Drug Injury Watch

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.

Ortho Evra Birth Control Patch Users Had Increased Risk Of Blood Clots

Large Study Shows Risk With The Patch Is Two Times Higher Than Observed In Women Using Birth Control Pill

(Posted by Tom Lamb at DrugInjuryWatch.com)

The February 2007 edition of the medical journal Obstetrics and Gynecology includes a study report which concludes that women who used the Ortho Evra birth control patch seem to be at double the risk of developing a dangerous blood clot in their veins as are woman who use birth control pills, or oral contraceptives.

This study involved 49,000 women who used the Ortho Evra patch -- an Ortho-McNeil Pharmaceutical, Inc. and Johnson & Johnson product -- and 202,000 who used oral contraceptive pills between April 2002 and December 2004.

We get more details from a February 17, 2007 Reuters article reporting about this new Ortho Evra study:

Dr. Alexander M. Walker and colleagues, from i3 Drug Safety in Auburndale, Massachusetts, note that it was not known if users of the [Ortho Evra] patch system ran the same risk of stroke, heart attack and venous blood clots as users of oral contraceptives....

The researchers found that the occurrence of blood clots or "venous thromboembolism" in [Ortho Evra] patch users was 2.2-times higher than in [birth control] pill users: 40.8 vs. 18.3 cases per 100,000 women per year.

Because heart attacks and strokes were so rare, the researchers could not tell from their data if the risk of these outcomes was any different, statistically speaking, between the [birth control] pill and the [Ortho Evra] patch users.

As background, in November 2005 the FDA together with Ortho-McNeil and Johnson & Johnson announced a change for the Ortho Evra label, or package insert, to warn doctors and patients about a possible increased risk of so-called "thrombotic events" because of a higher average circulating estrogen levels in women wearing the Ortho Evra patch.

Blood Thinner Medication Warfarin Linked To Brain Bleeds In Elderly

Patients More Than 80 Years Old At An Increased Risk Of Intracerebral Hemorrhage

(Posted by Tom Lamb at DrugInjuryWatch.com)

The January 9, 2007 edition of the medical journal Neurology has a report concerning a new study which reveals that elderly patients using the blood-thinning medicine warfarin may be at greater risk for having a serious brain hemorrhage.  Warfarin is sold under various different brand names, with one of the more popular being Coumadin.

According to a January 9, 2007 Newsday article by staff writer Jamie Talan about this Neurology article regarding the new warfarin study:

Scientists at the University of Cincinnati College of Medicine found that use of the anticoagulant medicine increased in the 1990s, and the surge in prescriptions caused a rise in the number of drug-induced intracerebral hemorrhages, especially in people over age 80.

"We've had no idea how often this was happening," said Dr. Matthew Flaherty, lead author of the study that appears in the journal Neurology. Use of the blood thinner increased after many studies showed warfarin was effective at preventing ischemic strokes in people with atrial fibrillation, an abnormal heart rhythm.

As background, ischemic strokes are caused by a blood clot that forms in the brain or travels to the brain.  By contrast, intracerebral hemorrhages involve a blood vessel bursting in the brain; as such, it is commonly referred to as a brain bleed. An intracerebral brain hemorrhage is a relatively rare form of stroke, accounting for less than ten percent of total annual stroke events.

The practical effect of this news about the increased risk of brain bleeds in elderly patients using warfarin, or Coumadin, was covered in a January 8, 2007 article by HealthDay reporter Steven Reinberg:

One expert thinks that doctors need to evaluate a patient's risk of stroke versus their risk of bleeding before prescribing warfarin.

"This study demonstrates that we need to be careful when we use these therapies," said Dr. Michael B. Rothberg, an associate professor of medicine at Tufts University School of Medicine.

Not all patients with atrial fibrillation will benefit from warfarin, Rothberg added. "Not all patients with atrial fibrillation should be getting warfarin," he said. "Patients at the highest risk for stroke will benefit the most, and patients at the highest risk for bleeding will benefit the least," he said.

Rothberg noted that although warfarin is standard treatment for atrial fibrillation, not everyone with atrial fibrillation is at the same risk of stroke. "I don't think that most doctors prescribing warfarin are assessing their patient's risk of stroke and risk of bleeding, but they should be," he said.

In closing, we want to make an important point:  As with all prescription medications, patients should talk to their doctors before making any decisions not to take warfarin, or Coumadin.

Permax And Dostinex Significantly Increase Heart-Valve Damage Risk

January 2007: NEJM Reports That Studies Show Increased Risk Of Four To Seven Times At Normal Doses

(Posted by Tom Lamb at DrugInjuryWatch.com)

The January 4, 2007 issue of The New England Journal of Medicine (NEJM) contains articles about two case studies that provide some of the strongest evidence that treatment with the Parkinson's disease drugs Permax (pergolide) and Dostinex (cabergoline) can cause cardiac-valve dysfunction.  Patients who take Permax or Dostinex, according to the NEJM articles, are four to seven times more likely to suffer damage to their heart valves than patients who did not take either of these medications.

While news of heart-valve damage associated with Permax and Dostinex is not new -- first getting some attention in 2002 -- the degree of increased risk of this serious side effect is resulting in calls for the use of these drugs to be discontinued for the treatment of Parkinson's disease.

A January 4, 2007 Wall Street Journal (WSJ) article by John Hechinger provides this insight on the reaction from the medical experts:

Bryan L. Roth, a University of North Carolina psychiatrist, said the fresh research marked the largest and most definitive findings of the heart risks of these drugs. Dr. Roth, who is also director of the National Institute of Mental Health's drug-screening program, said the findings should lead doctors to discontinue using the drugs and to tell patients to get echocardiograms to make sure they don't have damage.

"The incidence is kind of mind-blowing," said Dr. Roth, who wrote an article in the journal accompanying the studies. "It's so prevalent in people taking these medications, you kind of wonder why it was missed."

A January 3, 2007 Reuters article discussed how higher doses of Permax and Dostinex caused an even higher rate of heart-valve damage in patients:

The British study showed patients taking pergolide [brand name: Permax] were 7.1 times more likely to develop heart valve damage than those who took other treatments. Patients taking the highest doses of the drug had a 37 times greater risk.

The study showed patients taking cabergoline [brand name: Dostinex] were 4.9 times more likely to develop heart valve damage. At higher doses patients were 50.3 times more likely to suffer damage.

The January 4 WSJ article also gives some position statements from the drug companies responsible for these two ergot-derived dopamine antagonists, Permax (pergolide) and Dostinex (cabergoline).

As background, in 1989, Eli Lilly & Co. brought pergolide to market under the name Permax.  Valeant Pharmaceuticals International now markets the drug in the U.S.

Jeffrey D. Misakian, a Valeant spokesman, called Permax "a safe and effective treatment for patients with Parkinson's disease." He said the company "no longer promotes the drug" but makes "it available for those who prescribe it." He said the company recently worked with the FDA to modify its label to advise physicians that the product "should be used with caution."....

Pfizer markets cabergoline in the U.S. under the brand name Dostinex not for Parkinson's but for a hormone condition, the excessive production of prolactin. The company markets it for Parkinson's in Europe under a variety of brand names. Michael Berelowitz, a Pfizer senior vice president, said its safety monitoring noted a problem a year ago, leading to labeling changes that mention heart-valve risk. But, he said, "It still has a place in the treatment of patients."

The type of heart-valve damage that can be caused by Permax and Dostinex is the same kind of heart damage that led to the withdrawal of the diet drug combination "fen-phen."  Further, this damage to the heart valve can lead to heart failure and sudden death.

New Birth Control Patch Warnings In Canada About Being Overweight, Sauna Or Whirlpool Heat

No Similar Changes To Ortho Evra Label In U.S. As Of Early December 2006

On November 23, 2006 Health Canada released a drug safety alert -- which consisted of a so-called "Dear Doctor" letter and a public advisory for patients -- about the norelgestromin and ethinyl estradiol transdermal system, better known as the birth control patch or, more simply, "the patch".

Although this announcement by Janssen-Ortho Inc., in consultation with Health Canada, focused on new safety information pertaining to its product Evra, the birth control patch that is marketed in Canada, their alert seems to be equally applicable to the Ortho Evra patch sold in the U.S.

The EVRA* transdermal system marketed in Canada contains 6.0 mg norelgestromin (NGMN) and 0.60 mg ethinyl estradiol (EE) and is approved for use in contraception (prevention of pregnancy). ORTHO EVRA® is the formulation of EVRA* marketed in the United States and contains 6.0 mg NGMN and 0.75mg EE. Although EVRA* and ORTHO EVRA® are manufactured differently and therefore contain different total amounts of estrogen, the risk of side effects reported for ORTHO EVRA® is considered to apply equally to the EVRA* formulation available in Canada.

This birth control patch warning in Canada started by addressing the situation which arose in September 2006 when we learned about two conflicting studies about Ortho Evra concerning whether there is any connection between Ortho Evra and serious blood clot side effects. 

The results of a recent study indicate that women using the ORTHO EVRA contraceptive patch (the formulation of EVRA marketed in the United States) had an increased risk of blood clots in the legs and lungs compared to women using an oral contraceptive. Another study indicated no difference in the risk of blood clots in the legs and lungs in women using ORTHO EVRA compared to women using an oral contraceptive.

Next, there are two new safety warnings about the Evra birth control patch set forth in this November 2006 Health Canada safety alert.

• "Women who are obese are at particularly high risk of blood clots."
• "Due to a theoretical risk of unintentional increase in estrogen exposure from the patch, patients are recommended not to expose the patch area to sources of heat such as sauna or whirlpool bath."

As of December 3, 2006, however, no corresponding warning about being overweight nor the sauna and whirlpool heat exposure had been issued by Ortho-McNeil Pharmaceutical -- a Johnson & Johnson (J&J) company -- for their Ortho Evra product in the U.S.  It is not clear at present whether J&J intends to revise the package insert, or label, for Ortho Evra to warn women that they are perhaps at an increased of developing serious blood clots if they are overweight or if the birth control patch is exposed to certain heated environments such as saunas and whirlpools.

Further comparing conduct in Canada and the U.S., in September 2006 J&J and the FDA did announce that the conflicting recent studies had caused a renewed concern about the association between Ortho Evra and certain blood clot disorders like pulmonary embolisms and deep vein thrombosis (DVT).  J&J did not, however, issue any Dear Doctor letter to U.S. health care providers then, nor have they done so since September.  One must wonder, why the difference?

(Posted by: Tom Lamb)

Amount Of Epogen And Procrit Given To Patient Tripled Since Early '90s

Higher Levels Of Popular Anemia Drugs May Increase Risk Of Heart Problems And Death

The most recent discussion about safety issues surrounding the anemia drug epoetin -- sold by Amgen as Epogen, sold by Johnson & Johnson (J&J) as Procrit -- started with a November 8, 2006 article in the Boston Globe by Christopher Rowland.  He reported on the results of a study that was soon to be published in The New England Journal of Medicine as follows:

[Dr. Ajay Singh, clinical chief of the renal division at Brigham and Women's Hospital in Boston,] whose clinical trial linked aggressive use of anemia drugs to an increased risk of fatal heart attacks and strokes says the government is not doing enough to protect dialysis patients from the potential dangers.

... The trial, called CHOIR , was halted last year because patients whose red blood cell counts were boosted the most died at an unexpectedly high rate.

... In anticipation of the CHOIR study's publication, physicians and policy specialists are debating a basic question: How much Epogen is too much? Even though the drug is widely used to manage anemia in all kidney patients -- not just the 325,000 on regular dialysis -- as well as in cancer patients undergoing chemotherapy, definitive studies on its effectiveness and safety thresholds have not been performed.

Singh said the FDA should require Amgen and other manufacturers of the drugs -- synthetic hormones which stimulate red blood cell production in bone marrow -- to sponsor studies to establish a threshold for anemia treatment.

This was followed by a November 16, 2006 article called "Heart Risk Seen in Drug for Anemia", in The New York Times by Alex Berenson, from which we learn:

A medical study to be released today suggests that high doses of a best-selling drug used to treat anemia in dialysis and cancer patients may increase the risk of heart problems and deaths.

... The findings reinforce mounting concerns that kidney patients may be receiving too much epoetin, in part because dialysis clinics make bigger profits for providing larger doses. Studies show that the clinics make little, if any, profit on the actual dialysis services they provide for Medicare patients, who are the vast majority of patients.

The amount of epoetin received by the typical American dialysis patient has nearly tripled since the early 1990s....

But the studies show that the anemia of many patients is being overcorrected and that doctors should aim for lower levels of red blood cells in their patients, he said. The simplest way to do that would be to give patients less epoetin.

Indeed, the solution proposed by Dr. Singh seems sensible and simple enough to implement.  Why, then, is there resistance from Amgen to this solution? 

For that we turn to Merrill Goozner, who spent more than 25 years as a reporter for the Chicago Tribune and other publications.  In a November 20, 2006 email about his online newsletter, This Week in GoozNews, Mr. Goozner gives us some insight.

Nearly a decade ago, I was an economics reporter who stumbled onto the drug industry by attending hearings on Capitol Hill about the fate of Medicare. I eventually wrote a piece for the Chicago Tribune headlined "The Making of a Star Drug," where I documented the games played by Amgen around its best-selling drug Epogen, then as now the drug that Medicare spends more money on than any other. That story eventually became the first chapter of my book, "The $800 Million Pill." Epogen was back in the news last week. A new study appearing in the New England Journal of Medicine pointed what observers like myself have been arguing for years. The high doses of Amgen's pricey drug may be killing people on dialysis. Naturally, my posts last week focused on this issue. Read them and weep for the poor people on dialysis who have been victimized by this company.

Here are two recent articles by Mr. Goozner about this ongoing problem with epoetin:

• Amgen, NKF and the Dialysis Killing Fields  (November 17, 2006)
• The Trials of Amgen  (November 15, 2006)

Hopefully this renewed discussion about what levels of Epogen and Procrit are safe for use in patients with anemia will produce some results this time around.

(Posted by: Tom Lamb)

Ortho Evra: More Women Sue J&J Over Birth Control Patch

Lawsuits Allege Serious Blood Clots Conditions Such As Pulmonary Embolism, With One Young Woman Dying From Using Ortho Evra

In early November 2006 two new California Ortho Evra lawsuits were filed in San Francisco Superior Court, Bracken-Hodge v. Ortho-McNeil (Case No. 06-457523) and Abel v. Ortho-McNeil (Case No. 06-4575240), according to an Associated Press article published by the Washington Post. 

This November 1, 2006 article in the Post informs us that the first case concerns "25-year-old Kelly Bracken of Elk Ridge, Md., died of severe blood clots in her lungs and legs after she started wearing the skin patch," while the second case combines the personal injury claims of 43 women who suffered from various serious side effects caused by blood clots related to the women's use of the Ortho Evra birth control patch.

In September 2006 the FDA warned doctors and patients that women had an increased risk of developing blood clots in their legs -- called deep vein thrombosis or DVT -- and their lungs -- pulmonary embolism -- if they used the Ortho Evra birth-control patch instead of the traditional oral contraceptive pill.  Ortho Evra, which was approved by the FDA in 2001, is unique in that is a birth control patch that transfers the hormones estrogen and progestin through a woman's skin directly into the bloodstream.

The Post article tells us that the two companies named as defendants in the two new California Ortho Evra lawsuits filed in November 2006 are the drug's manufacturer, Ortho-McNeil Pharmaceutical Co., a subsidiary of Johnson & Johnson (J&J), and San Francisco-based distributor McKesson Corp.

In September 2006 the Ortho Evra package insert, or label, was updated by J&J to make doctors and patients aware of the results of two conflicting studies: one study that Ortho Evra doubled the risk of serious blood clots compared to the pill, while a second study found no difference in risk between the patch and the pill.

(Posted by: Tom Lamb)

FDA Approves New, Stronger Warnings For ADHD Drugs

Sudden Deaths, Strokes, And Heart Attacks In Adults At Usual Doses

Several drugs to treat attention deficit hyperactivity disorder (ADHD) -- including GlaxoSmithKline (GSK) Plc's Dexedrine, Novartis AG's Ritalin, Johnson & Johnson's Concerta, and Shire PLC's Adderall -- now carry a warning about the possible risk of sudden death and serious heart problems.

According to an August 21, 2006 Reuters article:

[FDA spokeswoman Susan Bro] could not confirm whether the heart warning was boxed. But a letter from Glaxo made public earlier on Monday advising doctors about the new warnings said the heart caution was a boxed warning.

Regarding that last point, the boxed warning actually addressed the misuse of amphetamines, a more general warning, as read in the June 2006 version of the Dexedrine package insert. 

Meanwhile, in the third week of August 2006 the FDA announced on its web site that GSK recently sent a so-called "Dear Doctor" letter regarding Dexedrine dated August 4, 2006 informing healthcare professionals about changes made to the June 2006 version of the Dexedrine package insert, or label.

The FDA's approval of this new, stronger warning for Dexedrine and some of the other ADHD drugs seems to be the resolution of conflicting opinions issued by two different FDA advisory committees which considered the safety of ADHD drugs in February and March 2006.  The primary distinctions between the recommendations made by these two advisory committees were, to start, the extent of cardiovascular risks associated with Adderall, Concerta, Ritalin, Dexedrine, as well as some other ADHD drugs and, then, whether those risks warranted the addition of a "black-box" warning on the package insert for these controversial stimulants.

In his August 21 article Gardiner Harris, of The New York Times, summarized the concerns of the February 2005 advisory committee:

At a meeting in February, an F.D.A. advisory committee focused attention on stimulants’ risks in adults after a report suggested that the drugs might double the risk of strokes and serious arrhythmias. Such an increase may not be significant in children, whose heart risks are low, but it could cause concern in adults, committee members said.

During the past year-and-a-half the FDA has been criticized for its handling of the cardiovascular safety issue associated with Adderall and other ADHD drugs. In particular, the agency came under increasing scrutiny after Health Canada pulled Adderall XR from the market in February 2005 based on reports that 20 people taking the drug died. Health Canada returned Adderall to the market in August 2005, and in May 2006 issued a safety alert warning against the use of ADHD drugs by people with high blood pressure, heart disease, and certain other medical problems.

An August 21, 2006 piece published on Bloomberg.com brought us the reaction of prominent cardiologist Steven Nissen, chairman of cardiology at the Cleveland Clinic, who served on the February FDA advisory committee:

It's a very strong warning....  It's appropriately worded. It basically lets physicians and patients know that these drugs do have serious cardiovascular side effects.

According to the August 21 Reuters article, the FDA estimates that the number of ADHD drug prescriptions written each month in the U.S. are about 1 million for adults and 2 million for children.

(Posted by: Tom Lamb)

Cox-2 Drugs Increase Risk Of Second Heart Attack Or Death When Used After First Heart Attack

Will June 2006 Circulation Article Affect Lawsuits Involving Bextra, Celebrex, And Vioxx?

In mid-June 2006 the medical journal Circulation published online an early-release version of a study which reveals that Bextra, Celebrex, and Vioxx were especially dangerous when used by people who had survived a heart attack.  In more detail, medical researchers in Denmark found that taking COX-2 inhibitors -- a drug class which includes Bextra, Celebrex, and Vioxx -- as well as another group of painkiller called nonselective nonsteroidal anti-inflammatory agents (NSAIDs), such as ibuprofen and diclofenac, are associated with an increased risk of a repeat heart attack or death in patients with established cardiovascular disease.

According to a Reuters Health article published June 20, 2006, Dr. Gunnar H. Gislason, from the Gentofte University Hospital in Hellerup, said in a press release issued by the American Heart Association: "Patients who have already suffered a heart attack appear be more vulnerable to the harmful effect of these medications."

This June 20 Reuters article summarized the increased risks for these drugs as follows:

Taking a low dose of a COX-2 inhibitor was tied to an approximate doubling of the risk of dying and about a 50 percent increase in the chances of having another heart attack. At higher doses, mortality risk was increased five-fold.

With high daily doses of NSAIDs, the likelihood of dying was doubled or quadrupled depending on the specific drug, and the risk of another heart attack went up 22 to 89 percent.

A June 19, 2006 Reuters Health article, meanwhile, pointed out that Dr. Gislason and his team of researchers reported in their Circulation article that this statistical analysis of Danish data "demonstrated a clear dose-related response in the increase in the risk of death for all drugs."

This June 19 Reuters article, also, provided more precise information about the extent of the increased risk of having a second heart attack or dying:

For [Vioxx] up to 25 mg/day, and [Celebrex] up to 200 mg/day (both considered to be low dose), the adjusted hazard ratios (AHR) were 2.49 and 1.92 for mortality and 1.68 and 1.47 for MI, respectively.

For [Vioxx and Celebrex] at higher doses, the adjusted hazard ratios for death were 5.26 and 4.69 for each, and for repeat MI, 1.27 and 1.64.

For high daily doses of more than 1200 mg of ibuprofen, the adjusted hazard ratio for death was 2.20, and for doses of diclofenac greater than 100 mg/day it was 4.44. For repeat MI, the corresponding adjusted hazard ratios were 1.22 and 1.89, respectively.

It remains to be seen whether these findings reported by Dr. Gislason and his team in their June 2006 Circulation article will have any affect on the ongoing Bextra, Celebrex, and Vioxx litigations.

(Posted by: Tom Lamb)

Birth Control Patch Lawsuits Being Settled Early By Johnson & Johnson

Ortho Evra Contraceptive Patch Causes Blood Clots Resulting In Strokes, Heart Attacks, Pulmonary Embolism, And Deep Vein Thrombosis 

According to a May 16, 2006 article in the New Jersey Law Journal, Johnson & Johnson has said it wants to settle those lawsuits where a woman who used its skin patch Ortho Evra was hospitalized with any of the following serious side effects: 

• strokes;
• heart attacks;
• pulmonary embolisms; and,
• deep vein thrombosis.

The Ortho Evra patch lawsuits have been designated for multi-district litigation, or MDL, treatment in the federal court system, and designated as a mass tort by the Supreme Court in New Jersey, where Johnson & Johnson has its headquarters.  According to the May 16 New Jersey Law Journal article, lawyers for Johnson & Johnson announced their "quick-settlement strategy" on May 2, 2006 during conferences with the respective judges who are presiding over the Ortho Evra MDL cases and the New Jersey Ortho Evra consolidated cases.

At a May 2 status conference with U.S. District Judge David Katz in Cleveland, where 73 cases from around the country have been consolidated, a Johnson & Johnson lawyer announced that the company is prepared to settle all suits in which plaintiffs were hospitalized for stroke, heart attacks, pulmonary embolisms or deep vein thrombosis. . . .

The same day, Johnson & Johnson lawyer Susan Sharko wrote to Superior Court Judge Peter Bariso in Hudson County that the company had reached confidential settlements with 11 of the 12 plaintiffs who sued there. . . .

The Ortho Evra lawsuits generally allege that this contraceptive patch causes blood clots due to heightened estrogen levels, with the result being that relatively young and healthy women -- mostly in their teens and twenties -- using the Ortho Evra patch have suffered heart attacks, strokes, and even death.

Reportedly, since January 2006 about 30 Ortho Evra lawsuits have already received confidential settlements, and Johnson & Johnson (J&J) has told plaintiffs lawyers that the drug company wants to evaluate their remaining personal injury and wrongful death cases for the purpose of settling those Ortho Evra cases.

The Ortho Evra patch was introduced in 2002 and remains on the market, but reports of birth control patch side effects prompted the FDA in November 2005 to order that J&J put a stronger warning on the Ortho Evra package insert, or label, regarding the increased risk of blood clots for women using this contraceptive patch.

(Posted by: Tom Lamb)

Already Poor Visibility In The Vioxx Litigation Seemingly Gets Worse

What Do The Latest Vioxx Study Results Mean, And What Will Merck Do?

The assertions, claims, and interpretations about what the new data from the so-called "Approve" study means regarding any increased risk of a heart attack or stroke during the first year after a person stopped taking Vioxx, and how it will influence the developing Vioxx litigation, are all over the place -- as you were starting to think after reading different articles.

The Wall Street Journal (WSJ) on May 12, 2006, under the headline "Merck Study Finds A Vioxx Risk After Use Ended", said that data for the fourth-year patients who were followed in the Approve study "suggests patients remained at risk of a heart attack or stroke during the first year after they stopped taking [Vioxx]."  The WSJ article pointed out:

In a follow-up analysis of the 2,587-patient study called Approve that led the company to pull the drug from the market in September 2004, Merck officials said patients who took the drug during a three-year trial were 1.64 times as likely to have a heart attack or stroke during a subsequent year when they weren't taking it, compared with those who had been on a placebo.

But this May 11, 2006 Associated Press (AP) article came at the new Approve data from a different angle, under this banner: "Study: Vioxx Users Not at Increased Risk -- Study Finds Vioxx Users Not at Higher Risk of Heart Attack, Stroke in Year After Stopping Drug".  This AP article showed the other side of the recent Approve data:

Merck said data from a "preliminary safety analysis" of an additional year of patient follow-up, part of the study's original plan, did not show a statistically significant difference in the rate of heart attacks and strokes among patients who had been on Vioxx and those who had taken a dummy pill. That means the differences over that year could have been due to chance.

Merck's general counsel Kenneth Frazier asserts that the new Approve results should help Merck defend itself against those legal cases -- among the more than 11,000 Vioxx lawsuits filed against Merck to date -- where a person blamed Vioxx for their heart attack or stroke event at some time in the year after they had already stopped using Vioxx.  As reported in the May 11 AP Vioxx article, Mr. Frazier told analysts and reporters on a conference call: "We [at Merck] believe that the data don't provide for a claim for a patient who had an event after they stopped taking [Vioxx]."

Perhaps Matthew Herper had the best handle on the situation when he used the headline "Vioxx: More Murk For Merck" for his May 11, 2006 online Forbes piece.

Merck says the data show that the heart risk from Vioxx does not persist, because the difference in outcomes between patients who stopped taking the drug and patients who stopped taking a placebo is not statistically significant. But responses from scientists and a Wall Street analyst were all over the map. . . .

The results do show that there is no statistically significant increase in heart attacks among patients who have stopped taking Vioxx compared to those who have stopped taking placebo. However, the data provide no certainty. The door is left open to arguments that Vioxx may increase the risk of heart attacks and strokes. Whether that is true could be crucial as Merck defends itself against more than 11,000 Vioxx-related lawsuits.

Meanwhile, just one week before this latest development in the Vioxx litigation, from "Vioxx Heart Risk Found to Be Early and Persistent", an online piece posted May 3, 2006 on MedPage Today, we learned that perhaps even very short-term Vioxx use -- as little as a week or two weeks of daily use -- could increase a Vioxx user's risk of heart attack or stroke. Moreover, in direct contradiction to some of the recent takes on the latest Approve data (see above), this MedPage article indicated that the increased risk on having a cardiovascular event ended on day seven after one stopped taking Vioxx.

The possible increased risk of having a heart attack or stroke after only short-term use was emphasized in this May 2, 2006 Bloomberg article, "Vioxx-Linked Heart Attacks May Occur Within 2 Weeks, Study Says", which starts:

Merck & Co.'s Vioxx painkiller may raise the risk of a heart attack within two weeks after patients start taking the drug, earlier than previous studies have shown, according to Canadian researchers.

More than a fourth of 239 elderly patients who had heart attacks while on Vioxx did so within six to 13 days after they first started taking the drug, according to a study published online today by the Canadian Medical Association Journal.

Of course, all of this is under consideration by the various interested parties as the two-year anniversary of the Vioxx recall, and the lawsuit filing deadline for many Vioxx plaintiffs, rolls around in September 2006.

(Posted by: Tom Lamb)

Concern Expressed About Heart Risks From Adderall, Ritalin, Other ADHD Drugs

Early Release of Dr. Nissen's NEJM Article: "ADHD Drugs and Cardiovascular Risks"

Cardiologist Steven E. Nissen believes that Shire Plc's Adderall, Novartis AG's Ritalin, and other drugs used to treat attention deficit-hyperactivity disorder (ADHD) may cause potential risks to the heart, and that these risks should be set forth in a "black-box" warning to heighten the awareness of doctors and patients.  Dr. Nissen is the interim chair of cardiology at the Cleveland Clinic and president of the American College of Cardiology.

On March 20, 2006 The New England Journal of Medicine (NEJM) published on its web site an "early-release" version of a "Perspective" article written by Dr. Nissen entitled "ADHD Drugs and Cardiovascular Risk".  This article, which will appear in the April 6, 2006 edition of the NEJM, takes us through the thought process that led Dr. Nissen to introduce his black-box warning motion at the February 9, 2006 meeting of the FDA's Drug Safety and Risk Management Advisory Committee.  This 15-member panel of experts voted 8 to 7 in support of Dr. Nissen's motion and, thereby, recommended a black-box warning be put on the respective labels, or package inserts, to describe the cardiovascular risks of stimulant drugs like Adderall and Ritalin used to treat ADHD.

Likely not by coincidence, the early release of Dr. Nissen's NEJM article on March 20 came just two days before the FDA convened an advisory panel of pediatricians which will consider the safety of drugs like Ritalin and Adderall. This FDA advisory panel is set to review data on a possible link between the ADHD drugs and cardiovascular problems like heart attacks and strokes, as well as psychiatric problems such as hallucinations and psychosis.

As background, the advisory panel of drug safety experts that met in February 2006 had been asked by the FDA to assist the agency in deciding what kinds of studies needed to be done to further study the side effects associated with Adderall, Ritalin, and the other ADHD drugs.  Dr. Nissen suggested that while further studies were warranted, something else was needed immediately -- a black-box warning about the reports of heart attacks, strokes, and sudden unexplained death (SUD) in children and adults that had been submitted to the FDA's MedWatch program.

According to a March 21, 2006 article by Matthew Herper published by Forbes:

"That's not the wrong thing to do," [Dr. Nissen] said in February. "I don't care what their benefits are." Nissen says he is proposing a new regulatory standard: That patients should be warned if there is a high level of suspicion that a drug might be dangerous, instead of waiting for definitive proof. "I am convinced we need to warn earlier and then back off the warnings if the drugs prove safe," he says.

The FDA, however, has said several times since the February 2006 meeting -- when Dr. Nissen's black-box warning motion was narrowly passed -- that the agency would wait to hear from this second advisory panel before deciding whether to strengthen or update warnings on the ADHD drug labels.

At the February 2006 advisory panel meeting, there was testimony presented that 2.5 million children currently take one of the ADHD drugs, including almost 10% of ten-year-old boys. Furthermore, 1.5 million adults take ADHD drugs, with a remarkable 10% over the age of 50.

While most concern to date has been focused on the children, for Dr. Nissen it is older users of ADHD drugs that he is particularly worried about as regards the risks of heart attacks and strokes. The substantial increases in heart rate and blood pressure caused by use of ADHD drugs, particularly during long-term therapy as seen in these adults, are known generally to increase morbidity and mortality.

(Posted by: Tom Lamb)

Pfizer's Painkiller Celebrex May Increase Heart Attack Risk, Like Vioxx and Bextra

New Zealand Study Indicates This Increased Risk Is "Class Effect" of COX-2 Inhibitors

Pfizer Inc.'s painkiller Celebrex doubles a patient's risk of having a heart attack, according to a report about a New Zealand study published in the Journal of the Royal Society of Medicine in the first part of 2006.

A March 1, 2006 Reuters article about the New Zealand study gave this summary:

[The researchers] looked at four trials involving 4,422 patients which compared Celebrex to a placebo. The study . . . showed [Celebrex] was associated with a 2.26 fold increased risk of a heart attack.

In six other studies, patients taking [Celebrex] had a 1.88 fold raised risk of a heart attack compared to patients taking older painkillers such as ibuprofen and paracetamol.

Richard Beasley, one of the lead researchers for the New Zealand study, said their analysis of these drug trials involving Celebrex (celecoxib) suggests this increased risk of having a heart attack is common to the entire class of drugs known as COX-2 inhibitors.

Merck & Co. Inc. withdrew Vioxx from the market in September 2004 after a study showed it doubled the risk of a stroke or heart attack in patients taking it for 18 months or more.  Thereafter, in April 2005, Pfizer voluntarily recalled Bextra due to these cardiovascular side effects as well as an increased risk of developing serious skin reactions like Stevens-Johnson Syndrome (SJS).  Due to these two drug recalls, Celebrex is the only the COX-2 inhibitor still available in the U.S.

In August 2005, however, Pfizer put a "black-box" warning on Celebrex label, or package insert, following a recommendation by the FDA, which warns that Celebrex may increase the risk of cardiovascular events, including heart attack and stroke.

In 2005, also, the European Medicines Agency (European Union's drug regulator) issued guidance about the use of COX-2 pain relievers, stating in relevant part that Celebrex should not be prescribed to people with ischemic heart disease or stroke, and when prescribed the lowest dose and shortest course of Celebrex should be used.

Returning to the March 1 article published by Reuters:

"Our evidence shows an increased risk of heart attack in patients taking [Celebrex]," said Beasley.

"Drug regulatory authorities need to urgently re-examine the assessment of [Celebrex] in light of these findings," he added in a statement.

"Given the popularity of [Celebrex] in the treatment of arthritis, drug regulators must undertake an up-to-date risk assessment based on the findings presented here," said Beasley.

A spokesman for Pfizer contested the analysis done by the New Zealand researchers in a March 1, 2006 article in The Wall Street Journal:

"The FDA, [the European Medicines Agency] and other health authorities around the world have concluded that the benefits of Celebrex continue to outweigh its risks, and, as a result, Celebrex is the only Cox-2 inhibitor remaining on the market today."

In December 2005 the Cleveland Clinic announced that it would lead an international study to learn whether painkillers taken for arthritis, including Celebrex, Ibuprofen and Naproxen, are safe for those at risk of heart problems.  The results from that study -- known as the PRECISION study -- will not be available, however, until 2010 at the earliest.

(Posted by: Tom Lamb)

FDA Reviewing Safety Of Bayer's Heart Surgery Drug Trasylol

Studies Link Trasylol To Kidney Problems, Heart Attacks, and Strokes

In mid-February 2006 the FDA issued a Public Health Advisory informing doctors and patients that the agency was evaluating the safety of Bayer AG's heart surgery drug Trasylol (aprotinin injection) after new studies had linked it to higher risks of kidney problems, heart attacks, and strokes.  At the end of February, a "Dear Doctor" letter from Bayer regarding Trasylol was posted on Health Canada's MedEffect web site.

Trasylol was approved by the FDA in 1993, and is typically used in patients who undergo coronary artery bypass graft (CABG) surgery to prevent blood loss during their surgery.

In January 2006 two medical journal articles were published which raised concerns about the safety of Trasylol.  The New England Journal of Medicine (NEJM) published an article which reported that Trasylol increased the risk of kidney failure and stroke by 100 percent, i.e., doubled the risk, and increased the chance of heart failure or heart attack by 55 percent.  In January 2006, also, the medical journal Transfusion published a second study report which suggested that Trasylol administration increased the risk for renal dysfunction or kidney failure, but those researchers did not find an increased rate of heart attacks nor strokes.

The FDA said it will hold an advisory committee meeting later in 2006 to investigate the benefits and risks of Trasylol as well as to determine if more safety measures are needed.  According to a statement issued by Dr. Steven Galson, Director of FDA's Center for Drug Evaluation and Research:

We're working to evaluate the potential risks and determine whether there is a need for further action.  In the meantime, we advise providers to carefully assess the benefits and risks of [Trasylol] for their patients.

In response to this news, a spokesman for Bayer said the drug company will cooperate with the FDA. At the same time, however, Bayer asserted that the study results set forth in the NEJM and Transfusion articles were "not consistent with the more than 15 years of clinical data and experience Bayer has amassed on [Trasylol]."  In addition, Bayer pointed out that both studies were observational studies, and as such have certain methodological limitations which prevent a direct assessment of whether Trasylol actually increased the risk for kidney problems, heart attacks, and strokes.

(Posted by: Tom Lamb)

Adderall and Ritalin: With Heart Risks Uncertain, What Should Patients Do?

Some Medical Advice About ADHD/ADD Drugs From Cardiologists And Psychiatrists

In mid-February 2006 came the news that an advisory panel of drug-safety experts recommended a "black-box" warning for Adderall, Ritalin, and the other ADHD/ADD drugs -- and that the FDA was not going to act on this advice, at least for the time being.  This situation left many people understandably confused.

To address some of these concerns and questions, New York Times (NYT) reporter Benedict Carey interviewed some prominent cardiologists and psychiatrists (free registration required) for an article which was published on February 21, 2006.  Mr. Carey's apparent aim was to provide some guidance to adult patients and the parents of pediatric patients in terms of how to proceed in view of the possible serious side effects associated with Adderall, Ritalin, and the other ADHD/ADD drugs.  Here is a summary of his findings.

Primarily, it is people with high blood pressure, heart murmurs, or other cardiovascular problems who should be consulting with their doctors in order to determine whether Adderall, Ritalin, or some other ADHD/ADD drug is safe for them. 

Along these line, concerning pediatric patients, Mr. Carey reports:

Some panel members expressed concerns about children with structural heart abnormalities who might be given stimulants. Perhaps the most common abnormality is hypertrophic obstructive cardiomyopathy, a thickening of the muscle that can cause a blockage — and death — when under stress.

Such problems are often not diagnosed before drug treatment begins, but a good pediatrician who is aware a child is being considered for stimulant treatment will often pick up a soft heart murmur that might reflect an abnormality, said Dr. Steven Nissen, chief of cardiology at the Cleveland Clinic and a panel member. "This seemingly small step could save a life," he said.

As for adult patients using Adderall or Ritalin, the emphasis is on one's blood pressure. From Mr. Carey's February 21 NYT article:

The biggest worry for adults is high blood pressure. Stimulants usually prompt slight increases in heart rate and raise blood pressure, and even these changes can increase the risk of heart problems in someone who is vulnerable, Dr. Nissen said.

"A smoker with high cholesterol and a family history of heart disease: that's a person I would be very concerned about taking stimulants," Dr. Nissen said.

From his interviews, Mr. Carey found that, generally, there are a few screening questions which would help a doctor determine whether or not Adderall or Ritalin is safe for a patient.

• Are there any congenital or structural heart defects?
• Are there unexplained bouts of dizziness or heart palpitations?
• Is there any family history of heart disease, in particular sudden deaths in close relatives who died young?

It seems advisable that doctors should be these few questions, at least, before prescribing Adderall, Ritalin, or another ADHD/ADD medication.  If your doctor, or your child's doctor, is considering such treatments but has not asked, you should "volunteer" this part of your medical history for their decision-making.

(Posted by: Tom Lamb)

Study Shows Blood-Clot Risk For Birth Control Patch Is Double That Of An Oral Contraceptive

However, According To Another Study Ortho Evra Skin Patch Use Presents No Increased Risk Of Blood Clots

On February 16, 2006 Ortho-McNeil Pharmaceutical, Inc., a Johnson & Johnson (J&J) unit, announced that some preliminary results from a yet-to-be-published study indicate there is a two-fold increase in the risk of blood clots among users of its Ortho Evra birth control patch when compared to women using a typical birth control pill.  At the same time, Ortho-McNeil pointed out the results from a second Ortho Evra study, this one just published on the Web site of the journal Contraception, which showed there was no increased risk of blood clots when Ortho Evra was compared to birth control pills.

As background, in November 2005 the FDA issued a MedWatch Alert telling doctors and patients that the contraceptive patch Ortho Evra might increase the risk of blood clots because the patch contains more estrogen than a typical birth control pill.  Specifically, the FDA said women using the Ortho Evra birth control patch are exposed to about 60% more estrogen than if they were taking a birth control pill with the typical 35 micrograms of estrogen. It is the exposure to this higher level of estrogen exposure from the Ortho Evra patch that could significantly increase a woman's risk of developing potentially fatal blood clots.

After the November 2005 FDA alert about Ortho Evra, Ortho-McNeil and J&J said they would conduct additional safety studies on the issue of whether Ortho Evra causes an increased risk of blood clots which, in turn, can produce heart attacks and strokes.  The two studies which were announced by the drug companies on February 16, 2006 are part of their effort on that front.

The first Ortho Evra study (not published yet) is being conducted by a unit of Ingenix, which is part of UnitedHealth Group.  According to a February 16, 2006 article in The Wall Street Journal (subscription required), by reporter Jennifer Corbett Dooren:

"[This Ortho Evra study] showed a two-fold increase in the risk of blood clots, or venous thromboembolic events, compared to women on a regular birth control pill. The same data does not show an increase in the risk of heart attacks and strokes, J&J said."

Then there is the second study, published online by the journal Contraception, where researchers examined a medical records database for 200,000 women.  Those researchers found that the risk of developing blood clots among Ortho Evra users was about the same as the risk among women using a typical birth control pill.

The heart attack and stroke risk aspect of this second study is still ongoing, Ortho-McNeil said in their February 16 statement, which added "the currently available data do not show an increase in the risk of the combined endpoint of heart attack and stroke."

A day after the Ortho-McNeil / J&J announcement about these Ortho Evra studies, the FDA said further investigation of the issue of whether Ortho Evra causes an increase in blood clots is warranted.  As Reuters reported on February 17, 2006, however, Dr. Daniel Shames, director of the FDA's division of reproductive and urologic drug products, made clear that the FDA does not plan to take any action at present based on these two Ortho Evra studies.

As of early 2006, it is estimated that the Ortho Evra birth control patch has been used by more than 5 million women since it was approved by the FDA in 2002. 

(Posted by: Tom Lamb)

Adderall Safety Is Not Proven By Health Canada's Decision To Reverse Ban On ADHD Drug

A Closer Look At How (Or Why) Adderall Got Back On The Market In Canada

In the October 7, 2005 edition of Psychiatric News there was an article by Jim Rosack entitled "Canada Reverses Ban On ADHD Medication" that examined how Adderall XR got back on the market six months after Health Canada had suspended sales of the popular attention-deficit/hyperactivity disorder (ADHD) drug.

As background, Health Canada announced on August 24, 2005 that Adderall XR could be reintroduced to the Canadian market.  Health Canada had recalled Adderall XR from the Canadian market in February 2005 after learning from Shire Pharmaceuticals Group Plc -- the company responsible for Adderall XR in Canada -- about 20 cases of sudden death and 12 cases of stroke in people using the ADHD drug.

An article published in the October 11, 2005 edition of the Canadian Medical Association Journal pointed out that Health Canada decided to allow Adderall back on the market in August 2005 not because the agency found Adderall to be safe but, rather, because "an independent panel found it impossible to accurately ascertain whether the drug increases the risk of cardiac death."

Given the February 2006 recommendation by an FDA advisory panel committee that a "black-box" warning be put Adderall and the other ADHD drugs, the "how-and-why" of Adderall getting back on pharmacy shelves in Canada is worth a second look. 

Health Canada rescinded its suspension order and allowed Adderall to return to the market after its committee of outside medical experts, called the Adderall XR New Drug Committee, had concluded that "an increased risk of sudden cardiac death and/or stroke with Adderall XR compared to alternate active treatments has not been proven."

It is important to know that the Health Canada committee concluded, also, that "such an increase [in risk of sudden cardiac death associated specifically with Adderall XR use] has not been ruled out due to limitations in the data currently available for analysis"  (emphasis added).

Faced with this predicament, the committee recommended several steps be taken by Health Canada and Shire before Adderall was put back on pharmacy shelves.  The full set of recommendations can be found in the report prepared by this Adderall XR New Drug Committee.  In his October 2005 Psychiatric News article, Rosack provides some of the highlights:

• recommended that Health Canada seek expert consultation "on the appropriateness of potential additional cautions (e.g., strenuous exercise, use of other stimulants, family history of sudden cardiac death) in patients treated with any ADHD drug (stimulant or non-stimulant) that might be considered in the assessment of benefit versus risk for an individual patient."
• recommended that Health Canada approve revised product labeling submitted by Shire in November 2004. That proposed labeling (virtually identical to the approved labeling in the United States) includes warnings regarding reports of sudden death in patients taking therapeutic doses of amphetamines, particularly children with structural cardiac abnormalities. The new Canadian labeling will also add myocardial infarction, sudden death, and stroke to the list of potential adverse events.
• recommended that Health Canada "enhance postmarketing surveillance for all stimulant drugs used in the management of ADHD," but did not list specific steps they thought should be taken. The committee also noted that while an increased risk of adverse cardiac events associated with stimulant medications "is lacking, even in the absence of this information, it may still be prudent for a baseline EKG be obtained prior to implementing drug therapy" for patients who are involved in strenuous exercise, use more than one stimulant medication, or have a family history of sudden cardiac death.

In the end, despite the fact that Health Canada let Adderall XR back on the market, it seems that there are some serious and yet unresolved safety issues for this ADHD drug.  As such, the FDA should give more consideration to the findings of its own advisory panel committee and, in particular, the recommendation that a black-box warning be added to Adderall and the other ADHD drugs.

(Posted by: Tom Lamb)

Ortho Evra Birth Control Patch Linked To Increased Risk of Serious Blood Clots

2005 Label Change Warns About Higher Levels Of Estrogen Found In Ortho Evra

In July 2005 the Associated Press (AP) published an investigative article that linked the birth control patch Ortho Evra to an increased risk of blood clots and deaths -- compared to older contraceptives -- in some young healthy women.

In November 2005 the FDA announced that it had approved an updated label, or package insert, for the Ortho Evra contraceptive patch.  This label change was intended to warn doctors and patients that the Ortho Evra birth control patch exposes women to higher levels of estrogen than a typical birth control pill. It is the higher levels of estrogen which women using the Ortho Evra skin patch are exposed to that causes the increased risk of developing blood clots and other serious side effects.

The AP's July 2005 article on Ortho Evra said that a review of adverse drug reaction reports for Ortho Evra revealed that 17 of the 23 death cases appeared to be related to blood clots.  The AP article stated that there were 12 deaths of Ortho Evra users reported to the FDA in 2004.  The actual number of deaths due to blood clots in Ortho Evra users, however, is probably much higher because the FDA estimates that the agency receives reports for only a small percentage -- in the range of 1% (1 out of 100) to 10% (1 out of 10) -- of the serious adverse drug reactions that actually occur in the U.S.

Ortho Evra was approved by the FDA in November 2001 and is the first contraceptive product to be approved for use is the U.S. as a skin patch. Ortho Evra is sold by Ortho-McNeil Pharmaceuticals, Inc. of Raritan, N.J.

By examining documents related to FDA reviews of clinical trial results submitted by Ortho-McNeil in support of Ortho-Evra, the AP found that the safety of Ortho Evra was disputed even before it was approved by the FDA in 2001.  The AP reported that the FDA medical officer reviewing the Ortho Evra application disagreed with Ortho-McNeil about whether or not two cases of blood clots in the lungs (pulmonary embolus) in young women participating in the pre-approval clinical trials were caused by the Ortho Evra. In relevant part, the FDA medical officer wrote:

"THE REVIEWER DOES NOT AGREE WITH THE SPONSOR’S [Ortho-McNeil] ABOVE CONCLUSIONS. The two cases of pulmonary embolus, a serious and potentially fatal condition, must be counted as two cases in the ... group [emphasis in the original]."

As concerns the increased risk of developing blood clots associated with Ortho Evra, it is generally advised that women using the Ortho Evra birth control patch should contact their physician if any of the following warning signals develop:

• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)
• Pain in the calf (indicating a possible clot in the leg)
• Crushing chest pain or tightness in the chest (indicating a possible heart attack)
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)

Lastly, like the other hormonal contraceptives, Ortho Evra has a "black-box" warning about the fact that cigarette smoking increases the risk of serious cardiovascular side effects. This risk increases with age and with heavy smoking (15 or more cigarettes per day).  Women over 35 years of age who use hormonal contraceptives, including Ortho Evra, especially should be strongly urged not to smoke.

(Posted by: Tom Lamb)

FDA Wants New Safety Studies For Adderall, Other ADHD Drugs

Reports Of Serious Adverse Events Involving Sudden Death, Heart Attack, and Stroke

Reports of sudden deaths, heart attacks, and strokes in both children and adults taking drugs to treat attention deficit hyperactivity disorder (ADHD) that have been made over time to the FDA has prompted the agency to look anew into the safety of Shire Pharmaceutical's Adderall XR and other ADHD drugs.

Cardiovascular events associated with Adderall and other ADHD drugs will be discussed at meetings of the FDA’s Drug Safety & Risk Management Advisory Committee on February 9 and February 10, 2006 in Gaithersburg, Maryland.  Specifically, the FDA wants members on this advisory committee to discuss the development of new studies aimed at determining “whether ADHD products increase the risk of adverse cardiovascular outcomes.”

In an announcement for the February 2006 advisory committee meeting, the FDA said:

• “Cases of sudden death and serious adverse events including hypertension, myocardial infarction, and stroke have been reported to the agency in association with therapeutic doses of drugs used to treat attention deficit hyperactivity disorder (ADHD) in both pediatric and adult populations."
• “The few controlled clinical studies of longer-term drug treatment of ADHD provided little information on cardiovascular risks."

In February 2005, Health Canada suspended the marketing of Shire’s Adderall XR due to reports of sudden death, heart attacks, and strokes in pediatric and adult patients.  Six months later, however, Health Canada reintroduced Adderall to the Canadian market in August 2005 not because the agency found Adderall to be safe but, rather, because "an independent panel found it impossible to accurately ascertain whether the drug increases the risk of cardiac death."

According to reporter Andrew Bridges, in a January 4, 2006 Associated Press article, Dr. Peter Gross, the chairman for this advisory committee, made this noteworthy comment on the paucity of longer-term safety studies for Adderall and other ADHD drugs: "It almost sounds like cox-2 inhibitor redux" -- alluding to the 2004 recall of Vioxx following the "delayed" discovery that Vioxx significantly increased one's risk of having a heart attack or stroke.

Dr. Gross's observation makes one wonder whether Adderall XR, essentially an extended release amphetamine, might be prove to be our next Vioxx-debacle.

(Posted by: Tom Lamb)

WHI Study Was Perhaps Flawed And Subsequent HRT Advice May Be Wrong

Cyclical Hormones, But Not Prempro, May Be Protective Against Heart Disease

Many people will recall that in July 2002 women were told to talk to their doctor about perhaps stopping their hormone replacement therapy (HRT) after the Women's Health Initiative (WHI) said a trial of Wyeth's Prempro showed that the drug raised the risk of heart attack, stroke, and breast cancer.

A recent study, which was published on December 16, 2005 in the medical journal Fertility and Sterility, now suggests that the broad-brush notion that hormone replacement therapy raises the risk of heart disease and breast cancer -- causing many women to stop using the HRT drugs -- was fundamentally flawed.

Accordingly, Dr. Edward Klaiber, a Worcester, Massachusetts endocrinologist and lead author of the new study, asserts "Women are now being told not to take hormones for heart disease prevention, and that may be totally wrong".

Prior to the 2002 WHI study results, hormone replacement therapy was routinely prescribed to women as they reached menopause for the purpose of not only relieving unpleasant symptoms like hot flashes but, also, because it was thought to protect against heart disease and osteoporosis. 

Based on the alleged problems he found with the WHI study, Dr. Klaiber believes that earlier medical research which showed that cyclical hormones are protective against heart disease is probably still valid, today.

According to Dr. Klaiber, the first problem with the WHI study results is that when the WHI trial was initially designed, hormone replacement therapy usually involved cyclical progesterone, meaning that it was taken just 10 or 12 days a month.  Then came Prempro, which combined estrogen and progestin in a daily pill -- a regimen that had never been associated with heart protection, Klaiber said.

Given this difference between the earlier approach to HRT and Prempro, Dr. Klaiber maintains: "The [WHI study] results might have been different if they had used a different form of estrogen that resembled a normal cycle."

Dr. Klaiber states that the WHI study's other major flaw was that the clinical trial participants were older, with a mean age of 62.7 years.  This population was already at a greater risk of cardiovascular problems. "The incidence of heart disease is 12 times higher for women in their 80s than it is in the 50s," Dr. Klaiber said.  Put otherwise, the WHI study began HRT for the first time in women who might have had pre-existing heart disease.

To determine the strength of his theory, Dr. Klaiber will be following a multi-center trial launched last year by the Phoenix-based Kronos Longevity Research Institute. In the Kronos study women aged 40 to 55 with be treated with hormone pills, hormones delivered through a skin patch, or a placebo.  Dr. Klaiber anticipates that the Kronos study will eventually show that hormone replacement therapy is not risky in women who are just beginning to go through menopause.  The Kronos study results, however, will not be available until 2010, according to Dr. Klaiber.   

Dr. Klaiber does allow that, regardless of its alleged flaws, the WHI study made a very significant contribution to the medical world because it showed that "Prempro was a mistake".

(Posted by: Tom Lamb)

Bextra Will Not Return In Canada As Safety Risks Outweigh Benefits

Health Canada Safety Panel Cites Heart Attacks, Strokes, and Severe Skin Reactions

Bextra, Pfizer's anti-inflammatory drug for arthritis patients, will not be returned to the Canadian market according to a Health Canada announcement in mid-December 2005.  Bextra was withdrawn voluntarily from the Canadian market in April 2005 by Pfizer after severe skin reactions affected seven people in Canada.

Citing the findings and recommendations of its expert safety panel, Health Canada said that the safety risks of Bextra outweighed its benefits.  In particular, Health Canada pointed out the serious cardiovascular risks associated with Bextra, including heart attack and stroke, and said that Bextra causes rare but severe and potentially fatal skin reactions more often than other drugs in its class.  Specifically, the severe skin reactions are erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

A Health Canada spokesman, Jirina Vlk, was quoted in a December 17, 2005 Toronto Star article: "We concluded that there is insufficient evidence to establish the safety of the drug for its recommended use."

Bextra is a COX-2 inhibitor.  This class of drugs includes Vioxx and Celebrex.  In September 2004 Vioxx, once the most popular painkiller in Canada, was pulled from the worldwide market.  Subsequent to the the Vioxx recall, new warnings about serious cardiovascular risks have been added to the package insert, or label, for Celebrex.

According to the Toronto Star article, in a written release, Pfizer Canada said "Bextra is an important treatment option ... (and) it should continue to be available for those patients who could benefit from it."

More information about this action as well as earlier actions by Health Canada concernng Bextra can be found in its December 16, 2005 Advisory, posted on the Health Canada web site.

(Posted by: Tom Lamb)

Large Study to Investigate Heart Risks Of Celebrex, Ibuprofen, and Naproxen

Cleveland Clinic's Dr. Nissen To Lead 20,000 Patient "Precision" Clinical Trial

In mid-December 2005 the drug company Pfizer Inc. announced that Dr. Steven E. Nissen, medical director of the Cleveland Clinic's cardiovascular coordinating center, will lead a large-scale clinical trial to compare three of the most commonly used painkillers -- Pfizer's Celebrex, and prescription-strength doses of ibuprofen and naproxen -- among arthritis patients who also have pre-existing cardiovascular disease or who are otherwise at high risk of heart problems.

In laymen's terms, the "end point" of this massive study will be to answer this simple question: What is the safest medicine for these patients to control their pain?

Earlier in 2005, the FDA mandated that increased warnings be added to the package insert labels of Celebrex, a COX-2 inhibitor, as well as ibuprofen and naproxen, which are non-steroidal anti-inflammatory drugs (NSAIDs). The reason behind this FDA action was that some clinical studies had raised concerns that Celebrex and the two NSAIDs, like the recalled painkiller Vioxx, may increase a patient's risk of having a heart attack, stroke, or other serious cardiovascular event. The problem for the FDA, not to mention doctors and their patients, was that these previous studies were not definitive on the cardiovascular safety issue.  In part, that "uncertainty" problem was the result of the fact that there had not yet been any large-scale clinical studies of Celebrex, or the two NSAIDs, which focused on patients who had one or more pre-existing risk factors for cardiovascular disease.

The aim of this new Pfizer-sponsored clinical study -- which will be called "Precision", according to Forbes reporter Matthew Herper -- is to track incidents of cardiovascular deaths as well as non-fatal heart attacks and strokes in order to determine whether Celebrex, ibuprofen, and/or naproxen are safe for use by patients already at risk for serious cardiovasucular side effects. 

To this end, the Pfizer study will enroll 20,000 patients "worldwide" (actually just Australia, the U.S., Eastern Europe, and Switzerland, according to a December 13, 2005 Forbes online article by Matthew Herper) over an eighteen-month period.  Those patients will be followed for an average of two years, at a cost to Pfizer in the range of $100 million.  The results of this "Precision" study are expected to be available in no less than four years.

In a December 13, 2005 article in The Wall Street Journal, Dr. Nissen commented:

• "The public and the medical community are confused.... The relative safety of these three drugs is simply not known.  We're going to answer the question are they the same or are they not."
• "There has been an erosion of public confidence in this class of drugs.... We need to get an answer that is done in a way that is completely transparent."

Not all medical researchers, however, believe this Pfizer-sponsored study is a good thing.  For example, Garret FitzGerald, a renowned pharmacologist at the University of Pennsylvania, thinks giving Celebrex or the two NSAIDs to patients already at a high risk of having a heart attack or a stroke may be "ethically questionable", according to the December 13 Forbes article.  That article by Mr. Herper states, also, that Dr. FitzGerald "expressed concerns that the study could be just a way to buy Pfizer some more time."

According to news reports, the first patient will not be enrolled in the "Precision" clinical trial until some time in 2006.

(Posted by: Tom Lamb)

Ortho Evra Lawsuits May Get MDL Status in Federal Court System

Birth Control Patch Allegedly Causes Serious Cardiovascular Problems

Late in 2005, a motion was filed with the Judicial Panel on Multidistrict Litigation (JPML) by a plaintiff's lawyer requesting the consolidation of all federal court lawsuits alleging injury or death due to use of the Ortho Evra birth control patch.

Ortho Evra is manufactured by Ortho McNeil Pharmaceutical, Inc. , a subsidiary of Johnson & Johnson.  The Ortho Evra birth control patch was approved by the FDA in 2001. 

On November 10, 2005 the FDA issued a warning about an increased risk of blood clots associated with Ortho Evra, which clots can cause serious injury or death.

In more detail, this recently filed legal motion calls for the creation of an Ortho Evra mulitidistrict litigation, or MDL, and requests that the Ortho Evra MDL, if granted, be assigned to the District of New Jersey in the federal court system. Specifically, the Ortho Evra MDL motion was filed on behalf of the plaintiff in Lydia M. Lilly v. Ortho-McNeil Pharmaceutical, Inc., et al. (Civil Action No. 2:05-cv-04313 (D. New Jersey).

At the time when the Ortho Evra MDL motion was filed there were about twenty individual Ortho Evra lawsuits already filed in the federal court system, and at least one federal class action.  Many more personal injury and wrongful death lawsuits concerning women who used Ortho Evra birth control patches are expected to be filed in the months to come.

The typical Ortho Evra lawsuit alleges that Ortho-McNeil was aware of the increased risk of serious side effects -- namely, strokes, pulmonary emboli, blood clots, deep vein thrombosis, and heart attacks resulting in serious injury or death -- associated with Ortho Evra before the drug was approved by the FDA in November 2001.  Moreover, the lawsuits generally allege that Ortho-McNeil failed to adequately warn doctors, patients, and the FDA about these serious cardiovascular side effects after the drug went on the market.  Significantly, over five million woman have reportedly used Ortho Evra since it went on the market in 2001.

The Ortho Evra lawsuits typically name as defendants some combination of the following entities: Johnson & Johnson; Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (formerly known as R.W. Johnson Pharmaceutical Research Institute); and, Ortho-McNeil Pharmaceutical, Inc.

Ortho Evra remains on the market today.  It has been reported, however, that the number of new and renewed Ortho Evra prescriptions written has declined since the FDA warning was announced in the first part of November 2005.

(Posted by: Tom Lamb)

Study On Cardiovascular Safety of Celebrex Reported at 2005 ACR Meeting

No Increased Risk Of Heart Attack Or Stroke For Patients Taking Celebrex   

According to a meta-analysis reported by Dr. Lee Simon, Associate Clinical Professor of Medicine at Harvard Medical School, the COX-2 specific inhibitor Celebrex (celecoxib) is not associated with an increased risk of serious cardiovascular thrombotic events compared to placebo or NSAIDs.  This meta-analysis, which covered 41 clinical studies involving 44,308 patients, evaluated the cardiovascular safety of Celebrex versus both placebo and nonselective NSAIDs ("ns-NSAIDs").

In summary, the meta-analysis showed that patients taking Celebrex had no more risk for heart attack, stroke, or CV death combined than those given placebo or ns-NSAIDs.

Dr. Simon presented his report about the meta-analysis at the American College of Rheumatology (ACR) 2005 Annual Scientific Meeting, held in mid-November at San Diego, California. Some of his findings included:

• “There were no cardiovascular signals that were any different to the active comparators. [Celebrex] was no different to non selective drugs in terms of cardiovascular risk,” Dr. Simon said. Comparators included placebo, naproxen, diclofenac, ibuprofen, loxoprofen, acetaminophen and ketoprofen.
• “In this large meta-analysis comprising studies of two weeks to three years duration involving patients with chronic conditions, [Celebrex] at doses of 200mg or more total daily dose was not associated with an increased risk of serious CV thromboembolic events compared with placebo or nonselective NSAIDs,” Dr Simon concluded.

Dr. Simon is a former Division Director of the Arthritis, Analgesic & Ophthalmologic Drug Product Division at the FDA's Center for Drug Evaluation and Research.

This meta-analysis was reportedly funded by the drug company Pfizer, which makes Celebrex.  Dr. Gail Cawkwell, a Senior Medical Director at Pfizer, said that this meta-analysis presented by Dr. Simon at the 2005 ACR meeting was being prepared for publication in a peer-reviewed journal.  Further, Dr. Cawkwell said the new meta-analysis data had been shared with the FDA as well as European Union regulators.

(Posted by: Tom Lamb)

Safety Warning Issued For Ortho Evra Birth Control Skin Patch

FDA: Possible Increased Risk of Blood Clots For Ortho Evra Users

In November 2005 the FDA announced that it had approved an updated label, or package insert, for the Ortho Evra contraceptive patch.  The purpose of the label change was to warn doctors and patients that the Ortho Evra birth control patch exposes women to higher levels of estrogen than a typical birth control pill. In turn, because of the higher levels of estrogen, women using the Ortho Evra skin patch for birth control are at an increased risk of developing blood clots and other serious side effects.

The new label, or package insert for Ortho Evra, includes a bold-letter, or "bolded", warning about higher exposure to estrogen for women using the weekly patch compared to taking a typical birth control pill.

A November 10 FDA News Release gives us a summary of the blood clot problem associated with Ortho Evra:

The addition of this new warning is a result of FDA's and the manufacturer's analysis directly comparing the levels for estrogen and progestin hormones in users of Ortho Evra with those in a typical birth control pill. In general, increased estrogen exposure may increase the risk of blood clots. However, it is not known whether women using Ortho Evra are at a greater risk of experiencing these serious adverse events.

The new bolded warning specifically states that women who use Ortho Evra are exposed to about 60 percent more estrogen than if they were taking a typical birth control pill containing 35 micrograms of estrogen. However, the maximum amount of estrogen to which women are exposed is about 25% lower with Ortho Evra than they are with typical birth control pills.

According to Dr. Sidney Wolfe, the Director of Public Citizen’s Health Research Group, the FDA's action is too late and too little:

The new warning by the U.S. Food and Drug Administration (FDA) belatedly acknowledges the increased dangers of using the drug. These dangers were noted by the FDA physician who reviewed the drug before the agency approved it. Despite the fact that the agency has now admitted  that “women who use Ortho Evra are exposed to about 60 percent more estrogen than if they were taking a typical birth control pill” - important because increased estrogen means increased risks - the agency still allowed the drug on the market and is stubbornly unwilling to ban it.

The Ortho Evra contraceptive patch is made by Ortho-McNeil Pharmaceutical, Inc., which is a unit of the drug company Johnson & Johnson.  The Ortho Evra skin patch has been used by more than five million women for birth control since it was approved by the FDA in 2002.

Ortho McNeil is reportedly in the process of conducting additional drug-safety studies for Ortho Evra about the degree of increased risk for women using Ortho Evra patch -- in comparison to women using typical birth-control pills -- of developing blood clots and other serious side effects.

(Posted by: Tom Lamb)

Danish Study Suggests Celebrex And Vioxx To Be Avoided After Heart Attack

Increased Risk Of Death For Post-Heart Attack Patients Taking COX-2 Drugs

In mid-November 2005 it was reported that Merck's Vioxx and Pfizer's Celebrex, as well as some similar painkillers, increase the risk of death among patients who had a previous heart attack, especially when the painkillers were taken in high doses.  These findings from a Danish study were released November 13, 2005 at the American Heart Association conference in Dallas, Texas.

The findings come from a study which was funded by the Danish Heart Foundation and the Danish Pharmaceutical Association.  This Danish study is reportedly the first to look at patients with known heart problems.  The study's lead researcher, Dr. Gunnar Gislason, of the Bispebjerg University Hospital in Copenhagen, said at the Dallas conference this study indicates that patients who have heart disease should not use Celebrex or Vioxx, also called COX-2 inhibitors.

The November 2005 Danish study results showed that heart disease patients 25 milligrams ("mg") of Vioxx or more on a daily basis had a 5.03 times greater risk of dying when compared to those patients not taking any COX-2 drug. For Celebrex, those post-heart attack patients taking 200 mg of Celebrex or more daily had a 4.24 times greater risk of dying, while patients taking 200 mg of Celebrex or less had a 1.7 times greater risk.

A Merck spokesman, Chris Loder, was "quick" to criticize the Danish study -- insofar that no one at Merck, according to Mr. Loder, had seen Dr. Gislason's study.  Merck's spokesman pointed out that randomized controlled clinical trials are the preferred way of establishing the safety of a drug, and that this study conducted by Dr. Gislason was not of this type. Mr. Loder asserted, "Randomized controlled clinical trials are the gold standard."

As is well-known by now, Merck pulled Vioxx off the market in September 2004 after such a clinical study showed an apparent increased risk of cardiovascular problems, including heart attacks and strokes, for patients who took Vioxx for at least 18 months. Merck maintains, however, that neither the earlier study nor any other randomized controlled clinical trial has established that there is an increased risk of death from using Vioxx, i.e., Merck disputes what this Danish study headed up by Dr. Gislason has found, now.

According to news reports, no Pfizer executives were immediately available to comment on the Danish study and its findings about Celebrex.

The Gislason study was based on the researchers' review of medical records for more than 58,000 Danish patients who had their first heart attack between 1995 and 2002.

(Posted by: Tom Lamb)

Merck Prevails In Its First New Jersey Vioxx Trial

Humeston Case Ends with Defense Verdict for Merck

Merck & Co. got what it wanted in its first New Jersey Vioxx trial: a defense verdict.

On November 3, 2005, a New Jersey state court jury concluded that the use of Vioxx did not play any role in causing the heart attack of Frederick "Mike" Humeston, the 60-year-old plaintiff in the nation's second Vioxx case to go to trial.  Significantly, Mr. Humeston said he took the painkiller Vioxx for only two months and not a regular, daily basis. 

In this Humeston Vioxx case the jury also found that Merck had not misrepresented the safety of Vioxx, and that Merck did not commit any consumer fraud in how the drug company promoted Vioxx to doctors and patients.

The Humeston jury had to consider the competing evidence which it heard during the seven weeks of testimony.  Somewhat remarkably, the Humeston jury deliberated for just a bit more than one full day before issuing its defense verdict in favor of Merck.

Essentially, as regards Merck's conduct concerning Vioxx, the Humeston verdict means one of two things.  The first possible conclusion is the jury determined that Merck did not know Vioxx posed cardiovascular risks back in 2001, when Mr. Humeston was prescribed Vioxx.  The second possible conclusion is the jury believed that, even though Merck knew about those cardiovascular risks in 2001, the drug company had adequately warned doctors about the risks associated with Vioxx.

On the medical aspect, the Humeston jury determined that Vioxx was not a substantial factor in causing the plaintiff's heart attack in this case.  Consistently during the Humeston trial, Merck made two primary arguments when defending on the medical causation issue. The first defense argument asserted by Merck was that low-dose, short-term use of Vioxx has not been found to cause heart attacks.  In addition, Merck's defense team told the jury that Mr. Humeston's pre-existing medical conditions -- elevated blood pressure, being overweight, and work-related stress -- caused his heart attack, not the limited Vioxx use.

Following the Humeston verdict, Jim Fitzpatrick, a spokesman for Merck, was quoted by The Wall Street Journal ("WSJ") as follows:

• "We're very pleased with the jury's verdict."
• "I think the science is very clear that there is no short-term risk."
• "This confirms our strategy" to fight each case individually based on the science.

When the dust settles, it will be interesting to see whether Merck reaches out to plaintiffs' lawyers in an attempt to settle those Vioxx cases which involve eighteen months or more of Vioxx use followed by a heart attack or ischemic stroke.

(Posted by: Tom Lamb)

Health Canada Put Adderall Back on the Market Based on "Inconclusive Evidence"

Safety of Adderall Cannot be Adequately Evaluated Says Expert Committee Chairman

In the October 11, 2005 edition of the Canadian Medical Association Journal ("CMAJ"), an article by Wayne Kondro reveals that Health Canada reintroduced Adderall (amphetamine salts) to the Canadian market in August 2005 not because the agency found Adderall to be safe but, rather, because "an independent panel found it impossible to accurately ascertain whether the drug increases the risk of cardiac death."

As some may know, Adderall is a central nervous stimulant used in treating attention-deficit hyperactivity disorder (ADHD).  Adderall was taken off the Canadian market in February 2005 after its manufacturer, Shire Biochem Inc., had  disclosed to drug regulators reports of 20 sudden deaths and 12 strokes worldwide among patients taking the standard formulation of Adderall or its one-a-day formulation Adderall XR -- which was (and is, again) the only version sold in Canada.

Adderall maker Shire had appealed the February 2005 recall decision to  Health Canada , which led to the establishment of an expert committee.  Its members were called upon to to determine the issue of whether Adderall was riskier than other ADHD drug therapies available in Canada.

As Mr. Kondro reports, however, this expert committee did not make any final determination on the Adderall-safety issue:

The committee, chaired by pharmaco-epidemiologist Dr. Mitchell Levine, director of the Centre for Evaluation of Medicines at St. Joseph's Healthcare in Hamilton, Ont., came down squarely on the fence. Levine's panel concluded Health Canada and Shire used different data sets for their risk analysis and that both used methodologically weak analyses, although Health Canada acted properly in withdrawing the drug as a precaution.

It was impossible to prove or disprove that using Adderall increases the risk of sudden cardiac death, stroke, or both, particularly in children, Levine says. Nor was it possible to determine whether Adderall XR "was particularly worse or more harmful."

According to the October 11, 2005 CMAJ article by Kondro, this expert committee did conclude that it is "biologically plausible" that there is an increased risk of adverse events, generally, from using any stimulants to treat ADHD. But -- in light of the uncertainties about whether Adderall was riskier than other ADHD drug therapies -- the committee recommended that Adderall should be returned to the Canadian market with a revised package insert label which warned against the use of Adderall by patients with structural heart abnormalities.

Dr. Levine, the chairman of this expert committee, offers the following advice about Adderall to doctors and patients.  Insofar that, according to Levin and his committee, the safety of Adderall cannot be adequately evaluated, before prescribing Adderall, doctors should consider obtaining a baseline ECG for:

• any patient with a family history of pediatric heart failure,
• any patient who regularly undergoes strenuous exercise, or
• any patient who has congenital abnormalities.

In the summer of 2005 Health Canada adopted the committee's recommendation that Adderall be reintroduced to the market.  The drug's manufacturer Shire has said that adequate supplies of Adderall will be available in Canada sometime in October 2005.

(Posted by: Tom Lamb)

Cardiac Drug ReoPro: Clinical Trial Is Suspended by Lilly and J&J

Drug Companies Had Been Testing ReoPro for Treatment of Ischemic Strokes

On October 5, 2005 it was reported that Eli Lilly & Co. ("Lilly") and Johnson & Johnson ("J&J") have temporarily suspended a late-stage (Phase III) clinical trial involving their cardiac drug ReoPro due to some emerging safety concerns.

Based on the advice of an independent safety committee overseeing the ReoPro clinical trial, Lilly and J&J elected to stop giving ReoPro to patients already enrolled in the drug study.  The purpose of this ReoPro study had been to test the cardiac drug for the treatment of acute ischemic strokes, the most common type of strokes, which are caused by the blockage of blood vessels.

It was reported by the Dow Jones Newswires that a spokesman for J&J's Centocor unit said the adverse events which raised safety concerns in the ReoPro study were intracranial hemorrhages and deaths. Insofar that the ReoPro clinical trial remains blinded, however, there is apparently no way for Lilly nor J&J to determine at this time whether the patients who suffered intracranial hemorrhages and deaths were taking ReoPro or a placebo used as part of the study.

In a press release, Jerome A. Boscia, senior vice president for clinical research at J&J's Centocor unit, stated:

Safety is our top priority, so we are halting enrollment in order for the SEMC [the independent safety committee] to carefully evaluate the data and determine whether the benefit-risk profile of ReoPro for the treatment of acute ischemic stroke warrants reinitiating trial enrollment.

ReoPro is known generically as abciximab.  It is an intravenous drug that binds to blood platelets and inhibits clotting.  ReoPro was first approved by the FDA in 1994 to be used along with noninvasive heart procedures to lower the risk of complications, and to treat chest pains before the procedures. In particular, ReoPro is suppose to help prevent blood clots in patients undergoing such coronary surgical procedures as angioplasty and stent insertion.

Lilly and J&J maintain that, despite halting the ReoPro study for safety reasons, there is no new data which indicates to the drug companies that the FDA will take any action to force them to change the package insert, or labeling, of ReoPro in order to warn about the possibilities of intracranial hemorrhage and death.

(Posted by: Tom Lamb)

Pfizer Agrees to New Celebrex Safety Guidelines in Canada

Health Canada Revisions to Celebrex Label Accepted by Pfizer Canada

On September 21, 2005 Pfizer Canada announced the drug company had agreed to make changes suggested by Health Canada that add new safety guidelines to the package insert for its arthritis drug Celebrex.

The newly revised package insert for Celebrex in Canada will contain the following safety guidelines:

• Celebrex should not be used before or after heart surgery;
• Celebrex should not be used in patients who are in a late-stage pregnancy;
• Celebrex should be used with caution by patients who have had heart attacks;
• Celebrex should be used with caution by patients who have high blood pressure; and,
• Celebrex should be prescribed and used at the lowest effective dose for the shortest possible duration.

Health Canada began its safety review of COX-2 inhibitors in the fall of 2004, after Vioxx was recalled following news about a study which showed that Vioxx increased the risk of heart attack and stroke.  The COX-2 class of drugs includes Celebrex and Bextra, also.  In the summer of 2005, Health Canada advisers met to study the side-effect risks of Celebrex and Bextra, along with Vioxx.  Ultimately, these advisers recommended in July 2005 that Celebrex be allowed to stay on the Canadian market, that Bextra should be kept off, and, surprisingly, that Vioxx should be allowed to return to the market in Canada.

On September 21, 2005, also, Health Canada sent an alert to doctors and patients that it had posted an "Important Safety Information on Celebrex (celecoxib)" bulletin on its web site.  The bulletin included a copy of the new Celebrex "Dear Doctor" letter as well as a a summary of the label changes for patients.

(Posted by: Tom Lamb)

Even One Day of Vioxx Use Can Cause Heart Attack or Stroke Says Expert

Dr. Benedict Lucchesi Testifies at Humeston Vioxx Trial in New Jersey

Dr. Benedict Lucchesi, a prominent heart and medication expert from the University of Michigan, told the jury hearing evidence at the Humeston Vioxx trial in Atlantic County, New Jersey that even a day's use of Vioxx could be enough to cause a heart attack or stroke.  Dr. Lucchesi testified at the Humeston trial on September 19, 2005.

Dr. Lucchesi's testimony at this New Jersey Vioxx trial included his opinions that intermittent or irregular use of Vioxx could cause a heart attack, and that Vioxx breaks down so slowly in the body that it takes about 85 hours to clear out of the blood.  Both of these points support the plaintiff's case at this Vioxx trial, which concerns 60-year-old Idaho postal worker Frederick "Mike" Humeston, who had a heart attack in 2001 after taking Vioxx for only two months and skipping some doses during that period.

"Based on the science, there's every reason to believe that a single dose, multiple doses, whatever, can lead to an adverse event," such as a heart attack or stroke, Dr. Lucchesi said.

This testimony by Dr. Lucchesi could be pivotal in Mr. Humeston's lawsuit against Vioxx maker Merck & Co.  An Associated Press article published just hours after Dr. Lucchesi's testimony on September 19 observed, however, that "at times, the jury appeared to struggle to follow brain-numbing details of the workings of Vioxx and the cardiovascular system, with expressions from puzzlement to weariness playing across their faces late in the day."

On another aspect of the liability case against Merck, Dr. Lucchesi told the Humeston jury that there was ample and repeated evidence, as well as other warning signs, which linked Vioxx to heart risks even before Vioxx was brought to the U.S. market in May 1999.  Lucchesi also testified that in reaction to a 2000 study that showed significant heart risks to Vioxx users, Merck took action on the news, but the direction taken was completely wrong.  Instead of Merck putting emphasis on the cardiovascular risks revealed by the 2000 study, the drug company continued to tell doctors and the public that Vioxx was safe.

Generally, the attorneys for Mr. Humeston have argued that Merck knew about the serious side effects of Vioxx for at least a few years before it took the drug off the market in September 2004, while the attorneys for Merck say the company first learned about the heart problems in September 2004 and acted responsibly be removing Vioxx from the market immediately, then.

The Humeston lawsuit is the first Vioxx case to go to trial in New Jersey, with about 2500 New Jersey Vioxx cases lined up after it.

(Posted by: Tom Lamb)

Anti-Cancer Drug Herceptin Associated With Significant Risk of Cardiotoxicity

Genentech Says Its Breast Cancer Drug Can Increase Risk of Heart Problems

The FDA and Genentech, Inc. have warned healthcare professionals by means of an August 2005 "Dear Doctor" letter of study data linking Herceptin (trastuzumab) therapy to a significantly increased risk of cardiotoxicity.  This news was broadcast by an alert sent on August 31, 2005 from MedWatch, the FDA's safety information and adverse event reporting system.

Herceptin is indicated for use alone in chemotherapy-experienced patients, and with paclitaxel in chemotherapy-naive patients, for the treatment of HER-2–positive metastatic breast cancer.

According to the Dear Doctor letter from Genentech, a preliminary analysis of the recent study data suggests that Herceptin can significantly increase the risk of heart problems.  The increase is "significant" compared with patients who received only chemotherapy.

In more detail, the study of 2,043 breast cancer patients found a higher incidence of damage to the heart in the 1,019 patients taking Herceptin. Such damage can lead to heart failure and, in some cases, death.  The August 2005 Dear Doctor letter from Genentech says:

A statistically significant increase in the 3-year cumulative incidence of . . . congestive heart failure and cardiac death was observed in patients who received the Herceptin-containing regimen, [amounting to 4.1 percent, compared with chemotherapy alone, which was put at 0.8 percent].

The Dear Doctor letter says that Herceptin's label already includes information about possible heart failure and heart ventricle problems. This recent study was intended to quantify the risk, according to the Genentech letter.

Genentech stated in their August 2005 letter to doctors and other healthcare professionals that their analysis of the study results, which were first presented at a conference in May 2005, is ongoing.

(Posted by: Tom Lamb)

Adderall: Health Canada Allows Shire's ADHD Drug Back on Market

Sudden Cardiac Death and Stroke Case Reports Had Caused Health Canada to Recall Adderall in February 2005

Health Canada announced on August 24, 2005 that Adderall XR, an attention deficit hyperactivity disorder ("ADHD") drug, can be reintroduced to the Canadian market.  Health Canada had recalled Adderall XR, a once-a-day treatment for ADHD, from the Canadian market on February 9, 2005 after learning about 20 cases of sudden death and 12 cases of stroke in people using the ADHD drug.  These case reports came from Shire Pharmaceuticals Group Plc, the company responsible for Adderall XR in Canada.

Health Canada's recall of Adderall XR was unusual in the fact that none of the 20 cases of sudden death and 12 cases of stroke occurred in Canada.  Moreover, the FDA had reviewed the underlying data for this set of case reports in the summer of 2004 and concluded that the rate of sudden deaths and strokes in Adderall XR users was not significantly higher than the so-called "background rate" -- the incidence rate of such events expected to occur in people who had not been taking the subject drug.

Health Canada's reversal of its Adderall recall decision comes after a panel of drug-safety experts -- called a New Drug Committee ("NDC") -- reviewed the safety data provided by Shire regarding Adderall XR.  Shire triggered this review by appealing Health Canada's decision to recall Adderall from the market earlier this year.

Health Canada spokesperson Jirina Vlk had these comments:

The NDC came to the conclusion that there was not enough evidence of an increased harm from Adderall compared to other therapies available....  The benefits of treating ADHD has to be balanced with the known harms of this class of drugs.

According to an August 24, 2005 News Release from Health Canada regarding Adderall, there are a number of steps that Shire must take in connection with Adderall XR being returned to pharmacies in Canada, among them:

• Revise the prescribing and patient information to reinforce the safe use of Adderall XR, as well as to reflect safety concerns, including the risk of sudden cardiac death; and,
• Distribute a letter to healthcare providers, i.e., "Dear Doctor" letter, to inform them about the risks of use of Adderall XR.

It is estimated by Health Canada and Shire that it could take two to three weeks before Adderall XR actually becomes available in Canadian pharmacies due to logistical matters.

(Posted by: Tom Lamb)

Abbott's Weight-loss Drug Meridia Gets a Confidence Vote by FDA

FDA Denies Public Citizen's Petition to Remove Meridia from Market
   

The FDA has decided that the benefits of Abbott Laboratories' prescription weight-loss drug Meridia continue to outweigh the drug's risks for select obese patients.  As such, on August 16, 2005 the FDA denied a petition that had filed by the consumer advocacy group Public Citizen three years ago asking the FDA to take Meridia off the market in the U.S.

Public Citizen filed its petition with the FDA because the group alleged that adverse event reports made to the FDA showed Meridia having contributed to more than 400 adverse patient reactions, including dozens of fatalities, since Meridia was approved by the FDA in 1997.

Meridia has had a checkered past as regards whether or not it should be on the market.  At the outset, an FDA advisory panel voted 5-4 against marketing approval for Meridia in 1996.  After the filing of the Public Citizen Meridia petition three years ago, attention to the drug-safety issues for Meridia faded for awhile.  However, those issues were at the forefront, again, in the fall of 2004 when FDA safety officer Dr. David Graham listed Meridia among five potentially dangerous drugs the agency needed to review -- a list that also included  Crestor (cholesterol drug), Bextra (painkiller), Accutane (acne drug), and Serevent (asthma medicine).

In more detail, the Public Citizen petition framed this issue for the FDA: Does Meridia's benefits outweigh the risks of high blood pressure and stroke.  Commenting on the FDA's decision to deny their petition, Public Citizen said the FDA's decision about the safety of Meridia was misguided and issued a statement by Sidney M. Wolfe, MD, Director of Public Citizen’s Health Research Group.  "This means the FDA has made another mistake," said Dr. Wolfe. "A lot of the people who died from this were very young, in their 20s, 30s and 40s. It is very difficult for the FDA to admit they made mistakes."

One hopes that for the sake of those people who are using Meridia, the FDA has made the right decision, here.

(Posted by: Tom Lamb)

Health Canada Not in Any Rush to Return Vioxx to Pharmacies

Expert Panel Finds That Vioxx is Safe Enough -- But is it, Really?

Health Canada is balking, so to speak, at the recommendation of an expert panel it appointed to consider the issue of whether Vioxx (rofecoxib) should be reintroduced on the Canadian market.  In July 2005 this expert panel advised Health Canada that Vioxx is safe enough to be marketed, again, in Canada.  Top officials at Health Canada, however, have expressed some doubt about one of the sources used by the panel in arriving at its pro-Vioxx conclusion.

Vioxx was voluntarily withdrawn from the Canadian market, and worldwide, in September 2004 after its manufacturer, Merck & Co., learned from an ongoing Vioxx study that patients taking the drug on a long-term basis faced twice the risk of suffering a heart attack or an ischemic stroke compared with patients receiving a placebo.

The Vioxx panel convened by Health Canada reportedly examined data from a wide range of sources.  One of those sources is a new meta-analysis of 138 studies on the cardiovascular risk of COX-2 inhibitors by researcher Dr. Colin Baigent, a senior scientist at the Clinical Trials Service Unit at Oxford University.  It is this particular source which has drawn some criticism from Health Canada officials, according to the August 16, 2005 edition of CMAJ.  Sally Murray reports:

Dr. Marc Berthiaume, Director of the Marketed Pharmaceuticals Division at Health Canada, is not sure about the results. "Some of the choices [Baigent] made can have skewed some of his findings: he lumped together short- and long-term findings for patients on NSAIDs." Berthiaume says Health Canada hasn't taken an official position on the study.

According to the CMAJ piece by Sally Murray, even if the expert panel is correct that Vioxx is safe enough to return to pharmacies in Canada, Merck's decision to withdraw Vioxx was the right thing for Merck to do given what was learned in September 2004.  "Their decision was based on the safety information available and it was a good decision," he said.  The CMAJ article quoted Merck Frosst Canada spokesperson Marlene Gauthier as agreeing: "At the time there seemed to be alternatives that had less risks."

Whether Vioxx returns to the market in Canada seemingly depends on how Health Canada ultimately views the expert panel's recommendation.  Any reintroduction of Vioxx in Canada would begin with Merck Frosst resubmitting the drug for approval.  According to the CMAJ piece, thereafter the Health Canada approval process could take anywhere from two to eighteen months.

(Posted by: Tom Lamb)

Celebrex "Black Box" Label Warning About Increased Cardiovascular Risks

"Class Effect": Like Bextra and Vioxx, Celebrex Can Cause Heart Attacks and Strokes

The pharmaceutical company Pfizer Inc. announced on August 1, 2005 that the FDA had finalized a new label for the arthritis drug Celebrex, which will include a "black box" warning informing doctors and patients about the associated increased cardiovascular risks, such as heart attacks and strokes.

The black box warning which to be added to Celebrex is similar to the black box warnings that will be added to older painkillers such as ibuprofen and naproxen in the near future. These package insert label changes are consistent with the February 2005 recommendations of an outside panel of medical experts which the FDA convened in February 2005 to address emerging concerns about whether Celebrex increased cardiovascular risks like Vioxx and Bextra, other drugs in the same COX-2 class as Celebrex; the panel agreed that there was a "class effect" at work.  The expert panel also studied the safety profile of the older painkillers.

Celebrex's revised label will include the recommendation to doctors that Celebrex be prescribed at the lowest dose and for the shortest duration possible. In addition, this new Celebrex label will carry a warning that Celebrex should not be used to treat pain associated with heart-bypass surgery.

Celebrex had been approved to treat pain associated with osteoarthritis as well as rheumatoid arthritis, and as a treatment for familial adenomatous polyposis -- a rare condition that leads to colon cancer.  Coincidental with the Celebrex label change, Pfizer announced that the FDA has recently approved Celebrex as a treatment for ankylosing spondylitis, a form of arthritis which affects the spine.

(Posted by: Tom Lamb)

All NSAIDs May Be Linked to Increased Risk of Heart Attack (or Not)

June 2005 BMJ Article Calls Into Doubt Cardiovascular Safety of All NSAIDs

There is new evidence that all selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of having a heart attack, or myocardial infarction (MI).  This evidence comes from work done by Dr. Julia Hippisley-Cox and Dr. Carol Coupland, who are associated with the University of Nottingham, in the UK.  The results of their recent observational study -- which the authors describe as a population-based nested case-control study using the QRESEARCH database of information from UK general practices -- is reported their in the June 11, 2005 issue of the British Medical Journal (BMJ).

Most noteworthy, perhaps, is the study's finding that diclofenac and ibuprofen seem to pose about as much risk as Vioox (rofecoxib), the COX-2 inhibitor which was withdrawn from the market in September 2004.  The adjusted odds ratio (OR) for Vioxx use within the 3 months before a first heart attack was 1.32; for ibuprofen that adjusted OR was 1.24, and for diclofenac the OR was 1.55 (p < 0.01).  For their study, the authors looked at 9218 cases of a first MI in people between the ages of 25 and 100 during study period from 2000 to 2004, and 86,349 controls matched by age, calendar time, gender and practice. 

Dr. Hippisley-Cox and Dr. Coupland note in their June 2005 BMJ article:

Given the high prevalence of the use of these drugs in elderly people and the increased risk of myocardial infarction with age, even the relatively large number of patients needed to harm could have considerable implications for public health.

Accordingly, Dr. Hippisley-Cox and Dr. Coupland reach this conclusion: "We think that enough concerns exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs."

An associated editorial in the same June 11 issue of the BMJ, however, urges that reaction to this apparent new evidence presented by Dr. Hippisley-Cox and Dr. Coupland be held in check.  Dr. Peter Juni, from the University of Berne in Switzerland, and some of his colleagues advise in their BMJ editorial that the data from this recent article must be "interpreted with caution," given that the underlying study is observational in method, and other drug-safety trials involving NSAIDs have yielded vastly different end results.

(Posted by: Tom Lamb)

Case Report: Adderall-induced Heart Attack in Young Boy

Reports of Sudden Unexplained Death (SUD) Involving Children Being Studied by FDA After Adderall Withdrawn in Canada

An article entitled "Myocardial infarction in an adolescent taking Adderall", by Pritesh J. Gandhi, et.al., was published recently in the American Journal of Health-system Pharmacy.

This medical journal article reports on the case of a boy who arrived at his local hospital's emergency room with symptoms of a heart attack, or myocardial infarction (MI), after taking Adderall for his attention-deficit/hyperactivity disorder (ADHD). To the author's knowledge, this the first published case report of an acute MI caused by oral use of Adderall without intent to overdose. The article acknowledges that there have been previous reports of patients who had heart attacks associated with amphetamines which involved intentional overdose or illicit drug use.

In more depth, a 15-year-old white male presented with some chest pain and a shortness of breath even when at rest.  At this point, we go to the article's text:

His medical history was significant for ADHD, for which various medication regimens had been prescribed since age six years. Four months before this arrival to the ED, treatment with Adderall tablets (Shire Richwood, Inc.) was started at a total amphetamine dosage of 5 mg (1.25 mg each of amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate) p.o. twice daily. The total daily amphetamine dosage was increased by 5 mg weekly based on the patient’s clinical response. The patient stated that, for the past four weeks, he was supposed to be taking two Adderall tablets, each containing 20 mg total of amphetamine and dextroamphetamine salts, in the morning. He voluntarily stopped taking the Adderall for about three weeks because he wanted to know how he would function without the medication. However, a teacher noted aggressive behavior and asked him to resume the medication. He restarted the medication (two 20-mg tablets daily) approximately one week before this admission without notifying his physician.

As some may be aware, Adderall XR (an extended-release amphetamine–dextroamphetamine product) was withdrawn from the market in Canada after Health Canada considered reports of sudden unexplained death (SUD) in children taking Adderall or Adderall XR in the U.S.  The FDA is currently evaluating that same data for SUD cases involving children receiving Adderall, as well as other post-marketing reports of serious side effects in patients treated with Adderall, to determine whether Adderall should stay on the market, here.

Although instances of sudden unexplained death had been reported in children with underlying cardiac abnormalities during Adderall treatment, recently SUD has also been reported in a small number of children without structural cardiac abnormalities who received Adderall.  Of 12 cases of pediatric sudden death reported to the FDA, only five of those cases occurred in children with underlying structural cardiac abnormalities. Several of the remaining cases were complicated by other medical conditions and factors, such as family history of ventricular tachycardia.

Read more about the withdrawal of Adderall from the market in Canada and the FDA's Adderall Alert.

(Posted by: Tom Lamb)

Recent Study Shows How Vioxx, Bextra, and Celebrex Can Damage Heart

A Theory of Why COX-2 Inhibitors Affect the Heart and Raise Heart Attack Risk   

In May 2005 it was reported that medical researchers affiliated with the University of Pennsylvania School of Medicine have completed a study which may help doctors understand why the so-called "COX-2 inhibitors" -- such as Vioxx, Bextra, and Celebrex -- can cause an increased risk of heart attack in patients who were previously at a low risk of developing cardiovascular problems.

Specifically, the University of Pennsylvania researchers looked at the effect of COX-2 inhibitors on the muscular wall of blood vessels. In so doing, these researchers found that a COX-2-derived fatty acid called prostacyclin controls the blood vessel response to stressors such as high blood pressure.  These researchers posit that, by inhibiting COX-2, one's use of Vioxx, Bextra, or Celebrex impairs the ability of their blood vessels to react normally to high blood pressure.

Earlier research has shown that the use of COX-2 inhibitors, by suppressing prostacyclin production, can predispose patients to high blood pressure which, in turn, aggravates atherosclerosis -- a condition in which the arteries gradually become clogged with plaque deposits. When the additional factor of impaired blood vessel response -- the new finding from this recent University of Pennsylvania study -- is combined with the earlier research, doctors may better understand why COX-2 inhibitors raise a patient's heart attack risk.   

Until last year, COX-2 inhibitors such as Vioxx, Bextra, and Celebrex were some of the most popular prescription drugs for arthritis and pain relief. In September 2004, however, Vioxx was voluntarily removed from U.S. market after a study linked Vioxx to an increased risk of heart attack.  Thereafter, in April 2005, Bextra was voluntarily recalled on the grounds that the risk of serious side effects associated linked with Bextra -- namely, heart attacks and strokes, as well as serious skin reactions -- outweighed the benefits of Bextra use.  Celebrex, the other COX-2 inhibitor widely prescribed in the U.S., has been linked to an increased risk of heart attacks and strokes, also.  As such, it seems that the cardiovascular side effect problems, at least, which have been associated with Vioxx, Bextra, and Celebrex are a "class effect" of the COX-2 inhibitors.

(Posted by: Tom Lamb)

Health Canada Advisory Panel Supports Return of Painkiller Vioxx to Market

Canadian Panel Votes Against Bextra Due to Increased Risk of Serious Skin Reactions

On July 7, 2005, a panel of medical experts advised Health Canada officials that, in its opinion, the arthritis drug and painkiller Vioxx be allowed to be marketed once again in Canada.

In September 2004 Merck withdrew Vioxx worldwide after clinical tests showed that patients taking the Vioxx for more than 18 months had an increased risk of developing cardiovascular problems such as heart attacks and ischemic strokes.

The Health Canada advisory panel voted 12 to 1 in favor of allowing Vioxx to return to the market in Canada.  Their recommendation will be reviewed by Health Canada, which said that its review would pay close attention "to the safe labeling issued raised by the panel."

Earlier this year, a panel of outside experts narrowly voted to recommend to the FDA to allow Vioxx back on the U.S. market.

After this Health Canada advisory panel vote in favor of Vioxx, a Merck spokesman commented that the drug company has not decided, yet, whether to bring Vioxx back to the Canadian market or any other market. He said, further, that Merck will discuss the matter with Health Canada, as well as the FDA, in the near future.

The Health Canada advisory panel also voted unanimously that Celebrex remain on the market in Canada.  This panel, however, voted 8 to 5 against Bextra being returned to the Canadian market because "there was not sufficient information available about cardiovascular risk." The panel members voting against Bextra also stressed the risk of rare but potentially fatal serious skin reactions associated Bextra, namely Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Erythema Multiforme (EM).

The maker of Bextra, Pfizer, withdrew Bextra in April 2004 from all markets after the FDA said "the overall risk vs. benefit profile for the drug is unfavorable." Pfizer said at the time of the Bextra recall that the drug company disagreed with the FDA's assessment of Bextra's safety profile.

(Posted by: Tom Lamb)

Novantrone: FDA MedWatch Alert Regarding Heart Damage Risks

April 2005 "Dear Doctor" Letter Also Addressed an Increased Risk of AML

In late May 2005 the FDA warned patients of the risk of heart damage from Serono's multiple sclerosis drug Novantrone.  In a MedWatch alert, the FDA said congestive heart failure, a potentially fatal condition, could occur either during Novantrone therapy, or months to years after termination of Novantrone therapy. The May 2005 MedWatch alert also included information about an increased risk of developing treatment-related leukemia due to Novantrone use.

An April 2005 "Dear Doctor" letter sent out by Serono, the drug company responsible for Novantrone, provided additional information concerning the risks of cardiotoxicity associated with Novantrone.  The April 2005 Serono letter to doctors and other healthcare professionals also provided supplemental information regarding secondary acute myelogenous leukemia (AML) reported in MS patients treated with Novantrone.

A pharmaceutical sector financial analyst, Karl-Heinz Koch, of Lombard Odier Darier Hentsch, opined that this new warning will likely have little impact on Novantrone sales:

The drug is burdensome already because it has a large side effect catalog....  It is only used in very severe cases anyway.  I don't believe it will have a big effect on Serono or a large impact on the use of the drug.

A spokesman for Serono concurred about the impact of this new set of warnings on Novantrone sales; "We believe it is not going to have an effect on the product. The product is for very severe forms of MS, for people who have no choice," the spokesman said.

(Posted by: Tom Lamb)

European Drug Regulators Want Increased Warnings on All COX-2 Inhibitor Drugs

Bextra: Suspension of Marketing in European Union to Continue

In a June 27, 2005 press release issued by the European Medicines Agency (EMEA), the Agency's Committee for Medicinal Products for Human Use (CHMP) said that additional side effect warnings and prescribing contraindications are necessary for all COX-2 inhibitors due to the cardiovascular risks linked to this class of drugs. 

Further, because the CHMP concluded that the additional risks of serious and potentially fatal skin reactions associated with the use of Bextra outweigh its benefits, it was recommended that the current suspension of the marketing of Bextra should continue.  Bextra's manufacturer, Pfizer, had voluntarily suspended marketing of Bextra in the European Union in April 2005 at the request of the EMEA.  The suspension of Bextra in the E.U. will be reviewed within one year, according to this June 2005 EMEA press release, during which time Pfizer has the opportunity to provide Bextra drug-safety data for consideration by the CHMP.

The CHMP confirmed its February 2005 finding that the probability of suffering a cardiovascular reaction such as a heart attack or stroke from one's use of COX-2 inhibitor drugs like Bextra was a function of dose and duration, i.e., dose-related. The Committee also confirmed its earlier finding that while serious skin reactions such as Stevens-Johnson Syndrome (SJS) occur with the use of other COX-2 inhibitors, the others are not near the relatively high skin reaction incident rate that has been associated with Bextra.

The CHMP recommended several prescribing contraindications and precautions for the remaining COX-2 inhibitors products. 

In concluding its review, the CHMP maintained that when these COX-2 inhibitors are prescribed in accordance with these additional contraindications and precautions, the risk-benefit analysis for this class of drugs remains positive.

(Posted by: Tom Lamb)

Black-box Warning for Celebrex and Other NSAIDs

FDA Requires Warning Label Changes for Painkillers

In June 2005 the FDA advised Pfizer, the maker of Celebrex, and several other drug manufacturers that the package insert, or warning label, for their prescription NSAID painkillers must contain a so-called "black-box warning".  Specifically, the new black-box warnings are intended to alert doctors and patients about the association between these painkillers and the increased risks of heart attacks, ischemic strokes, and gastrointestinal bleeding.  Further, the black-box warnings must describe early symptoms of a serious skin reaction, Stevens-Johnson Syndrome, which has been linked to use of certain NSAID painkillers.

Prescription NSAIDs include Vioxx, which was voluntarily taken off the market by Merck in September 2004 because of the increased heart-attack (MI) and stroke (CVA) risks for Vioxx users .

The FDA initially indicated the need for stronger warning labels for prescription NSAIDs in April 2005 after Pfizer suspended sales of its Bextra painkiller.  The Bextra "recall" ordered by Pfizer was precipitated by a growing number of drug study reports which linked Bextra to cardiovascular side effects and serious skin reactions.  The skin disorders, which are relatively rare but potentially fatal, include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Erythema Multiforme (EM).

Beyond the prescription NSAIDs, the FDA said warning labels on over-the-counter (OTC) medications containing ingredients such as generic ibuprofen, ketoprofen, or naproxen must also inform patients about the increased risks of cardiovascular side effects, gastrointestinal (GI) bleeding, and serious skin reactions.

For all prescription drug and OTC products in this class, the FDA has said that the mark "NSAID" must be displayed prominently on the respective package insert label in a contrasting color or in bold type.

Read more about Bextra and its serious side effects:

• http://www.druginjurylaw.com/Bextra-information.html

Read more about Toxic Epidermal Necrolysis:

• http://www.drug-injury.com/druginjurycom/2005/06/toxic_epidemal_.html

(Posted by: Tom Lamb)

Sudden Cardiac Death Caused by Some Commonly Prescribed Drugs

Increased Risk of Sudden Death Linked to Use of Some Widely Used Medications

A study which analyzed 775 cases of sudden cardiac deaths in the Netherlands has found some commonly prescribed drugs may interfere with the electrical activity controlling the heartbeat, thereby increasing the risk of sudden cardiac death.

The researchers found that the use of certain anti-psychotic and gastro-intestinal ( GI ) drugs was probably responsible for 320 sudden cardiac deaths a year in the Netherlands.  The study, by extrapolation, estimated these drugs caused a total of around 9,000 sudden cardiac deaths a year in Europe and 6,000 such deaths a year in the U.S.

The drugs involved in the study are those that prolong the QTc interval in the heart.  Specifically, the drugs studied were Cisapride and Domperidone ( GI drugs ), Chlorpromazine, Haloperidol and Pimozide ( anti-psychotics ) and Erythromycin and Clarithomycin ( antibiotics ).   While each of these drugs have previously been implicated in cardiac arrhythmia, the new study is believed to be the first to evaluate the link between these prescription drugs and sudden cardiac death.

The highest sudden cardiac death risk level was for those using higher daily doses of GI or anti-psychotic medications.  Risk also tended to be higher among women than men and among older patients than younger, although these differences were not statistically significant according to the researchers.

In Europe and the U.S., the normal annual incidence of sudden cardiac death is one to two deaths a year per thousand of population.  This risk rises to around three per thousand per year in those taking these particular drugs.

(Posted by: Tom Lamb)