Drug Injury Watch

November 2007 FDA Advisory Panel Recommends That Serevent And Advair Get Stronger Warnings About Use By Children

Some Panel Members Want Serevent Withdrawn From Market; FDA And GSK Say Asthma Drug Recall Is Not Appropriate

(Posted by Tom Lamb at DrugInjuryWatch.com)

On November 28, 2007 an FDA pediatric advisory panel recommended that the safety warnings on Serevent and Advair needed to be strengthened in order to emphasize the increased risk of hospitalization and death for children using these two asthma drugs from GlaxoSmithKline PLC (GSK).

For some information about the extent of use by children, we get this sales information about  Advair and Serevent from a November 29, 2007 article, "New Warnings Sought For Two Asthma Drugs", published by The Wall Street Journal:

Advair, known as Seretide outside the U.S., is Glaxo's biggest-selling drug, with global sales of $6.1 billion last year. Serevent sales totaled $538 million. The company estimates 13.3% of Advair and 3% of Serevent prescriptions were for children. According to an FDA analysis of data from Verispan, 779,006 U.S. patients ages 16 or younger got retail prescriptions for Serevent or Advair between April 2006 and March 2007.

With the stage set, we now consider what the experts on this FDA advisory panel had to say about the safety aspect of Serevent (salmeterol).  For that we turn to a November 28, 2007 Reuters article, "Glaxo asthma drug needs kid risk warning: FDA panel", by Kim Dixon:

"The data is very troubling because both the increase in hospitalization and in mortality is so different" from what doctors currently believe, said Thomas Newman, an epidemiologist at the University of California, San Francisco, and panel member....

At least two panel members said the data was so convincing that Serevent should be pulled from the market. The FDA said it will consider the safety of all drugs in the class, called long-acting beta agonists, at a future meeting....

FDA staffers said no date for the meeting has been set.

Those "other" asthma drugs to be consider at this future FDA meeting would be GSK's Advair and Foradil, made by Novartis AG (NVS) and sold in the U.S. by Schering-Plough Corp.

As for the suggestion that Serevent and Advair should be recalled from the market, this idea was rejected by an FDA official and a GSK representative. 

The November 29 WSJ article gave us the FDA's apparent position on this issue:

Dianne Murphy, director of the FDA's office of pediatric therapeutics, said, "We don't think it's appropriate to take the drugs off the market" or restrict use to adults only. In 2005, another FDA committee voted unanimously to keep salmeterol on the market.

For the GSK statement we return to the November 28 Reuters article:

Kathy Rickard, vice president for respiratory clinical development at Glaxo, said the company believes data shows no increased risk of hospitalization and mortality for Advair and she is not aware of a pending FDA meeting on the issue.

Despite this wishful thinking by GSK that the FDA will not further scrutinize the safety of Serevent and Advair, we anticipate an increasing debate on this issue in the time leading up to the next FDA meeting concerning these allegedly dangerous asthma drugs.

FDA Report Says Popular Asthma Drugs Serevent And Advair May Have Deadly Side Effects For Some Children

November 2007 Advisory Panel Meeting To Consider Safety of These Glaxo Drugs As Well As Novartis' Foradil

(Posted by Tom Lamb at DrugInjuryWatch.com)

An October 24, 2007 FDA staff report about Serevent (SUBJECT: 1-year Post-Pediatric Exclusivity Postmarketing Adverse Event Review) concluded that this inhaled beta-2 agonist asthma drugs as well as Advair "may have an unfavorable risk-benefit ratio" for children's asthma.

The October 2007 FDA staff report was prepared in advance of a meeting of an advisory panel of pediatricians later this week being convened to consider the safety of Serevent and Advair (made by GlaxoSmithKline PLC), both of which contain the active ingredient salmeterol, as well as another asthma drug, Foradil (made by Novartis AG and marketed in the U.S. by Schering-Plough Corp.), which contains the active ingredient formoterol.

In relevant part, for this asthma drug safety report FDA staff reviewed their adverse event reporting system database and found nine cases, including five deaths, in children under age 16 years in the 13 months since Serevent was approved for use in children.

To put this latest development into context, we provide some background from our earlier coverage of the issue of whether Serevent, Advair, and Foradil are unsafe drugs:

• In November 2005 the FDA issued a MedWatch alert regarding Serevent, Advair, and Foradil to inform doctors and patients that the use of use of these inhalation powders containing long-acting beta 2-adrenergic agonists ("LABA") may increase one's risk of severe asthma episodes and death.
• In March 2006 GlaxoSmithKline finally agreed with the FDA to revise a "black-box" warning on Advair and Serevent to further heighten awareness of an increased risk of death associated with salmeterol, but Novartis refused to take similar action as regards Foradil and formoterol.
• In June 2006 the Annals of Internal Medicine published the findings of a new analysis of 19 previous studies concerning Serevent, Advair, and Foradil.  The authors of that study were so concerned about their findings they suggested that Advair possibly should be taken off the market after estimating that Advair "may be responsible" for as many as 4,000 of the 5,000 asthma-related deaths each year in the United States.

Some more general contextual information is provided by Wall Street Journal (WSJ) reporter Jennifer Corbett Dooren in her November 23, 2007 article, "Asthma Drug Safety Review Needed for Children, FDA Says":

• While clinical studies have showed all three drugs [Serevent, Advair, and Foradil] are successful at controlling asthma in the vast majority of patients, some have showed that salmeterol can cause severe -- and sometimes fatal -- asthma attacks in a small group of patients. Asthma is a chronic disease that causes narrowing of the airways and affects 22 million Americans, including about 6.5 million children.
• National treatment guidelines recommend low-dose, inhaled corticosteroids for routine management of the disease along with an inhaler, or so-called rescue medication, to manage attacks. The guidelines recommend that drugs like Serevent, Advair and Foradil should only be used as add-on therapy in patients 12 and older whose asthma isn't controlled by corticosteroids.

This November 23 WSJ article also summarized the October 2007 FDA report's findings about the deaths of children using Serevent or Advair and, thereafter, it went on to present the GlaxoSmithKline response to this data:

• A review of pediatric deaths possibly associated with Serevent from 1994 through 2007 showed 23 deaths, the FDA said, with 14 of the cases being reported as being caused by asthma exacerbation or a worsening of the condition. The agency noted that some patients will experience asthma exacerbations even when receiving appropriate therapy. A review of deaths possibly linked to Advair showed 15 pediatric deaths from 1999 through 2007.
• GlaxoSmithKline said it believed Serevent and Advair were appropriately labeled to reflect the safety profile of the products. The company also said "salmeterol continues to exhibit a favorable safety profile in pediatric subjects and the safety profile is similar to that seen in adults."

Lastly, from a November 23, 2007 Bloomberg article, "Glaxo's Asthma Drugs May Harm Children, U.S. FDA Staff Says, we learn that:

• Global revenue for Serevent and Advair rose 12 percent to $6.13 billion last year, making the medicines the second-best-selling in the world behind Pfizer Inc.'s cholesterol drug Lipitor.

According to that same Bloomberg article, this level of sales makes Serevent and Advair "the company's biggest-selling medications".

We will watch for guidance from the FDA's pediatric advisory committee following its November 28, 2007 meeting to discuss the safety of Serevent, Advair, and Foradil.  Of course, we await further comment from GlaxoSmithKline, also.

FDA Announces In November 2007 That It Will Investigate Possible Link Between Maxipime And Increased Risk Of Death

A Medical Journal Article Published In May 2007 Suggested This Emerging Drug Safety Issue; Why Was There A Six-Month Delay In Starting This FDA Investigation?

(Posted by Tom Lamb at DrugInjuryWatch.com)

In mid-November 2007 the FDA sent an MedWatch Email Alert to inform the public about an emerging drug safety issue involving Maxipime (cefepime), an injectable antibiotic that was approved by the FDA in 1996.  In summary, the FDA announced the start of its investigation into a possible increased risk of death associated with Maxipime use, and said that their safety evaluation should take about four months to complete.  Maxipime is manufactured by Bristol-Myers Squibb Co. (BMY).  Maxipime is marketed in the U.S. by Elan Corp. PLC (ELN).

More detail is set forth in the FDA's "Early Communication About an Ongoing Safety Review Cefepime (marketed as Maxipime)", which the agency issued in November 2007:

An article in a recent issue of The Lancet Infectious Diseases has raised the question about increased mortality with the use of cefepime (Yahav D, Paul M, Fraser A et al. Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis 2007; 7: 338–48).  FDA is currently reviewing some safety data and has requested additional data to further evaluate the risk of death in patients treated with cefepime.  Cefepime is a broad spectrum cephalosporin antibiotic currently approved for the treatment of a variety of infections due to susceptible strains of microorganisms.  It is a member of the class of antibiotics known as ß–lactams.

The article in the May 2007 issue of The Lancet Infectious Diseases describes a higher all-cause mortality in patients treated with cefepime compared to other ß–lactams. Overall, the all-cause mortality was higher with cefepime than other ß-lactams (risk ratio [RR] 1·26 [95% CI 1·08–1·49]) and for the subgroup of patients with febrile neutropenia (RR 1·42 [95% CI 1·09–1·84]).

As an aside, this additional information raises the issue of why did it take six months for the FDA to start its safety review of Maxipime.  Perhaps more will be learned about this delay in the months to come (especially if the timing of this Maxipime safety review comes to the attention of some of our more inquisitive members of Congress who have had their eyes on the FDA, recently).

A November 14, 2007 article by Bloomberg reporter Beth Jinks, "Bristol-Myers, Elan's Maxipime Will Get U.S. Review", presented some information from BMS spokesmen relevant to this new FDA safety investigation:

• "Bristol-Myers Squibb has conducted a detailed review of cefepime data from BMY-sponsored trials as well as data from post-marketing safety databases and a review of the literature," said Tony Plohoros, a company spokesman.  "The review of the totality of data indicates that the safety profile of cefepime is unchanged from that previously described in regulator submissions."
• The drug is approved in the U.S. to treat lower respiratory, urinary, gynecological and skin infections as well as bacteria in the blood and febrile neutropenia, a fever and reduction in white blood cells usually resulting from chemotherapy, according to Bristol-Myers spokesman Jeffrey Macdonald.

As with all serious side effects involving prescription drugs, in their November 2007 announcement about this Maxipime safety review, the FDA urged both healthcare professionals and patients to report side effects from the use of Maxipime to the FDA's MedWatch Adverse Event Reporting program by one of the following means:

1. online at www.fda.gov/medwatch/report.htm;
2. by returning the postage-paid FDA form 3500 available in PDF format at www.fda.gov/medwatch/getforms.htm to 5600 Fishers Lane, Rockville, MD 20852-9787;
3. faxing the form to 1-800-FDA-0178; or,
4. by phone at 1-800-332-1088.

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.

Trasylol Sales In U.S. And Canada Suspended Temporarily By Bayer In Early November 2007

Market Withdrawal Or Recall Of Trasylol Seems Possible As Bayer Waits For Final Data From Halted BART Study

(Posted by Tom Lamb at DrugInjuryWatch.com)

On November 5, 2007 the FDA announced and Health Canada announced that sales of Bayer AG' s anti-bleeding drug Trasylol (aprotinin) would be suspended temporarily in the U.S. and Canada while investigations continued about whether Trayslol is linked to a higher risk of death than competing heart surgery drugs.

As we had reported previously, the FDA has been reviewing the safety of Trasylol since early 2006:

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 2006, a "Dear Doctor" letter from Bayer regarding Trasylol was posted on Health Canada's MedEffect web site.

Later, in September 2006, an FDA advisory panel reviewed data from medical journals that suggested that Trasylol might increase the chance of kidney damage, heart attacks, and strokes.

A second Trayslol advisory panel meeting was scheduled for September 2007.  Two days before, FDA staff released 235 pages of briefing documents they had prepared for that Trasylol advisory panel meeting which seemingly foreshadowed this most recent development in the Trasylol saga.

From a September 10, 2007 Reuters article, "Bayer's Trasylol may boost death risk: FDA staff", by reporter Kim Dixon:

FDA staff, in briefing documents ahead of Wednesday's advisory panel, said the totality of three recent studies support the risk of renal failure and dysfunction, and noted a "mortality disadvantage detected" in the Bayer study.

A Bayer spokeswoman said the company looks forward to discussing the drug's merits at the advisory panel meeting....

"There is still no new clinical data, so the question is whether (Bayer's) observational study is enough of an alarm," said Ira Loss, an analyst at the investor research firm Washington Analysis.

"My assumption is this drug is being put into the dead-end of drug land," he added.

While the September 2007 Trasylol advisory panel decided this heart surgery drug should remain on the market despite its increased renal and cardiovascular risks, it urged Bayer to conduct a randomly controlled clinical trial on Trayslol.

Bad news for Bayer, however, soon followed when a Canadian study -- the BART study, an independent randomized, controlled trial that was being conducted in high-risk cardiac surgery patients -- was suddenly stopped in mid-October 2007 due to emerging serious safety concerns regarding Trayslol.

On October 25, 2007 the FDA posted on its web site an "Early Communication about an Ongoing Safety Review Aprotinin Injection (marketed as Trasylol)" which said, in part, stated that the 30-day mortality risk in the Trasylol group of the BART trial was nearing statistical significance, compared with other treatments Trasylol was being tested against.

A November 5, 2007 Reuters article about the suspension of Trayslol sales brings us up-to-date with this information:

• On [November 5, 2007] Bayer said it had been informed that BART trial data were now being collected from centers throughout Canada and final data analysis would emerge in around eight weeks.
• "Once the complete BART dataset is available, Bayer will work with health authorities to evaluate whether these data have any impact on the positive benefit-risk assessment for Trasylol," Bayer said [November 5, 2007].
• "Bayer believes that the totality of the available data continue to support a favorable risk-benefit profile for Trasylol when used according to labeling," the company said.

We will wait to see whether or not the final analysis of this BART study data and any other relevant information leads to Bayer withdrawing Trasylol from the market altogether in the months to come.  Of course, it is possible that based on their findings the FDA or Health Canada may make that choice for the drug company.

New Information From FDA On Alleged Problems With Ketek Safety Study 3014

October 2007 FDA Letter Says Aventis Did Not Follow Regulations And Statutory Requirements; Company Contends Study Conducted In Good Faith

(Posted by Tom Lamb at DrugInjuryWatch.com)

On October 24, 2007 the FDA posted on its web site a copy of an 11-page "Warning Letter" to Sanofi-Aventis (SNY) about problems with Ketek Study 3014.

In her October 25, 2007 Wall Street Journal article, "FDA Says Aventis Failed To Act on Ketek Drug Fears", Anna Wilde Mathews provided this summary the FDA's Ketek letter:

In yesterday's letter, the FDA said visits from an Aventis contractor and the drug maker's own audits documented "serious protocol violations and regulatory noncompliance by multiple clinical investigators." The agency said it was "unable to find evidence" that the company either fixed the problems or threw the problematic doctors out of the study and told the FDA. The FDA also faulted Aventis for failing to make sure the study was properly conducted and for allowing unqualified investigators to participate in the trial.

According to an October 25, 2007 story, "Sanofi slammed by FDA over failure to act on Ketek fraud", by Kristy Barnes that was posted on DrugResearcher.com:

[Study 3014 of Ketek (telithromycin) was] carried out between 2001 and 2002 after the FDA said that it needed more safety information on Ketek following fears that it could cause liver problems. The studies were carried out by Pharmaceutical Products Development (PPD) on behalf of Aventis, prior to its merger with Sanofi-Synthelabo.

In July 2002, Aventis submitted the results of study 3014 to the FDA. Subsequent data validation inspections by the agency of several clinical investigators participating in the study raised red flags and the FDA requested in January 2003 that Aventis provide information on its sponsor monitoring and auditing of clinical investigator sites for the trial.

Aventis subsequently provided this information to the FDA and following a lengthy investigation, the agency has now concluded that: "Aventis did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations".

At least two Sanofi-Aventis representatives have disputed the FDA's suggestion that Aventis acted improperly as regards its Study 3014 concerning the safety of Ketek.

As reported by Kim Dixon in "U.S. FDA cites Sanofi for shoddy study oversight", published online by Reuters October 24, 2007:

Sanofi-Aventis spokeswoman Emmy Tsui said the company intends to provide a detailed response to the letter.

She said the study was conducted in good faith, but has been the subject of much discussion. Sanofi has acknowledged that "various deviations occurred, including investigator fraud, and FDA did not rely upon this study in approving Ketek," she added.

And returning to the October 2007 Ketek story by Kristy Barnes on DrugResearcher.com:

Salah Mayhaoui, head of product communications for Sanofi-Aventis told DrugResearcher.com that: "Study 3014 was the first large "real world" study of an antibiotic and Aventis conducted this study in good faith."

"However, non-conformance in the form of deviations [from protocol] and other issues occurred, including clinical investigator fraud."

Mayhaoui said that the firm would provide a "detailed response" to the FDA's letter in the coming days. As part of this response we will "highlight some of the steps Aventis took to prevent the problems that occurred in 3014."

He said that at this point he did not know the next course of action that the FDA may take in regard to this matter. "I think they will review our arguments and then it is up to them to decide what happens next."

We will watch for further developments regarding this controversial clinical study of Ketek and, more generally, for new reports of liver damage and liver failure associated with the use of this particular antibiotic.