Drug Injury Watch

Off-Label Prescribing Of Drugs: An Explanation And Some Practical Guidance For Patients

Don't Be Afraid To Talk With Your Doctor About Any Medication You Are Prescribed -- Especially If The Drug Is Being Used As A Treatment NOT Approved By FDA

(Posted by Tom Lamb at DrugInjuryWatch.com)

Let's start with an informal and short definition of so-called "off-label" prescribing: A drug is being prescribed "off-label" when it has not been approved for treatment of the patient's medical condition and, instead, is being used experimentally.

To put this practice into context, we draw from a provocative article, "Informed Consent and Shared Decision-Making: A Requirement to Disclose to Patients Off-Label Prescriptions", written by Michael Wilkes and Margaret Johns, which was published November 11, 2008 by the Public Library of Science (PLoS):

Because a basic premise of the US Federal Food, Drug, and Cosmetic Act is that manufacturers are prohibited from marketing drugs or devices without FDA approval, the public commonly assumes that all uses of prescription drugs have been approved by the FDA. However, after a drug is approved for one set of indications, researchers and doctors often discover new applications for it. Even when the FDA approves a drug for a single, specific use, doctors may legally prescribe the drug to any patient for any use. Physicians are not restricted to prescriptions that comply with the FDA approval. The FDA considers such treatments “off-label” because substantial evidence regarding their safety and efficacy has not been presented or evaluated. But such uses are perfectly legal. In fact, FDA policy explicitly states that “once a [pharmaceutical] product has been approved for marketing, a physician may prescribe it for uses in treatment regimes of patient populations that are not included in the approved labeling”. Indeed, as the Supreme Court has recognized, off-label prescribing “is an accepted and necessary corollary of the FDA's mission to regulate in this area without directly interfering with the practice of medicine”.  [footnotes omitted]

This PLoS article by Wilkes and Johns points out that, in fact, there are many examples of responsible off-label prescribing -- one is aspirin being prescribed to reduce the risk of heart attack long before it was FDA-approved for this purpose -- but cautions that other off-label uses can be dangerous -- a prime example is fenfluramine for weight loss, which caused heart valve damage to thousands of people (it was onepart of the notorious "fen-phen" combination).

So what should a patient do when it seems that their doctor is suggesting, or prescribing, a drug for an "indication", or treatment use, other than what that drug was approved for by the FDA?

The Agency for Healthcare Research and Quality (AHRQ) publishes online an advice column from Carolyn M. Clancy, M.D., who wrote "Off-Label Drugs: What You Need to Know".  Here is some guidance for patients offered by Dr. Clancy in that April 21, 2009 article:

Talk with your doctor if you have concerns about any medicine or treatment, particularly if it may be off label. Here are several questions to ask:

• Is this the approved use of the medicine? You may not know if the use is off label. This question can help you start the conversation with your doctor about your medicines. 
• Is the off-label use of this drug likely to be more effective than one approved to treat my illness? This is important because the off-label drug may not be as well tested for your condition.
• What evidence shows that this off-label drug can treat my condition?
• What are the risks and benefits of off-label treatment with this drug? Will my health insurance cover off-label treatment with this drug?

As we like to say at AHRQ, "Questions are the answer," meaning that it's important to ask your doctor plenty of questions about any medicines he or she prescribes. When you understand why you are taking certain medicines—including off-label drugs—you are more likely to take them correctly.

The bottom line is that you should not be afraid to talk with your doctor if you know or suspect that a drug is being prescribed off-label, i.e., as a treatment which has not been approved by the FDA.

FDA Staff Wants Amgen To Add Stronger Warning About Enbrel Side Effects In Children

June 2008 Staff Report Cites Cancers, Infections, And Neurological Problems Similar To Serious Side Effects In Adults

(Posted by Tom Lamb at DrugInjuryWatch.com)

On June 16, 2008 the FDA released a staff report, "Enbrel (etanercept) for the Treatment of Pediatric Plaque Psoriasis", which was prepared for the Dermatologic and Ophthalmic Drugs Advisory Committee's June 18, 2008 meeting.

In part, that FDA advisory committee will consider whether or not Amgen Inc. -- which markets Enbrel with Wyeth -- should be permitted to promote Enbrel for use by children with moderate to severe forms of the skin condition psoriasis.  At present, Enbrel is prescribed to treat psoriasis in children on an "off-label" basis, which means that the FDA has not approved Enbrel for that type of use but doctors are allowed to prescribe it to children with psoriasis when using their medical judgment.

According to a June 16, 2008 Reuters article, "UPDATE 2-Amgen's Enbrel in kids 'concerning'-FDA staff", by reporter Susan Heavey:

Regardless of whether the regulators approve the new use, FDA staff reviewers recommended the agency strengthen the drug's label to include reports of serious side effects in children that could lead to deaths or hospitalizations....

FDA safety reviewers looked at 949 reports of serious complications in children ages 4 to 17 taking Enbrel, or etanercept, for psoriasis as well as arthritis.

Among them, 61 reports were for psoriasis patients, according to the documents. No deaths were reported, but five patients were hospitalized.

Overall, the FDA found 14 deaths and 76 other life-threatening cases. Complications included serious infections as well as seizures and anemia.

"Given that the drug usage in pediatric population is estimated to be fairly small at this time, the numbers and types of post-marketing adverse events reported are concerning," the reviewers wrote.

The FDA staff who prepared this June 2008 report will present their findings to the Dermatologic and Ophthalmic Drugs Advisory Committee which, in turn, will make a recommendation to the FDA about whether or not Enbrel should be approved for the treatment of psoriasis in children.

As we reported recently, the FDA also is investigating whether Enbrel, along with rival products Johnson & Johnson's Remicade and Abbott Laboratories Inc's Humira, are linked to cancer in children.

According to the June 16 Reuters news article:

FDA reviewers found seven cases of cancer in children taking Enbrel, and two cases were reported in an Amgen study, according to the documents released on Monday.

We will watch for the advisory panel's recommendation about whether Enbrel should be used for pediatric psoriasis and for developments in the FDA's investigation about whether Enbrel, Humira, and/or Remicade are linked to cancer in children.

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.

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.

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.

Natrecor: An Example Of How Drug Companies Might Influence Doctors

"Off-label" Prescribing Is At Center Of Ongoing Natrecor Controversy

A recent article of interest is "The Rise And Fall Of Natrecor For Congestive Heart Failure: Implications For Drug Policy", by Aaron S. Kesselheim, Michael A. Fischer, and Jerry Avorn, in the July/August 2006 edition of the journal Health Affairs.  This recently published article uses Scios's drug Natrecor as a vehicle for exploring three important aspects of our nation's prescription drug policy: drug approval by the FDA; drug promotion by the drug companies; and, drug prescribing by the doctors.  In the authors' words:

We use [Natrecor] as a case study to assess how FDA standards for drug approval, marketing practices by drug manufacturers, and physicians’ prescribing choices can shape the risk-benefit relationship of new drugs. Based on the [Natrecor] experience, we suggest several ways to improve policies for drug approval, postmarketing surveillance, and drug utilization.

Coincidence or not, a June 28, 2006 article in The New York Times (NYT) included a discussion of Natrecor which gave us some insight into how some conduct engaged in by Scios (and other drug companies) might serve to influence the opinion of certain doctors.  In relevant part, this NYT article by Reed Abelson, entitled "Charities Tied to Doctors Get Industry Gifts", focuses on the more than $300,000 Scios reportedly gave to the Midwest Heart Foundation -- which, in the article, is described as a nonprofit entity that is closely related to a for-profit Illinois medical group that includes a cardiologist by the name of Dr. Mitchell T. Salzberg.

As background, while doctors are free to prescribe FDA-approved drugs for any purpose they deem appropriate, a practice commonly known as "off-label" prescribing, a drug company is prohibited by federal law from actively promoting in any manner such off-label prescribing by doctors.  In this instance, Natrecor was approved by the FDA in 2001 to be administered only to hospitalized patients who were in an extreme, or decompensated, stage of heart failure. 

In mid-2005 two medical journals published articles which raised safety concerns about Natrecor, specifically whether Natrecor was causing kidney problems in some patients.  In turn, there was renewed debate about whether or not this heart failure drug is properly used when administered not in a hospital setting but, instead, in outpatient clinics on a periodic or "tune-up" basis, i.e., "off-label" use.

According to the June 28 NYT article, some Midwest Heart doctors were in the practice of administering Natrecor to patients in outpatient clinics when these safety issues concerning Natrecor surfaced.  For the purpose of accuracy, we refer to Mr. Abelson's description of the situation:

In mid-2005, after researchers elsewhere published an article in a scholarly medical journal raising concerns that Natrecor could seriously impair kidney function, one of Midwest Heart's cardiologists, Dr. Mitchell T. Saltzberg, continued to staunchly defend the drug.  Dr. Saltzberg, who has also been a paid Scios consultant, wrote to Medicare officials in July 2005 to argue that the drug was being "unfairly targeted."

Dr. Saltzberg's letter cited a study of Natrecor's outpatient use — a study for which the foundation had provided some work — saying that this research and "the body of anecdotal experience" indicated the drug posed no kidney risks.

His comments to Medicare, though, came a few days after Scios itself sent a safety alert to doctors warning against the outpatient use of Natrecor. The Scios alert, issued in consultation with the F.D.A., relied on the findings of an expert panel that the company had asked to look into issues involving the drug's safety.

The Scios alert referred to the very study Dr. Saltzberg had cited and found it lacking. That study "was not powered to adequately assess the effectiveness or safety of serial infusions of Natrecor," the alert said. "The size of the study, its design and its findings provide an inadequate basis to recommend the use of intermittent, serial or scheduled repetitive infusions of Natrecor." Through the foundation, Dr. Saltzberg declined to comment. Foundation officials, though, said they agreed with the Scios panel's findings.

The Department of Justice (DOJ) has been investigating whether Scios improperly marketed Natrecor so as to encourage its "off-label" use in outpatient clinics, and the DOJ has reportedly issued a subpoena to the Midwest Heart Foundation among others as part of this investigation.

(Posted by: Tom Lamb)

Natrecor: A Definitive Safety Study Is Long Overdue

Off-label Use Of Natrecor Continues To Be A Problem

A year ago two medical journal articles raised serious safety issues about Natrecor; in summary: (1) a 50% increased risk of kidney damage or renal failure; and, (2) a 75% increased risk of Natrecor-associated death within 30 days of use when compared to similar drugs. 

At that point in time Scios, the Johnson & Johnson subsidary which makes Natrecor, convened a panel of experts who told the drug company that a study of these safety issues should be done immediately.

What happened?  According to a May 30, 2006 article in The Wall Street Journal, Johnson and Johnson (J&J) recently provided this update about their new Natrecor safety study:

"There are just a couple of details that we're putting the finishing touches on," said Roger Mills, vice president of medical affairs at Scios, the J&J unit that makes Natrecor. . . . 

[Another] company spokeswoman said the study would be the largest and most comprehensive to date in this group of patients. The study, she said, will demonstrate the "commitment and confidence" the company has in Natrecor.

This one-year delay in launching this Natrecor study, according to the May 30 WSJ article, drew a scathing comment from Milton Packer, a member of the advisory committee convened by J&J a year ago: "I think no one on the panel imagined that the recommendation would be followed by silence for a year. . . .  It's an unacceptably long period of time."

On other fronts, the WSJ's Scott Hensley reported:

J&J said in a recent quarterly securities filing that "there is no new data supporting the conclusions" of the safety critics. And unpublished data from a new study of the drug in patients undergoing heart-bypass surgery indicated that Natrecor might protect kidneys from damage related to the operations. . . .

The FDA hasn't asked J&J for a safety study of Natrecor.

In part, it is the so-called "off-label" prescribing of Natrecor (nesiritde) -- an infusion in outpatient clinics to avoid acute congestive heart failure episodes with severe breating problems vs. use in hospitalized patients whose hearts pump so weakly that they have trouble breathing -- which has contributed to the growing controversy about J&J's Natrecor.

Meanwhile, perhaps due to the Natrecor side effects controvery, according to this May 30, 2006 WSJ article the sales of Natrecor has gone from $375 in 2004 to a projected $100 million in 2006.

The fate of Natrecor remains to be seen.

(Posted by: Tom Lamb)

"Black-box" Warnings Are Forgotten Or Ignored By Some Doctors

The So-called Black Box Is FDA's Highest Form Of Drug Safety Alert

In the February 14, 2006 edition of the medical journal Archives of Internal Medicine there is a report that many patients are told by their doctors to use prescription drugs with "black-box" warnings in situations contrary to the drug-safety information and guidance set forth in those warnings.

Black-box warnings are the highest form of drug safety alert and, because of their importance, usually appear at the top of a drug's package insert, or label.  Typically the black-box warning brings attention to serious side effects associated with the drug, and provides guidance about how to minimize the risks of those side effects -- such as to not prescribe a particular drug with another drug, or to patients with certain pre-existing medical conditions.

In this study report published by the Archives of Internal Medicine, researchers examined the health records of 324,548 outpatients seen at several Boston-area medical clinics from January 1, 2002 to December 31, 2002.  The researchers found that 33,778 patients were prescribed a medication that had a black-box warning; of those, 2,354 prescriptions were contrary to the guidance set forth in the subject black-box warning.

In about 1,000 cases, the patients were simultaneously taking one or more drugs that the black-box warning said should be avoided so as to prevent a possible drug-drug interaction.  It is presumed that in most of those situations the black-box warning was forgotten by the prescribing doctor.

Interestingly, most of the instances which involved a black-box drug, about 90%, also involved prescribing the black-box drug to treat a disease or medical condition for which use of that drug was not even approved by the FDA. This type of prescribing is commonly referred to as "off-label" use.  In some of those cases, just as the doctor decided to use his or her own discretion as opposed to relying on the FDA-approved use, it is presumed that the prescribing doctor may have purposely chosen to ignore a black-box warning.

While this study found that the number of patients who received a black-box drug in a situation contrary to the substance of the black-box warning is relatively small, i.e., compared with the total number of outpatient prescriptions examined for the study, according to the researchers "the absolute number of outpatients at risk is substantial."

As always, we urge patients to know about the serious side effects, and the symptoms thereof, which are associated with any prescription drug they are taking.  To that end, we provide this listing of side effects and drug interactions for reference.

(Posted by: Tom Lamb)

Scios Says Two Deaths In Natrecor Trial Were Not Reported To FDA

Latest Natrecor News Increases Safety Concerns About J&J Heart Failure Drug

The Scios unit of Johnson & Johnson (J&J) did not immediately report to the FDA two deaths from a clinical trial, or study, intended to determine the safety of Natrecor, its heart failure drug, according to several news reports published in early January 2006.  In addition, the deaths of these two patient using Natrecor were omitted from a report of this Natrecor study that was published in the October 2005 edition Journal of Emergency Medicine.

In more detail, the October 2005 study article reported five deaths of patients within 30 days of their using Natrecor in hospital emergency rooms in 2001 and early 2002.  Of the 237 patient covered by this Natrecor study, there was one additional death following the use of some other heart failure treatment. The two new deaths now divulged by Scios involved patients who had used Natrecor, which raises the total to seven deaths among Natrecor patients in the subject clinical trial. 

According to a January 4, 2006 story in The New York Times (NYT):

"Neither Scios nor Dr. W. Franklin Peacock 4th of the Cleveland Clinic, the principal investigator in the study, disclosed yesterday how the deaths had been omitted from the results, but said they had learned only recently that the deaths occurred within the 30-day study period. A final analysis of the results is under way and will be submitted to the Food and Drug Administration, said Mark Wolfe, a Scios spokesman. He said he did not yet know the causes of the two additional deaths."

Meanwhile, a J&J spokesman said the drug company will look again at the results of this Natrecor study, taking into account the two "new" deaths.  It seems that, by means of this study, J&J was seeking to establish support for its contention that Natrecor does not cause a higher risk of death in the first 30 days following a patient's use of the drug. As background, some earlier studies concerning Natrecor had suggested that patients using this J&J heart-failure drug had an increased incidence of kidney problems and mortality.

In addition, according to a January 3, 2006 article published online by Reuters, Scios is conducting further analysis of the Natrecor trial data in order to "evaluate all-cause mortality through 180 days following treatment with Natrecor or placebo", and a final report on this "expanded analysis" should be submitted to the FDA by the first quarter of 2006.

Returning to the January 4, 2006 NYT article, the paper's Stephanie Saul reported that "a spokeswoman for the Cleveland Clinic, Eileen Sheil, said that Dr. Peacock strongly believed that the deaths had been accidental and not related to problems with Natrecor."

Natrecor was approved in August 2001 by the FDA for isolated use in acutely ill heart-failure patients, and only in a hospital setting.  Over time, however, there was increasing "off-label" use of Natrecor to treat less severely ill patients who had breathing difficulties caused by congestive heart failure, which treatment was done on a regular, i.e., repeated, basis in outpatient clinics or in cardiologists' offices.

Away from the safety issue, the U.S. Justice Department is investigating whether Scios wrongfully promoted the off-label prescribing and use of Natrecor.  More recently, it was announced that Medicare and Medicaid will no longer cover the costs of outpatient Natrecor use.

(Posted by: Tom Lamb)

"iPLEDGE" Registry for Accutane Patients Is Mandatory Starting In 2006

Primary Aim Is To Reduce Number Of Accutane-related Birth Defects

Enrollment in the "iPLEDGE' national registry for the anti-acne drug Accutane is mandatory starting January 1, 2006.

This "iPLEDGE" registry concerns any and all doctors, patients, and pharmacists involved with Accutane (isotretinoin), or the three generic versions of the drug, which are known as Amnesteem, Claravis, and Sotret.

About 100,000 Americans a month use Accutane and its generic versions (hereinafter, collectively referred to as Accutane). If a woman uses Accutane during pregnancy -- or becomes pregnant within a month of taking Accutane -- her baby runs a significant risk of suffering brain and heart defects or mental retardation.

According to Dr. Paul Seligman, director of the FDA office responsible for post-marketing drug surveillance, although the FDA has tried for more than 20 years to limit the exposure of fetuses to Accutane, anywhere from 100 to 140 pregnancies a year are still being reported in women using Accutane. "We hope [iPLEDGE] will be the program that ensures that we can get as close to the goal of the least pregnancy exposures as possible," Seligman said.

All Accutane users must enroll by telephone at (866) 495-0654 or through the Internet at http://www.ipledgeprogram.com in order to receive the drug after January 1, 2006.

Furthermore, each Accutane user must sign a document informing them of serious side effect risks associated with Accutane, including the possibility that the anti-acne drug contributes to depression or suicidal thoughts.

In addition, all female patients of childbearing age who plan to use Accutane must:

• undergo two pregnancy tests before the initial Accutane prescription can be filled;
• have a monthly follow-up pregnancy test before each Accutane refill;
• use two different forms of birth control at the same time or agree not to have sexual intercourse for one month before starting Accutane, during the entire course of Accutane treatment, and for one month after her Accutane treatment has ended.

Accutane is approved by the FDA for treatment of only the most severe acne, but the drug is widely prescribed "off-label" for more minor cases of acne.

The FDA has received reports of more than 2,000 pregnancies among Accutane users since it was introduced to the U.S. market in 1982. Of those pregnancies, most ended in abortion or miscarriage, but the FDA has received reports of more than 160 babies born with Accutane-related birth defects. 

It is generally thought that less than ten percent of adverse drug reactions and serious side effects in the U.S. are ever reported to the FDA, so the number of birth defects caused by Accutane over the years is most likely significantly higher than 160. 

Visit the FDA's dedicated web page for more information about Accutane.

(Posted by: Tom Lamb)