Drug Injury Watch

Tequin Revisited: Health Canada And The FDA Failed To Take Action, At Our Expense

Bristol-Myers Squibb Was Allowed To Withdraw Their Unsafe Drug For "Economic Reasons", And Only After Selling Off Its Inventory

(Posted by Tom Lamb at DrugInjuryWatch.com)

An article by Joel Lexchin, MSc MD, "Information about a discontinued drug", published in the March 11, 2008 edition of the Canadian Medical Association Journal (CMAJ), reminded me about how Health Canada and the FDA failed to order a recall of Tequin (gatifloxacin) a couple of years back.  Instead, Bristol-Myers Squibb (BMS) was allowed to do a gradual withdrawal of Tequin and, in so doing, the drug company largely succeeded in not drawing any additional attention to Tequin's safety problems.

In the spring of 2006, Bristol-Myer said that a continuing decline in Tequin sales was the reason for deciding to stop selling Tequin.  In fact, however, Tequin was an unsafe drug that had been linked to various blood-sugar disorders -- but the FDA as well as Health Canada let the drug company have it their way.

For the following review of developments and events leading up to how BMS ended its Tequin sales in the U.S. and Canada, I draw from two of my earlier reports about this dangerous antibiotic:   

• Bristol-Myers Squibb To Stop Selling Antibiotic Drug Tequin
• Antibiotic Tequin Should Be Banned By FDA, Says Public Citizen Petition

Mid-February 2006: BMS, the FDA, and Health Canada announced that the Tequin label would be changed to include stronger warnings about the threat of life-threatening events from blood-sugar changes.

March 1, 2006: The New England Journal of Medicine (NEJM) published online an early-release version of a study which found that patients using Tequin had four times the risk of hypoglycemia (low blood sugar) and an astounding 17 times the risk of hyperglycemia (high blood sugar) -- collectively referred to as dysglycemia -- when compared to other antibiotics.

April 27, 2006:  A newspaper article is the first announcement that BMS has decided to stop selling Tequin.  According to this Wall Street Journal article, however, Tequin product shipments would not end in most markets until sometime in May or June 2006.

May 1, 2006: Public Citizen asked the FDA to ban Tequin in order to immediately get this unsafe drug off pharmacy shelves in the U.S.  According to the Public Citizen petition, an analysis of adverse event reports submitted to the FDA reveals that during the period January 1, 2000 through June 30, 2005 there were 388 cases of hypoglycemia and hyperglycemia; 20 on those reports involved patient deaths.

To my knowledge, the FDA never banned Tequin in the U.S. as requested by Public Citizen.

The March 2008 CMAJ article which is mentioned at the outset of this piece confirms that Health Canada did nothing:

Health Canada issued a number of alerts about the potential for this product to interfere with glucose metabolism but never bothered to formally inform either the public or health care professionals that oral and intravenous forms of this drug were withdrawn from sale in Canada. The only place where one can find this information is by searching the discontinued products in Health Canada's Drug Product Database (http://cpe0013211b4c6d-cm0014e88ee7a4.cpe.net.cable.rogers.com/dpdonline/searchRequest.do). This failure to communicate important information about a drug raises serious concerns about Health Canada's ability to keep health care professionals and the public informed about safety issues.

I believe the same thing -- "raises serious concerns" -- can be said about how the FDA let the drug company Bristol-Myers Squibb seemingly sell-off its inventory of Tequin instead of the FDA ordering an immediate recall of Tequin. 

In the end, this history of Tequin appears to be a prime example of putting profits over public safety.

FDA Letter Concerning Sybmyax May Result In More Zyprexa Lawsuits For Lilly

According To Bloomberg Report, FDA Wants Information About Weight Gain And High Levels Of Blood Sugar Added To Zyprexa Label

(Posted by Tom Lamb at DrugInjuryWatch.com)

On June 29, 2007 Bloomberg published an article by its reporters Rob Waters and Margaret Cronin Fisk about a March 2007 "approvable letter" that the FDA sent to Eli Lilly & Co. on its drug Symbyax, which is a combination of Lilly's antipsychotic drug Zyprexa and the antidepressant drug Prozac.

According to this June 29 Bloomberg article, the March 2007 letter stated that the FDA "would delay the approval of Symbyax for depression because the agency wanted more information about the risk of diabetes in the medicine's prescribing label." 

The reporters said in their article Bloomberg had obtained a copy of this letter by Thomas Laughren, director of the FDA's division of psychiatry products, although "the letter hasn't been publicly released."

Bloomberg's June 29 article provides this content from and description of the Symbyax FDA letter:

"We are concerned that the proposed labeling is deficient with regard to information about weight gain" and high levels of sugar and fat in the blood of patients who took the drug, the FDA said in the letter, referring to proposed prescribing information on Symbyax.  "We do not feel that current labeling for either Symbyax or Zyprexa provides sufficient information on these risks." ....

Lilly's proposed prescribing information for Symbyax failed to disclose that almost half of patients who had high or borderline levels of blood sugar when they started taking the drug ended up with levels high enough to be considered diabetic, the FDA said in its letter. That was more than nine times the number of patients on placebos, or inactive dummy pills.

"We were troubled that this important information was not included in your proposed label," the agency said in the letter.

As covered previously, Lilly has already settled more than 29,000 Zyprexa claims brought by patients alleging that were not adequately warned that Zyprexa can cause diabetes other serious side effects.

As background, the FDA required Lilly and other drugmakers in September 2003 and, again, in March 2004 to warn that Zyprexa and other atypical antipsychotics are associated with weight gain and an increased risk of diabetes.

More recently, this March 2007 FDA letter concerning Symbyax reportedly says that the current label for Zyprexa is still insufficient in terms of its information about the risks of weight gain and blood sugar problems associated with Zyprexa.

As regards the affect of this March FDA letter on the current Zyprexa litigation:  First, it will seemingly benefit the plaintiffs in those cases have been filed but not settled and, second, it may allow additional, new claims to be filed that were previously thought to be barred by operation of the statute of limitations, i.e., filing deadline, in most states.

900 More Zyprexa Lawsuits Settled By Eli Lilly And Co.

Drug Maker Still Faces Product Liability Cases Involving 750 Zyprexa Patients

(Posted by Tom Lamb at DrugInjuryWatch.com)

A June 12, 2007 Associated Press (AP) article reports that the Eli Lilly and Co. has settled another 900 Zyprexa lawsuits.  These legal cases have generally involved allegations by patients that their Zyprexa use has caused diabetes or high blood sugar and that the Zyprexa package insert, or label, failed to adequately warn users of these side effect risks.

In June 2005 Eli Lilly & Co. started reaching settlement agreements with certain groups of plaintiffs' lawyers to resolve these Zyprexa cases.

According to this June 12 AP article about the 900 latest Zyprexa settlements:

• "The Indianapolis-based drug maker declined to release the settlement amount. But spokeswoman Marni Lemons said Tuesday it would have no material impact on the company's financial statements."
• "The company was scheduled to go to trial July 9 in federal court for four Zyprexa claims, but those cases are part of the latest settlement, Lemons said."
• "Lilly has settled roughly 28,500 product liability claims involving Zyprexa over the past two years. In June 2005, the company settled 8,000 claims for $690 million. This past January, it settled more than 18,000 for roughly $500 million."
• "Lilly still faces product liability lawsuits from roughly 750 patients."

Zyprexa is an anti-psychotic Zyprexa used to treat patients who have been diagnosed with schizophrenia and bipolar disorder.

Zyprexa, Lilly's top-selling drug, generated $4.4 billion in sales last year and $1.1 billion during the first quarter of 2007.

Levaquin Associated With Blood Sugar Problems And Liver Disorders

January 2007 Article Sets Forth Reports Made To Health Canada In Past Ten Years

(Posted by Tom Lamb at DrugInjuryWatch.com)

The January 2, 2007 edition of the Canadian Adverse Reaction Newsletter (Volume 17, Issue 1) includes an article concerning reports of blood sugar problems and liver disorders associated with Levaquin (levofloxacin) made to Health Canada during the past ten years

According to this article, entitled "Levofloxacin: dysglycemia and liver disorders":

• "[Levaquin] is a broad-spectrum fluoroquinolone antibiotic that is indicated for the treatment of certain respiratory tract, skin and urinary tract bacterial infections in adults."
• "From Jan. 1, 1997, to June 30, 2006, Health Canada received 22 domestic reports of dysglycemia suspected of being associated with levofloxacin. Described dysglycemic adverse reactions (ARs) included 1 report of diabetes mellitus, 2 reports of hyperglycemia alone, 16 of hypoglycemia alone and 3 of hyperglycemia and hypoglycemia combined."
• "With regards to liver disorders, from Jan. 1, 1997, to June 30, 2006, Health Canada received 44 domestic reports of liver and biliary disorders suspected of being associated with levofloxacin. Of these 44 cases, there were 5 cases of hepatic failure, 9 of hepatitis and 1 of hepatorenal syndrome. Five of these 15 cases of liver disorders were fatal. The remaining 29 reports included ARs of increased liver enzyme levels, cholestatic hepatitis and jaundice."

This January 2007 article concludes by stating that Health Canada will continue to monitor adverse drug reactions that may be associated with Levaquin, and urges doctors as well as other health care providers to report any new cases of blood sugar problems or liver disorders possibly involving the use of Levaquin.

Case Reports: Serious Blood Sugar Problems In Patients Taking Tequin

Article Finds Tequin Is "Probable Cause" of Hyperglycemia And Hypoglycemia, Or Dysglycemia, In Most Of Subject Cases

There is a Case Reports article concerning Tequin (gatifloxacin) causing serious blood-sugar problems, or dysglycemia, in the November 1, 2006 edition of American Journal of Health-System Pharmacy (Vol. 63, Issue 21, 2087-2092).

This article, entitled "Gatifloxacin-induced dysglycemia", describes 13 cases where patients using the antibiotic Tequin developed hyperglycemia (abnormally high blood sugar) or hypoglycemia (abnormally low blood sugar).  While noting that Tequin might not be the exclusive cause of the dysglycemia, the article concludes that Tequin was "the probable cause in the majority of these cases".  From the abstract for this article:

The Naranjo et al. probability rating scale revealed that gatifloxacin was the probable cause in the majority of the 13 cases, primarily because of the temporal relationship with gatifloxacin and, in some instances, resolution of dysglycemia after drug discontinuation.

This November 2006 Tequin article is by Rosemary Zvonar, an Antimicrobial Pharmacy Specialist in the Pharmacy Department at The Ottawa Hospital.  The author provides some detail as regards the three most serious cases of Tequin-related blood-sugar problems that she has identified, including this finding (from the abstract, again):

Three elderly patients developed dysglycemia after initiation of gatifloxacin therapy. Both patients who developed hypoglycemia were receiving concomitant insulin or oral antidiabetic agents.

In late April 2006 Bristol-Myers Squibb announced that it would no longer sell Tequin.

(Posted by: Tom Lamb)

Antibiotic Tequin Should Be Banned By FDA, Says Public Citizen Petition

Tequin Ban Is Needed To Prevent Any Further Use Of This Unsafe Drug

On May 1, 2006 the consumer advocacy group Public Citizen asked the FDA to ban Tequin, an antibiotic made by Bristol-Myers Squibb Co. (BMS).  The FDA needs to ban Tequin, according to this Public Citizen petition, in order to immediately get this unsafe drug off pharmacy shelves in the U.S.

A week before Public Citizen requested that Tequin be banned, BMS announced that it planned to stop selling Tequin.  According to an April 27, 2006 article in the Wall Street Journal, however, Tequin product shipments would not end in most markets until sometime in May or June 2006.  Put otherwise, this would be a gradual withdrawal process by the drug company; there would not be any immediate recall of Tequin by Bristol-Myers.  This means, in effect, that Tequin could still be prescribed by doctors and taken by patients in the next couple of months -- a situation that Public Citizen finds unacceptable due to the serious side effects associated with Tequin.

According to the Public Citizen petition, an analysis of adverse event reports submitted to the FDA reveals that during the period January 1, 2000 through June 30, 2005 there were 388 cases of hypoglycemia (low blood sugar) and hyperglycemia (high blood sugar) -- collectively referred to as dysglycemia; 20 on those reports involved patient deaths.

Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, alleges that changes made to the package insert, or label, for Tequin in February 2006 are insufficient.  Moreover, there are at least six other antibiotics available which, according to Public Citizen, are all safer than Tequin.  Therefore, Dr. Wolfe asserts, "This drug carries unique risk but has no unique benefits and therefore should not be on the market."

By going the course of a gradual withdrawal as opposed to a Tequin recall, it seems that BMS -- as it did with the now withdrawn anti-depressant Serzone -- is trying not to draw any additional attention to Tequin's safety problems.  Like it did when withdrawing Serzone from the market, BMS says that a continuing decline in Tequin sales is its reason for deciding to stop selling Tequin.

(Posted by: Tom Lamb)

Bristol-Myers Squibb To Stop Selling Antibiotic Drug Tequin

BMS Action Follows Reports Of Serious Blood-Sugar Problems And Recent Warning Label Changes

An April 27, 2006 article by Peter Loftus for Dow Jones Newswires broke the news that Bristol-Myers Squibb Co. has decided to stop selling Tequin (gatifloxacin), an antibiotic that has been associated with potentially fatal blood-sugar problems.

As background, in mid-February 2006 Bristol-Myers Squibb (BMS), the FDA, and Health Canada announced that the package insert, or label, for Tequin would be changed to include stronger warnings about the threat of life-threatening events from blood-sugar changes.  The February 2006 label change also recommended that Tequin not be taken by diabetics, who must carefully control blood-sugar levels to avoid complications.

On March 1, 2006 the New England Journal of Medicine (NEJM) published online an early-release version of an editorial and an article alerting doctor about serious blood-sugar problems associated with Tequin. Specifically, the study reported in this March 2006 NEJM article found that patients using Tequin had four times the risk of hypoglycemia (low blood sugar) and a remarkable 17 times the risk of hyperglycemia (high blood sugar) when compared to other antibiotics.  These types of changes in blood sugar can induce coma and other serious medical problems, including death. 

Tequin was used to treat lung, sinus, skin, or urinary-tract infections, as well as certain sexually transmitted diseases. Tequin was approved by the FDA in 1999.

(Posted by: Tom Lamb)

Two Studies Link Antibiotic Tequin To Side Effects That Can Be "Life Threatening"

NEJM Editorial Urges "Black-box" Warning For Tequin, And Suggests That This Antibiotic Should Be Recalled

On March 1, 2006 The New England Journal of Medicine released early an article about two Canadian studies concerning Tequin (gatifloxacin) which indicate that this antibiotic can have "life threatening" side effects including low blood sugar.  At least one of the researchers who conducted the two Tequin studies is urging doctors to stop prescribing this antibiotic, which is made by Bristol-Myers Squibb Co.

The most alarming news in the NEJM March 2006 article about these two Canadian studies is that elderly patients who took Tequin were almost 17 times more likely to develop hyperglycemia (high blood sugar) than if they took another antibiotic.  The researchers also reported that older patients were four times more likely to be hospitalized for hypoglycemia (low blood sugar).  If untreated, both of these blood-sugar disorders can be fatal. 

The significance of this news prompted The New England Journal of Medicine to make the Tequin article available online a month in advance of its scheduled March 30, 2006 publication date.

The NEJM posted online, also, an editorial about Tequin by Dr. Jerry Gurwitz, of the Meyers Primary Care Institute in Worcester, Massachusetts.  Dr. Gurwitz said the FDA should consider mandating that a "black-box" warning be put on the Tequin label, or package insert.  In the NEJM editorial, Dr. Gurwitz said further that when the increased risk of serious side effects from Tequin is compared to those of other drugs that have been pulled from the U.S. market in recent years, it seems that Tequin should be recalled, and that "this choice should not be a difficult one for physicians, patients, regulators and manufacturers."  In support of his call that Tequin be pulled from the market, Dr. Gurwitz pointed out: "For every approved indication for [Tequin], there are safer, equally effective and less costly alternatives."

In mid-February, the FDA and Health Canada issued warnings for Tequin which said Bristol-Myers Squibb had told doctors that Tequin should not be used in diabetics, and that the elderly and those patients with kidney problems are more likely to have serious side effects from Tequin.  The FDA and Health Canada also announced at that time there would be a labeling change for Tequin which would include stronger warnings about the blood-sugar problems linked to Tequin.

It is clear that Dr. David Juurlink, a researcher involved in the two Canadian studies and a physician at Sunnybrook and Women's College Health Sciences Center in Toronto, does not think stronger warnings on the Tequin label are the answer.  Instead, he strongly urged doctors to no longer prescribe Tequin.  In a March 2, 2006 Wall Street Journal article, Dr. Juurlink said: "There are multiple alternatives that are just as good and do not have this set of side effects that is unpredictable and potentially life threatening."

A March 1, 2006 article by Reuters quoted Dr. Juurlink stating that the blood-sugar problem "can happen to anybody" whether they have diabetes or not, and it "typically appears within a day or two of taking the drug."  Therein, Dr. Juurlink remarked also that the actual risk of the drug is probably greater than the study revealed; "We can't identify everybody, only those who survived [a seizure from low blood sugar and made it] to the hospital or those sick enough to go to the hospital."

The Reuters article reported, also, that company spokesman Eric Miller said that Bristol-Myers Squibb has decided to stop actively marketing Tequin.  Mr. Miller's comments surrounding that statement, however, were seemingly intended to make it appear that this decision to no longer "promote" Tequin had to do with economics, and not with the drug's safety profile.  From the Reuters article:

Tequin was introduced onto the market in 1999 but only generated $150 million in sales for Bristol-Myers in 2005, a fraction of the group's $19.2 billion total revenue, said company spokesman Eric Miller. Tequin's sales totaled about $100 million in the United States.

This diversion tactic is not new for Bristol-Myers Squibb.  As you may recall, in April 2004 the drug company voluntarily withdrew its antidepressant Serzone (nefazadone) from the U.S. market purportedly for economic reasons, and all the while denying that the Serzone recall had anything to do with the mounting reports of serious liver problems that had been associated with Serzone use.

(Posted by: Tom Lamb)

FDA and Health Canada Issue Warnings For Antibiotic Tequin

Advising Diabetic Patients Not To Use Tequin Due To Concerns About Blood Sugar Disorders

In mid-February 2006 the FDA and Health Canada issued separate alerts regarding the threat of rare but potentially fatal side effects associated with use of the antibiotic Tequin (gatifloxacin).  According to both agencies, Bristol-Myers Squibb Co. will put stronger warnings on the label, or package insert, about serious cases of hypoglycemia (low blood sugar) and hyperglycemia (high blood sugar) in patients receiving Tequin. 

Tequin is an antibiotic approved for the treatment of pneumonia, bronchitis, and other infections. According to the FDA MedWatch alert, "[s]ince the approval of Tequin in 1999, there have been rare cases of life-threatening events reported globally in patients treated with [Tequin]."   Warnings about the risk of low and high blood sugar were added to the Tequin label by Bristol-Myers in 2002.  The new, stronger warning will provide additional information concerning the types of patients that are more likely to have the blood-sugar problems.

In a February 15, 2006 "Dear Doctor" letter regarding Tequin, Bristol-Myers said the label changes point out the risk factors for developing hypoglycemia (low blood sugar) and hyperglycemia (high blood sugar); these risk factors include:

• advanced age;
• renal insufficiency; and,
• concomitant glucose-altering medications while taking Tequin.

The Health Canada alert regarding Tequin advises diabetic patients, as a precaution, not to use this antibiotic due to concerns about these blood sugar disorders.

(Posted by: Tom Lamb)