them. Certain parts of ODS’s role in the process were unclear, including ODS’s participation in the meetings of scientific advisory committees organized by OND to discuss safety issues for specific drugs. In the case of Arava, for example, ODS staff were not allowed to present their analysis of postmarket safety at an advisory committee meeting held to review Arava’s safety risks and benefits.  (emphasis added)

As preparation for this testimony by Marcia Crosse, the GAO interviewed FDA officials and reviewed FDA documents in February and March 2007 in order to gather information on FDA’s initiatives since March 2006.  Based on that work by the GAO, Ms. Crosse testified that the FDA has introduced some initiatives that, if implemented, could address some of the GAO's March 2007 recommendations that could improve the FDA's oversight of postmarket drug safety.  She pointed out in her testimony, however, that none of these FDA initiatives was fully implemented as of March 2007, so it was too early to evaluate their effectiveness.

It seems, therefore, that the inability of our FDA to manage postmarket drug safety issues -- which has been in the spotlight since the Vioxx recall back in September 2004 -- is still a problem we need to be concerned with today.

FDA Issues March 2007 Safety Alert For Pfizer Antibiotic Zyvox

Study Suggests That Higher Chance Of Death Is Related To The Type Of Organism Causing A Patient's Infection

(Posted by Tom Lamb at DrugInjuryWatch.com)

On March 16, 2007 the FDA issued a safety alert about the antibiotic Zyvox, also known as linezolid.  This FDA Alert is based on findings from an open-label, randomized drug study which compared Pfizer Inc.'s Zyvox to vancomycin, oxacillin, or dicloxacillin, three generic antibiotics.

In more detail, this Pfizer-sponsored study compared Zyvox to the three other generic antibiotics in patients with bloodstream infections related to catheters.  This use of Zyvox is not currently approved by the FDA, and therefore would be considered an "off-label" use of Zyvox.  At present, Zyvox is approved by the FDA for the treatment of various bacterial infections.

As background, bacteria can be either gram-negative or gram-positive depending on their type of outer membrane. The types of infections for which Zyvox use has been approved by the FDA are gram-positive.

According to the FDA, the chance of death for Zyvox patients was related to the type of organism causing the infection:

Patients with Gram positive infections had no difference in mortality according to their antibiotic treatment.  In contrast, mortality was higher in patients treated with [Zyvox] who were infected with Gram negative organisms alone, with both Gram positive and Gram negative organisms, or who had no infection when they entered the study.   

It is unclear what Pfizer had hoped to establish by means of this Zyvox study as, according to a March 16, 2007 Reuters article by Susan Heavey, a Pfizer representative said that the drug company would not seek FDA approval for any use of Zyvox in patients with catheter-related infections:

"We don't have plans at this point in time to file for this indication," Dr. Mark Kunkel, head of Pfizer's anti-infective division, told Reuters.

Results from the study have not yet been made public, but will be presented at upcoming meetings and may be published, Kunkel said. He added the findings met their main goal of curing infection within 7 to 14 days.

The FDA is currently reviewing the results of this Pfizer drug study as well as other available information about Zyvox.  In the meanwhile, the FDA advises doctors not to use Zyvox if they suspect an infection in caused by gram-negative bacteria.

Parkinson's Drug Permax Increases Risk of Cardiac Valve Regurgitation With Long-term Use

Authors of March 2007 Report Advise That Permax Use Should Be Stopped If Possible Due To Risk of Valvulopathy, Or Heart Valve Damage

(Posted by Tom Lamb at DrugInjuryWatch.com)

A new study published in the March 2007 issue of the medical journal Archives of Neurology provides further support to the theory that the long-term use of Permax (pergolide) for Parkinson's disease increases the risk of valvulopathy, primarily cardiac valve regurgitation. In comparison, the same study found that Mirapex (pramipexole) and Requip (ropinirole), two non-ergot-derived dopamine agonists used for the treatment of Parkinson's disease, were not associated with this increased risk of heart valve damage.

The new study report is called "Cardiac Valve Regurgitation With Pergolide Compared With Nonergot Agonists in Parkinson Disease".  According to the abstract for this March 2007 report, the objective of this case-control study was to determine if cardiac valve regurgitation occurs more commonly in patients with Parkinson disease (PD) treated with Permax (pergolide) than in those treated with Mirapex and Requip, the nonergot agonists, at a comparable dose.

In more detail, as reported in the March 2007 issue of Archives of Neurology, the occurrence of cardiac valve regurgitation was compared in 36 Permax users and 36 matched users of Mirapex or Requip.  In the Permax group, the average regurgitation scores were 0.83 for the aortic valve, 1.42 for the mitral valve, and 1.43 for the tricuspid valve, whereas in the Mirapex / Requip group the average regurgitation scores were 0.19 for aortic valve, 0.39 for mitral valve, and 0.19 for tricuspid valve.

As reported in a March 14, 2007 Reuters Health article, the lead author of this study, Dr. Richard B. Dewey, from the University of Texas Southwestern Medical Center in Dallas, made the following observations:

Based on these and earlier findings, "we continue to advise patients who are taking pergolide to stop taking the drug if possible and, if not, to undergo yearly echocardiography looking for valve regurgitation," the authors state.

"Our practice of recommending non-ergot dopamine agonists as first-line therapy for patients needing a dopamine agonist appears to be relatively safe from the standpoint of cardiac valve function."

As background, while several studies have linked Permax with cardiac valve regurgitation, the authors of this March 2007 report state that just one study has suggested that non-ergot-derived agents also increased the risk of this type of heart valve damage.

Procrit, Epogen, And Aranesp: New "Black Box" Warnings Only First Part Of FDA's Safety Re-evaluation

Popular Anemia Drugs Have Increased Risk Of Death, Blood Clots, Strokes, And Heart Attacks, Especially In Context Of Off-label Prescribing And Use

(Posted by Tom Lamb at DrugInjuryWatch.com)

On March 9, 2007 the FDA announced that Amgen Inc. and Johnson & Johnson (J&J) would add strong new warnings to their anemia drugs Procrit, Epogen, and Aranesp after several recent studies showed a higher risk of death and life-threatening side effects in some patients.  The timing of this announcement by the FDA surprised some observers -- and not just because the FDA issued this drug safety alert late on a Friday afternoon -- given that this new "black box" warning for Procrit, Epogen, and Aranesp comes just two months before an advisory committee of outside experts is scheduled to meet and discuss the serious cardiovascular risks that have been associated with these popular anemia drugs.

In fact, in its March 9 FDA News release entitled "FDA Strengthens Safety Information for Erythropoiesis-Stimulating Agents (ESAs)", the agency hinted that there may be more revisions to the label, or package insert, for Procrit, Epogen, and Aranesp:

"The agency is in the process of re-evaluating the safety of Aranesp, Epogen, and Procrit on the basis of the results of recent clinical studies," said Steven Galson, MD, MPH, director of FDA's Center for Drug Evaluation and Research. "The new studies provide significant new information for both prescribers and patients, and the new information applies to all ESAs, which share the same mechanism of action. The safety of these products will be discussed when the Oncologic Drugs Advisory Committee (ODAC) meets in May and further revisions to the labeling may occur after that meeting."

According to a March 9, 2007 Reuters article by Lisa Richwine, Amgen as well as J&J will be sending out so-called "Dear Doctor" letters to notify healthcare providers about the new warnings being added to labels, or package inserts, for Procrit, Epogen, and Aranesp:

• "Amgen, in a statement, said it was informing doctors about the new warnings."
• "Johnson & Johnson also said it was contacting doctors about the warnings."

Usually these types of letters provide explanation and guidance as regards significant changes to a drug's label, such as the addition of a black-box warning, which can be helpful to doctors and patients, both

As of March 12, 2007, however, there was no link on the FDA's web site to any such "Dear Doctor" from either drug company.

Given the current absence of that further explanation and guidance from Amgen and J&J, we draw this information for patients from the March 9, 2007 FDA Public Health Advisory, "Erythropoiesis-Stimulating Agents (ESAs)":

Patients currently using or considering the use of an ESA should know the following:

• A higher chance of death and an increased rate of tumor growth were reported in patients with advanced head and neck cancer receiving radiation therapy and in patients with metastatic breast cancer receiving chemotherapy, when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
• A higher chance of death was reported and no fewer blood transfusions were received when ESAs were given to patients with cancer and anemia not receiving chemotherapy.
• A higher chance of death was reported and an increased number of blood clots, strokes, heart failure, and heart attacks was reported in patients with chronic kidney failure when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
• A higher chance of blood clots was reported in patients who were scheduled for major surgery and given ESAs.
• ESAs are not approved for treatment of the symptoms of anemia, such as fatigue in patients with cancer, surgical patients and patients with HIV.
• If you have any questions you should talk with your health care provider.

A March 10, 2007 article in The Wall Street Journal derived what is, perhaps, the essence of the new black-box warnings being put on Procrit, Epogen, and Aranesp -- namely, that off-label prescribing of these anemia drugs is in large part the problem:

FDA officials said the black box was sparked by recent studies that have pointed to risks tied to the drugs, particularly when doctors used them for very aggressive treatments. Karen Weiss, deputy director of the agency's office of oncology drug products, said the "bulk of the data that has raised concerns" came when patients were given higher-than-recommended doses, whether they were suffering from anemia tied to kidney problems or cancer treatment. The evidence is that "this type of strategy is not beneficial and in fact has some evidence of harm," she said....

The FDA's alert advises doctors treating anemia in patients with kidney disease or cancer not to push hemoglobin levels in the blood over 12 grams per deciliter of blood. Tests for the level of hemoglobin -- the protein in red blood cells that binds with oxygen -- measure the oxygen-carrying capacity of the blood.

Pushing hemoglobin to levels as high as 13, 14, or 15 -- done by physicians acting on their own against label recommendations or by researchers testing benefits of more intense treatment -- carries a heightened increased risk of death, or serious cardiovascular events....

If not before, we will bring you further developments about the safety of Procrit, Epogen, and Aranesp after the scheduled May 2007 advisory committee meeting.

Big Pharma Has Its Way With The FDA Once Again As Regards Drug Safety

Agency Flops And Drops Its Proposed Drug Watch Site, Which Was Intended To Provide Early Warning About Emerging Unsafe Drugs

(Posted by Tom Lamb at DrugInjuryWatch.com)

In May 2005 the FDA announced that they would establish a new web site, to be called Drug Watch, that would alert doctors and patients about emerging drug safety issues.  One could think of it as the FDA's early-warning system for serious side effects that might be linked to FDA-approved prescription drugs.

As one may recall, this new Drug Watch web site was suppose to be a key part of the FDA's effort to improve its performance in fulfilling its drug safety monitoring role, which was roundly criticized following the September 2004 Vioxx recall.

After details of the FDA's proposed Drug Watch web site were published in the Federal Register back in May 2005 -- and after allowing for the 90-day comment as well as the time required for other administrative procedures -- it was anticipated that the FDA Drug Watch site would be available online in late 2005 or early 2006.

As reported previously, to most people this Drug Watch web site sounded like a step in the right direction for the FDA. But then there is Big Pharma:

The large drug companies oppose the Drug Watch plan because they imagine that there will be unnecessary confusion and "irrational fears" about their respective drugs if patients are given access to early information about potential drug side effects.

In a March 2, 2007 Reuters article by Lisa Richwine we learned that Big Pharma is going to have its way with the FDA, again, and that there will be no Drug Watch web site after all.  According to this Reuters article:

Instead of a "Drug Watch" list, the Food and Drug Administration will place red asterisks next to the names of the medicines on an existing Web page that lists dozens of prescription drugs. Consumers can click on the drug name to link to FDA advisories and other information.

"I feel strongly that such an approach meets our goal" of providing useful information to doctors and patients, Dr. Paul Seligman, associate director for safety policy and communication in the FDA's drug center, told reporters.

The FDA made the change because there was concern about potential confusion between "Drug Watch" and "MedWatch," an FDA program that provides alerts about new information on medical products, Seligman said.

The Reuters article also brought us the rather smug reaction of the pharmaceutical industry about this most recent "flop" by the FDA when it comes to standing up for patients as regards drug safety issues:

Drugmakers are pleased the FDA abandoned Drug Watch and was embracing a more balanced approach, said Alan Goldhammer, associate vice president for science and regulatory affairs at the Pharmaceutical Research and Manufacturers of America industry group.

The new plan "looks at the whole spectrum of information on both drug benefit and risk. That's been one of the points we've tried reinforcing - that one can't look at risk in the absence of benefit," Goldhammer said in an interview.

We encourage you to take a look at the FDA's apparent replacement for the Drug Watch proposal.  You will notice that some currently suspected unsafe drugs, such as Dostinex and Permax, are not even found on this Index to Drug-Specific Information page.

Let us know what you think:  Is this new approach taken by the FDA good for doctors and patients, or good for Big Pharma?

P.S.  In a March 6, 2007 post on his Pharma Marketing Blog, titled "Drug Safety -- A Mere Asterisk to the FDA", John Mack gives his perspective on this decision by the FDA to abandon their purposed Drug Watch web page.  I recommend it.

List Of Internet Sites That Provide Medication Information And Drug Interaction Checkers

Patients Should Use These Free Self-help Resources In Addition To Telling Doctor About All Current Drugs And Supplements

(Posted by Tom Lamb at DrugInjuryWatch.com)

In the February 27, 2007 edition of the Washington Post staff writer January W. Payne compiled a list of free internet sites which patients can use to research newly prescribed drugs and to check for possible dangerous drug interactions.

There are actually two lists of internet medical sites in this Post article, the first is "Medication Information" and the second is "Drug Interaction Checkers".

Of course, as pointed out in the prelude to these two lists, a patient should let their doctors and pharmacist know about every prescription drug as well as any and all dietary supplements -- vitamins, minerals, herbs -- they are currently using when there is any talk about a new medication being added to their drug therapy regimen.

To be clear, the internet resources compiled in this February 27 Post article are meant to supplement, not replace, the patient's discussion with their doctors and pharmacist.

In an era where patients seem to be prescribed more and more drugs by their several different doctors, self-help as regards potentially fatal drug interactions is vital.