Drug Injury Watch

Hydroxycut Weight-Loss Products Are Recalled Due To Cases Of Serious Liver Injury

Reports Made To The FDA Have Involved Hepatitis, Liver Failure, Liver Transplant, And Death

(Posted by Tom Lamb at DrugInjuryWatch.com)

On May 1, 2009 the FDA warned people to stop using Hydroxycut products -- made by Iovate Health Sciences Inc., of Oakville, Ontario and distributed by Iovate Health Sciences USA Inc. of Blasdell, N.Y. -- due to the fact that some Hydroxycut products are associated with a number of serious liver injuries. Furthermore, the manufacturer, Iovate, has agreed to immediately recall Hydroxycut products from the U.S. market.

The list of Hydroxycut products being recalled by Iovate currently includes:

Hydroxycut Regular Rapid Release Caplets
Hydroxycut Caffeine-Free Rapid Release Caplets
Hydroxycut Hardcore Liquid Caplets
Hydroxycut Max Liquid Caplets
Hydroxycut Regular Drink Packets
Hydroxycut Caffeine-Free Drink Packets
Hydroxycut Hardcore Drink Packets (Ignition Stix)
Hydroxycut Max Drink Packets
Hydroxycut Liquid Shots
Hydroxycut Hardcore RTDs (Ready-to-Drink)
Hydroxycut Max Aqua Shed
Hydroxycut 24
Hydroxycut Carb Control
Hydroxycut Natural

The FDA's reasoning for this May 2009 recall of Hydroxycut products can be found in a Health Hazard Evaluation Board document entitled "The Problem: Liver toxicity following consumption of dietary supplement, Hydroxycut".  From the Conclusion section of this Health Hazard Evaluation document:

Three lines of evidence derived from multiple disparate sources suggest it is very likely that exposure to Hydroxycut can cause idiosyncratic hepatotoxicity. First, many of the subjects described in the adverse event reports to CAERS, in the peer-reviewed literature, and in the case series described by hepatologists reported no history of liver disease or risk factors for liver disease (e.g., alcohol consumption, previous viral infection, hereditary factors, etc.) prior to experiencing liver injury following the ingestion of Hydroxycut. Second, in many subjects, thorough diagnostic evaluations performed in multiple settings ruled out a number of known causes of liver disease, including viral hepatitis, autoimmune diseases, and metabolic/inherited disorders. Third, prompt resolution of liver disease occurred in a number of patients following cessation of Hydroxycut ingestion.

In a Consumer Advisory, "FDA Warns Consumers Not to Use Dietary Supplements Labeled Hydroxycut because of the Potential Risk of Severe Liver Injury", the FDA provides the following medical information:

Consumers who use a Hydroxycut dietary supplement and who experience signs of illness associated with liver disease should immediately consult their health care provider. Symptoms of serious liver disease include jaundice (yellowing of the skin or whites of the eyes) and brown urine. Non-specific symptoms of liver disease can include nausea, vomiting, light-colored stools, unusual tiredness, weakness, stomach or abdominal pain, itching, and loss of appetite.  FDA has also identified several other serious adverse events associated with Hydroxycut, including cases of seizures, rhabdomyolysis (a type of muscle damage that can lead to other dangerous problems, such as kidney failure), and cardiovascular problems, ranging in severity from irregular heart beat to a heart attack.  [bold in original]

The FDA -- as opposed to Iovate, the manufacturer of Hydroxycut products --has issued a "Dear Doctor" letter to healthcare providers in the U.S.

In addition, the FDA has put on its web site a Consumer Questions and Answers document regarding this Hydroxycut recall.

In closing, the FDA has stated that it will continue to investigate the relationship between the use of Hydroxycut dietary supplements and liver injury.

If you are aware of any case of liver damage caused by the use of Hydroxycut products, please consider sharing that information with us by submitting a Comment, below.

P.S.  North of FDA-land, Health Canada says it will continue to monitor adverse reaction reports associated with Hydroxycut products, and will provide Canadians with any new safety information. 

From "Health Canada Reviewing Hydroxycut Products in light of U.S. Advisory":

Health Canada has received 17 domestic adverse reaction (AR) reports associated with Hydroxycut products in Canada. These adverse reactions relate to the cardiovascular, respiratory, gastrointestinal, and neurological systems. None of the adverse reactions reported in Canada relate to liver injury.

It will be interesting to see if Health Canada follows the lead of our FDA and issue a Hydroxycut recall in Canada.  (5/4/09)

P.S.  On May 7, 2009 the FDA announced that Iovate Health Sciences USA, Inc. has provided Universal Product Codes (UPCs) for its products that were part of the May 1 Hydroxycut recall.  (5/8/09)

March 2009 Update: Sprint Fidelis Heart Device Connected To At Least 13 Deaths

Newly Released FDA Report Indicates Medtronic Had First Reports Of Lead Wire Problems In Late 2004

(Posted by Tom Lamb at DrugInjuryWatch.com)

A March 14, 2009 New York Times (NYT) article, "Medtronic Links Device for Heart to 13 Deaths", by reporter Barry Meier gave us the latest developments regarding the problems that gave rise to the October 2007 recall of Sprint Fidelis lead wires used in defibrillators.

Mr. Meier's March 14 NYT article was published a day after Medtronic sent a March 13, 2009 "Dear Doctor" letter, "Sprint Fidelis® Model 6949 Lead Performance".  In that document, the medical device company states:

Approximately 268,000 Fidelis leads have been implanted worldwide. The FDA’s MAUDE database currently has 107 Medical Device Reports (MDRs) that include allegations that the Fidelis lead may have caused or contributed to a patient death. Most of these MDRs were not initiated by medical professionals; the majority were initiated by family members or attorneys with minimal supporting data. Medtronic’s Independent Physician Quality Panel has reviewed 89 of the 107 reports. It is not possible to determine cause of death with certainty.

The Panel has identified 13 patient deaths in which a Sprint Fidelis lead fracture may have been a possible or likely contributing factor. The Panel noted that four of the 13 deaths were associated with lead extraction, highlighting the risks associated with that procedure. With the exception of the appearance of deaths associated with lead extraction, no new or unexpected trends have been observed.

Building upon this March 2009 Sprint Fidelis "Dear Doctor" letter, Mr. Meier adds some contextual information:

The death statistics Medtronic released [March 13] underscore both the scope of the Sprint Fidelis problem and the difficult choices that doctors and patients face in deciding what to do about it. About 150,000 people in this country still have the Sprint Fidelis leads in their bodies.

Along with fatalities, the F.D.A. has received about 2,200 reports of serious injuries related to the leads. Medtronic officials said they believed that reflected the number of people who had undergone surgery to have a failed lead replaced with a new one.

But the larger part of Mr. Meier's March 14 article has to do with a "new" FDA report that was provided to this NYT reporter by lawyers involved with product liability lawsuits concerning serious injury or death caused by the defective Sprint Fidelis lead wires.  Here is how Mr. Meier describes that FDA report:

[A] previously undisclosed Food and Drug Administration report indicates that Medtronic began receiving reports soon after the device reached the market in late 2004 that the cable, known as the Sprint Fidelis, was fracturing....

The F.D.A. report is based on a visit by regulators to a Medtronic facility in Mounds View, Minn., soon after the device was removed from the market, where the officials interviewed executives and inspected records.

The report shows that by late 2005 the company had received 30 complaints about device fractures and had identified several possible ways in which the lead might be failing. About that time, the company opened an internal investigation into the problem, according to the report.

What happened next is not clear, because the F.D.A. redacted portions of the report before releasing it. But the document indicates that Medtronic engineers met often about the problem throughout 2006 and that they performed a “statistical analysis of the three failure modes” of the lead in October of that year, the report states.

This FDA report is significant as regards some critical issues in any Sprint Fidelis lawsuit filed against Medtronic, specifically: (1) When did Medtronic first learn about the potentially fatal failures involving its Sprint Fidelis lead wire products; and, (2) What did Medtronic do about these Sprint Fidelis failure reports from that point time up until when the company finally issued its October 2007 Sprint Fidelis recall?

We will continue to provide updates on this Sprint Fidelis recall and the thousands of related legal claims.

New Warning About Dostinex Side Effect Fibrotic Cardiac Valvulopathy In U.K.

September 2008 Dear Doctor Letter From Pfizer Follows 2007 EMEA Safety Review Of Cabergoline

(Posted by Tom Lamb at DrugInjuryWatch.com)

Pfizer's Dostinex (cabergoline) remains on the market despite the January 2007 reports in the New England Journal of Medicine that Dostinex, like Permax, was linked to valvular heart disease.

In June 2007 the European Medicines Agency (EMEA) initiated a safety review of ergot-derived dopamine agonists, including cabergoline, which is sold in Europe under the brand name Cabaser as well as Dostinex.

More recently, in September 2008 the U.K.'s Medicines and Healthcare products Regulatory Agency (MHRA) brought renewed attention to the association between Dostinex / Cabaser and fibrotic cardiac valvulopathy when the agency posted online the item "Information sent to healthcare professionals in September 2008 about the safety of medicines". 

Therein was listed the so-called "Dear Doctor" letter about Dostinex and Cabaser which Pfizer Ltd. sent out in the U.K. on or about September 15, 2008.  From the Dostinex section of that Septmeber 2008 Dear Doctor letter we get these warnings:

Dostinex—treatment of hyperprolactinaemic disorders

• Contraindication in patients with a history of fibrotic disorders and evidence of cardiacvalvulopathy as determined by pre-treatment echocardiography

• Warnings including mandatory echocardiography monitoring before initiating treatment and regularly during treatment and clinical monitoring of other fibrotic events

• Undesirable effects to include cardiac valvulopathy and related disorders (pericarditis and pericardial effusion) as very common side-effects

• The recommended initial dose remains 0.5 mg per week given in one or two doses per week and titrated according to prolactin levels. The therapeutic dose is usually 1 mg per week.

We will let you know when any similar "Dear Doctor" letter about Dostinex is sent by Pfizer in the U.S.  If somehow we missed that corresponding Dostinex letter, here, and you have a copy of it, please let us know.

August 2008: Byetta Associated With Hemorrhagic Pancreatitis And Necrotizing Pancreatitis

FDA Has Learned Of Six Such Cases Since October 2007 "Dear Doctor" Letter About Acute Pancreatitis In Patients Taking Byetta

(Posted by Tom Lamb at DrugInjuryWatch.com)

On August 18, 2008 the FDA issued a MedWatch email alert regarding Byetta (exenatide) which informed us that the agency had received reports about six cases of hemorrhagic pancreatitis or necrotizing pancreatitis since October 2007.

As background, the FDA last updated us on the link between pancreatitis and Byetta five months ago, which we covered in a post titled "More Information About Reports Of Byetta Use Being Linked To Acute Pancreatitis":

The quarterly issue of the FDA's online Drug Safety Newsletter [DSN] which was published on March 18, 2008 includes an article about a postmarket safety review of Byetta (Exenatide) that associates this diabetes drug with acute pancreatitis.

As background, one may recall that in October 2007 the FDA issued an alert to doctors informing them that the agency had reviewed 30 postmarketing reports of acute pancreatitis in patients taking Byetta, which was approved by the FDA on April 28, 2005 to treat adults with type 2 diabetes.

Now, from the "Information for Healthcare Professionals" page for Byetta we get this update from the FDA:

[UPDATED 08/18/2008] Since issuing Information for Healthcare Professionals in October 2007, FDA has received reports of 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta. Byetta is a medicine given by subcutaneous injection to help treat adults with type 2 diabetes. Of the 6 cases of hemorrhagic or necrotizing pancreatitis, all patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases.

Byetta and other potentially suspect drugs should be promptly discontinued if pancreatitis is suspected. There are no signs or symptoms that distinguish acute hemorrhagic or necrotizing pancreatitis associated with Byetta from the less severe form of pancreatitis. If pancreatitis is confirmed, initiate appropriate treatment and carefully monitor the patient until recovery. Byetta should not be restarted. Consider antidiabetic therapies other than Byetta in patients with a history of pancreatitis.

For your convenience, we provide these additional resources:

• The January 2008 revised Byetta package insert, or label, for Byetta from Amylin Pharmaceuticals, Inc.; and,

• The October 2007 so-called "Dear Doctor" letter about Byetta from Amylin Pharmaceuticals, Inc. and Eli Lilly and Company.

The October 2007 Byetta Dear Doctor letter was reportedly updated on or about February 27, 2007, but we have been unable to find the revised document on the FDA web site or elsewhere .  If anyone can provide us with a link to that document, or a copy, we will share this with our readers.

Of course, if and when we see any Dear Doctor letter in connection this August 2008 FDA alert about Byetta and hemorrhagic pancreatitis or necrotizing pancreatitis, we will add it to this article.

Will There Be An Avelox - Liver Toxicity Warning Letter From Bayer Coming Soon In The U.S., Or Not?

In July 2008 FDA Said Avelox, With Other Antibiotics In Fluoroquinolone Class, Would Add A "Black-Box" Warning For Tendinitis And Tendon Ruptures

(Posted by Tom Lamb at DrugInjuryWatch.com)

On July 8, 2008 the FDA announced that a so-called "black-box" warning would be added to the Avelox (moxifloxacin) package insert, or label, to strengthen existing warnings about the increased risk of developing tendinitis and tendon rupture.  At the same time, the FDA announced similar action for these other antibiotics in the fluoroquinolone class of drugs:

Ciprofloxacin (marketed as Cipro and generic ciprofloxacin)
Ciprofloxacin extended release (marketed as Cipro XR and Proquin XR)
Gemifloxacin (marketed as Factive)
Levofloxacin (marketed as Levaquin)
Norfloxacin (marketed as Noroxin)
Ofloxacin (marketed as Floxin and generic ofloxacin)

While reading through some of the material that the FDA made available online in connection with this July 2008 label change for these fluoroquinolone antimicrobial drugs, I found the following:

Fluoroquinolones, like any drug, have possible side effects associated with their use.  Rarely, some side effects may be serious or even fatal; however, most of the risks are mild.  Some of the most serious side effects include seizures, hallucinations, depression, heart rhythm changes (QTc prolongation and torsade de points), and intestine infection with diarrhea.  Rarely, damage to the liver, kidneys or bone marrow, and changes to blood sugar may occur.  (Emphasis added.)

This last sentence brought to mind the February 2008 "Dear Doctor" letter about Avelox / Avalox that Bayer sent out in Europe, which was reportedly intended to emphasize a 2007 label change Bayer made in Europe about, in part, severe and possibly fatal liver toxicity.

I concluded my February 2008 article about this Avelox letter that Bayer sent to doctors in Europe, only with this remark:

We will watch for any similar Avelox "Dear Doctor" letter from Bayer here in the U.S.

So where is the corresponding letter to health care providers in the U.S. from Bayer about Avelox and its association with liver toxicity?

Further, is the FDA looking at Avelox specifically for serious side effects such as drug-induced hepatitis and liver failure, which seem to be unique to this antibiotic among the fluoroquinolones?

If you have any insight concerning what is going on with Bayer or the FDA about serious adverse reactions to Avelox involving liver toxicity -- ranging from hepatitis to liver transplant -- there are some of us who are curious. 

I would like to hear about what you know regarding this Avelox safety issue.  Of course, I will share that information with our readers; our "source" can choose, however, to remain anonymous (like over at the Cafepharma Message Boards) or not.  Send me an email or submit a Comment, below.  Thanks.

February 2008 "Dear Doctor" Letter About Avelox / Avalox Is Sent By Bayer In Europe

Action Reportedly Intended To Emphasize 2007 Label Change About Severe, Possibly Fatal Liver And Skin Side Effects

(Posted by Tom Lamb at DrugInjuryWatch.com)

A February 14, 2008 Reuters article, "Bayer warns doctors on rare Avelox side effects", reports that this German drug company is sending warning letters to doctors in Europe about the antibiotic Avelox, one of its top-selling drugs. This February 2008 letter -- which would be generally referred to as a "Dear Doctor" letter -- is reportedly intended to emphasize severe liver reactions and serious skin rashes that can be caused by Avelox use.

From the February 14 Reuters article about this Avelox letter from Bayer:

Bayer has included the additional warnings in the packaging of Avelox products since autumn last year after some incidents of severe side effects were monitored, but is now reinforcing this by writing to doctors.

"The side effects are very rare. But when it happens, it is quite severe to patients. We want doctors to be more aware," said Yvonne Moeller, a spokeswoman at Bayer.

Avelox, or Avalox in Europe, is used by patients as treatment for respiratory and other infections.

Some additional details about this development were provided by a Thomson Financial News article, "Avelox: Bayer warns of liver damage risk linked to Avelox antibiotic, changes label", also from February 14:

Bayer AG (NYSE:BAY) has warned doctors that its Avelox antibiotic may lead to potentially fatal liver damage and skin disease in rare cases, following a routine analysis of recent data on side effects.

The link between Avelox and the side effects has been known but the analysis has yielded very rare new cases, prompting the German drug maker to adjust the labelling of Avelox and informing doctors, a Bayer spokeswoman said, confirming a report in Dutch newspaper Algemeen Dagblad.

We will watch for any similar Avelox "Dear Doctor" letter from Bayer here in the U.S.

Cholesterol Drug Zetia May Cause Serious Liver Injury Including Hepatitis And Liver Failure

Health Canada First Raised This Zetia Safety Issue In February 2005; News Reporter Discovers In December 2007 That Information Known By Merck and Schering-Plough About These Zetia Side Effects May Have Been Withheld

(Posted by Tom Lamb at DrugInjuryWatch.com)

Back on February 1, 2005 Health Canada posted on its web site a so-called "Dear Doctor" letter about Zetia (ezetimibe) -- called Ezetrol in Canada -- from Merck Frosst / Schering Pharmaceuticals that was intended to draw attention to some serious side effects associated with Zetia.  That 2005 Dear Doctor letter included the following:

The Warnings, Precautions, and Adverse Events sections are being updated to reflect the occurrence of the following adverse events in patients taking Ezetrol® (ezetimibe) alone or in combination with a statin:

• myalgia;
• rhabdomyolysis;
• hepatitis;
• acute pancreatitis;
• thrombocytopenia; and
• suspected interaction between Ezetrol® (ezetimibe) and warfarin 

In the U.S., however, Merck and Schering-Plough -- the drug companies responsible for Zetia, here -- chose not to send any corresponding Dear Doctor letter to American health care professionals, nor did the FDA mandate that they do so.

Returning to this 2005 Dear Doctor letter about Zetia, here is what was said about liver injuries to patients using Zetia and a statin drug (such as Zocor, Lipitor, Crestor, Lescol, Mevacor, or Pravachol):

Adverse hepatic events:

Elevations of liver transaminases and cases of hepatitis have been reported in patients treated with [Zetia]. Liver function monitoring is recommended when therapy with [Zetia] is initiated in patients treated or about to begin treatment with a statin.

Health care professionals should be aware that the use of [Zetia] in combination with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of liver transaminases.

In the two years since this 2005 Dear Doctor letter about Zetia was sent by the Merck and Schering group in Canada there have been some case reports of serious liver injury in patients using Zetia and statins -- but for the most part Zetia-induced liver injury had been off-the-radar for most drug safety observers. 

Now we have some idea about why, perhaps, Zetia-induced liver injury side effects were not more widely known.

In a December 21, 2007 article, "Data About Zetia Risks Was Not Fully Revealed", New York Times (NYT) reporter Alex Berenson broke the story that Merck and Schering-Plough had conducted several studies of Zetia which, in fact, raised the possibility that Zetia can cause liver damage when used long-term with other statins -- but these drug companies decided not to publish the results of those Zetia studies.

In preparing for his December 2007 Zetia article, the Times' reporter Alex Berenson spoke to a drug company representative and some medical doctors about this reporter's discovery of unpublished research about Zetia and liver-related side effects. 

We'll start with comments from two doctors who spoke with Mr. Berenson about this emerging drug safety issue:

“You don’t want to have data missing,” said Dr. Bruce Psaty, a professor of medicine and epidemiology at the University of Washington. “When there have been adverse effects, when the benefits don’t look impressive, those are the trials that historically don’t make it to press.”...

“We keep telling people we want to practice evidence-based medicine, and what we keep finding out is that much of the evidence is obscured,” said Dr. Harlan Krumholz, a cardiologist at Yale, when told about the previously undisclosed studies. “There is important evidence, but it’s not in public view. It’s hidden from investigators.”

On the other side of things, the Schering-Plough representative had this to say :

A Schering executive, when asked by a reporter about the unpublished [Zetia] studies, confirmed their existence. But the executive, Dr. Robert J. Spiegel, said the companies had not considered the [Zetia] studies scientifically important enough to publish their findings. Some may eventually be published, he said.

"We’re pretty comfortable that people don’t have trouble tolerating Zetia,” said Dr. Spiegel, the chief medical officer of the Schering-Plough Research Institute, Kenilworth, N.J.  (Emphasis added.)

In his December 2007 NYT article Mr. Berenson provides some reasons, however, why doctors and patients may not want to go along with this "reassurance" from Schering's Dr. Spiegel:

Most of the studies about Zetia in which Merck and Schering have published the results covered periods of only 12 weeks — not enough time for liver problems to develop in most patients....

But the F.D.A.’s documents show that Merck and Schering conducted several other long-term trials of Zetia without releasing their findings.

Together those studies cover several thousand patients who took Zetia along with statins for one to two years. The statins include Lipitor and Crestor, as well as Zocor, which is usually prescribed generically as simvastatin and is the statin used in the Vytorin pill....

The companies’ own published studies have generally played down the risk of liver problems. But Dr. Mark Stolk, a gastroenterologist in the Netherlands, last year reported two cases of patients who had developed hepatitis, a liver disease, after taking Zetia alongside Lipitor. One of the patients has since died, Dr. Stolk said in an interview last month. While Zetia is safe for most patients, doctors should carefully monitor patients for liver damage, he said.

“I think other cases will emerge,” he said.

What does the FDA have to say about this news reporter's discovery of unpublished studies suggesting that Zetia can cause serious liver injury when taken with statins?  Mr. Berenson tells us: "The agency did not respond to requests for comment."

To be sure, we will be reporting further developments as more is learned about the safety of Zetia -- one way or the other.

P.S.  Given how NYT reporter Alex Berenson discovered that Merck and Schering-Plough failed to publish some studies about Zetia and liver damage, Ed Silverman timely posted "How To Find Documents On The FDA Site" on his Pharmalot blog:

This cheat sheet should help you find briefing documents - the reams of supporting paperwork submitted by a drugmaker when seeking FDA approval for its med. It was compiled by a professor and students at the Lake Erie College of Osteopathic Medicine’s School of Pharmacy and recently published in the letters section of The Annals of Pharmacotherapy.

Thanks Ed for this insight about how emerging drug-safety issues (like the NYT Zetia story) can be found and exposed.  (12/21/07)

P.S.   Dr. Aubrey Blumsohn, over at the Scientific Misconduct Blog, gives us his strongly worded opinion about the position asserted by Schering's medical director in the NY Times story about Zetia and Vytorin, which I have bolded above. 

In his post, "More problems with Ezetimibe (Zetia, Vytorin): Let there be light", Dr. Blumsohn writes:

... Dr. Spiegel, it's not your decision. When patients might die it's always "scientifically important".

In addition, Dr. Blumsohn provides links to some other articles about this emerging Zetia study data controversy.  (12/23/07)

Will New Black Box Warning About Heart Attacks Lead GlaxoSmithKline To Withdraw Avandia From Market?

One Wonders Whether GSK Might Do A "Soft" Recall Of Its Embattled Diabetes Drug, As Was Done By BMS With Serzone And Tequin In Recent Years

(Posted by Tom Lamb at DrugInjuryWatch.com)

Avandia (rosiglitazone) is a prescription drug from GlaxoSmithKline (GSK) approved by the FDA in 1999 to treat Type 2 diabetes.  As many people are aware now, while Avandia might have helped diabetic patients in some regards, it seems that this benefit comes at an increased risk of developing serious heart-related side effects including heart attacks and strokes.

The Avandia safety story started for most of us in May 2007, as follows:

On May 21, 2007 the Los Angeles Times published an Associated Press (AP) article entitled "Diabetes drug linked to heart attack risk" which broke the story about a new analysis of Avandia data that was published online earlier this same day by the New England Journal of Medicine (NEJM).  The new Avandia article, "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death", by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H., will appear in the June 14, 2007 print edition of the NEJM.

More recently, on November 6, 2007 Health Canada issued a MedEffect email alert about Avandia -- as well as the related Avandamet and Avandaryl -- to inform us that GlaxoSmithKline is informing Canadian doctors and patients about new restrictions on the use of its rosiglitazone products (Avandia, Avandamet and Avandaryl) due to "cardiac safety concerns".

More detail was provided in the November 2007 Public Communication document about Avandia posted by Health Canada:

• Rosiglitazone (Avandia®) is no longer approved for use alone to treat type 2 diabetes, except when metformin* use is contraindicated or not tolerated.
• Rosiglitazone is no longer approved for use with a sulfonylurea drug** (such as glyburide), except when metformin is contraindicated or not tolerated.
• Rosiglitazone should not be used if you have heart failure, or have experienced heart failure in the past.
• Patients who are taking rosiglitazone, especially those with underlying heart disease, or those who are at high risk of heart attack or heart failure, should talk to their doctor about the benefits and risks of continuing rosiglitazone therapy.

There was also a November 2007 "Dear Doctor" letter about Avandia posted on the Health Canada web site.

Two weeks before this news from Health Canada, in the U.S. the FDA had announced that it wanted Glaxo to add a "black box" warning about the increased heart attack associated with Avandia, according to an October 24, 2007 article in The Wall Street Journal, "Tougher Avandia Warning Is Urged":

Agency officials are pushing for a "black box" warning, [according to people with knowledge of the matter]. The new label is still being discussed with the company and its final form isn't yet clear. In high-profile safety matters, the agency tends to have strong leverage....

An FDA spokeswoman said the agency "is still involved in internal discussions on this matter" and that when there is a final decision it will become public. A GlaxoSmithKline spokeswoman said the company is "working diligently with the FDA to finalize the label, but it would be inappropriate for us to discuss the ongoing conversations with the agency."...

If it goes into effect, the new warning would focus on Avandia's potential for increased ischemic risk: a risk of events in which blood is choked off from the heart. An FDA analysis that crunched together multiple Avandia studies found that the drug appeared to be linked to a 38% higher risk of ischemic events....

When Avandia gets its new "black box" warning about increased heart attack risks, Avandia sales may be even further diminished going forward.  In turn, GlaxoSmithKline could follow the lead of Bristol-Myers Squibb (BMS) when that drug company experienced increasing scrutiny about the safety of its antibiotic Tequin in 2006.  Rather than do a Tequin safety recall, Bristol-Myers announced that it would stop marketing Tequin in the U.S. for "business" reasons -- which was very similar to what they did with their besieged anti-depressant drug Serzone back in 2004.

This new Big Pharma practice of withdrawing an alleged unsafe prescription drug for said-to-be business reasons (rather than safety reasons) could be called a "soft" recall.

We'll wait to see what Glaxo decides to do about its embattled diabetes drug as more is learned about Avandia side effects going forward.

Is This What Medtronic's March 21, 2007 "Dear Doctor" Letter Said About Sprint Fidelis Lead Problems?

One Person Took The Impression That Medtronic Was Trying To Lay Blame For Lead Wire Failures On Those Physicians Who Were Doing The Defibrillator Implants

(Posted by Tom Lamb at DrugInjuryWatch.com)

To start, our thanks to a fellow in Florida who was kind enough to share with us what he found as a result of some investigation into that hard-to-find March 21, 2007 "Dear Doctor" letter about problems with Medtronic's Sprint Fidelis defibrillator leads. Unfortunately, his motivation came from the fact that he has one of the recalled Sprint Fidelis leads implanted currently. 

The following material comes from an April 8, 2007 article posted on a somewhat obscure blog called Random Thoughts on Pacemakers & Personal Finance that this fellow found after some looking-around on the Internet:

... On March 21st, Medtronic issued a "Dear Doctor" letter concerning higher than expected conductor fracture rates with the Sprint Fidelis lead. The Sprint Fidelis is Medtronic's premium defibrillation lead. It is the first sub-7 french ICD to be released (St Jude Medical released the Riata ST lead approximately 18 months after the Sprint Fidelis).

The body of the letter is as follows:

Dear Doctor,

Medtronic has received reports from a limited number of implanting physicians indicating they have experienced higher than expected conductor fracture rates in their centers with Sprint Fidelis leads. While current overall Sprint Fidelis performance is consistent with other leads, Medtronic is actively investigating these reports, has reviewed them with our Independent Physician Quality Panel, and would like to share what we know at this time.

Through detailed assessment of reported fractures, we have identified two primary locations where conductor fractures have occurred: 1) distal portion of the lead and 2) near the anchoring sleeve tie down. The distal conductor fractures affect the anode (ring electrode) and fractures that occur around the anchoring sleeve affect the cathode (helix tip electrode). Fractures at both locations appear to prsenet clinically as over-sensing, increased interval counts and inappropriate shocks. Medtronic has worked closely with physicians who have experienced fractures and conducted significant bench testing in an attempt to reproduce the fractures and identify root cause. At this point, our investigation suggests that variables within the implant procedure may contribute significantly to these fractures.

For distal conductor fractures, our investigation has identified severe bending or kinking of the distal end of the lead over the lead body while passing through tortuous vasculature as a significant contributing factor. If the lead is severely bent or kinked at the distal end, the conductor may be compromised such that the conductor may fracture after implant due to chronic fatigue from natural cardiac motion. The venous structure or pathway, venous access location, length of introducer sheath and lead insertion force are all factors that may contribute to sever bending or kinking of the lead. Medtronic recommends avoiding severe bending or kinking of the lead during implantation. If you encounter excessive resistance resulting in severe bending or kinking while advancing the lead, please remove the lead and return it to Medtronic.

For conductor fractures that occur around the suture sleeve, our preliminary investigation suggests that under certain implant techniques, the lead appears to be exposed to severe bending or kinking in the pectoral area. We are still investigating and actively partnering with physicians to better understand this type of fracture. If excessive kinking or bending is observed during lead suturing and/or pocket formation, Medtronic recommends the lead be re-sutured and/or pocket reassembled per guidelines in the Medtronic lead implant manual. In addition, positioning the anchoring sleeve against or near the vein may be helpful.

Sprint Fidelis lead models 6949, 6948, 6931, and 6930 were market released in the U.S. and internationally in September and October 2004. Performance of model 6949, the Sprint Fidelis lead currently followed in our System Longevity Study, indicated survival is 98.9% at two years. Sprint Fidelis 6949 performance based upon return product analysis shows 99.86% chronic fracture-free survival at two years. Both evaluation methods suggest performance is in line with other Medtronic leads and consistent with lead performance publicly reported by other manufacturers.

The unknown person who posted this April 8 article on the Random Thoughts on Pacemakers & Personal Finance blog then went on to make these comments regarding this March 2007 Dear Doctor letter from Medtronic about its Sprint Fidelis lead failures:

This letter was sent to all implanting U.S. physicians and nowhere was there any request for confidentiality. That is why I posted it.

Well, the lead fails and they state, "variables within the implant procedure may contribute significantly to these fractures." It's the implanter's fault. Of course, that makes perfect sense. The same physician who has implanted endocardial defibrillation leads since 1992 now suddenly doesn't know how to operate one of these new-fangled leads. Are they suggesting that for patients with a tortuous anatomy a different lead should be used - possibly a Sprint Quattro Secure? I don't know. What's going to happen if physicians get nervous and every time they try to implant the lead and "excessive kinking" occurs, they abandon the lead a try a different lead? Will returns to Medtronic increase?

Of course, if and when we learn that the (said-to-be) text of this March 21 Dear Doctor Sprint Fidelis letter from Medtronic which was posted on the Random Thoughts on Pacemakers & Personal Finance blog back in April 2007 is not accurate or correct somehow, we will let you know, immediately. 

Until then, this fellow in Florida seems to have found one of the pieces that might help us further fit together an evolving Sprint Fidelis story.

Cephalon Added Warning To Provigil Label About Serious Skin Reactions In August 2007

A "Dear Doctor" Letter About Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated With Provigil Was Sent In September 2007

(Posted by Tom Lamb at DrugInjuryWatch.com)

On October 24, 2007 the FDA sent an email alert to inform doctors and other healthcare providers that the drug company Cephalon issued a revised package insert, or label, for Provigil (modafinil) in August 2007.

According to this October 2007 FDA alert about Provigil:

• Provigil is indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder....  Healthcare professionals and consumers should also be aware that Provigil is not approved for use in pediatric patients for any indication.
• The revised labeling updates safety information to include warnings regarding serious rash, including Stevens-Johnson Syndrome (SJS) and hypersensitivity reactions, and psychiatric symptoms. Rare cases of serious or life-threatening rash, including Toxic Epidermal Necrolysis, and Drug Rash with Eosinophilia and Systemic Symptoms have been reported in adults and children in worldwide postmarketing experience....  Physicians should instruct their patients to immediately discontinue the use of Provigil and contact them if a rash or other hypersensitivity reaction occurs.

Cephalon sent a so-called "Dear Doctor" letter about Provigil in September 2007 to convey this information about serious skin reactions such as SJS and TEN as well as to bring attention to the revised label for this sleep disorder drug.

As we had reported in September 2007, the Fall 2007 FDA Drug Safety Newsletter (Volume 1, Number 1) included a report that the FDA had been monitoring cases of serious skin rashes associated with Provigil.