Drug Injury Watch

FDA Investigating Obesity Drugs Xenical And Alli For Possible Link With Liver Damage

Agency Has Received Case Reports Of Hepatotoxicity For Orlistat, The Active Ingredient For Xenical And Alli

(Posted by Tom Lamb at DrugInjuryWatch.com)

There was only this brief mention in the Memorandum of Meeting Minutes for the FDA's April 16, 2009 Drug Safety Oversight Board Meeting:

The Drug Safety Oversight Board (DSB) discussed two topics: the product orlistat and the potential risk of hepatotoxicity and alcohol-based skin antiseptics and the risk of a fire in the operating room.

Now, about a month later, we have some additional information about the orlistat - hepatotoxicity part of that DSB April 2009 meeting.   

As background, the anti-obesity agent orlistat is the active ingredient in the prescription drug Xenical (Roche) and the over-the-counter drug Alli (GlaxoSmithKline).

Reporter Sue Sutter, in her May 21, 2009 article "US FDA examining reports of liver damage with orlistat", published online by Scrip News (subscription required; free trial available), takes us forward from there:

"Orlistat was discussed in the context of both non-prescription and prescription versions and the potential risk of hepatotoxicity based on several postmarketing reports," the FDA told Scrip.

The agency said it was still reviewing the case reports to determine the extent of orlistat's contribution, if any, to the development of liver damage. The FDA declined to provide the number of postmarketing reports it has received and said any action would depend upon results of its ongoing analysis....

Roche said more than 35 million patients have been exposed to orlistat therapy, and obesity is a high risk factor for hepatic injury. "The available information – postmarketing spontaneous reports, clinical trial data and published literature as well as epidemiology data for drug-induced liver disease – does not suggest that orlistat is causally related to hepatic events."

The current package insert, or label, for Xenical (accessed 5/22/09) mentions rare reports of hepatic, or liver, injury.

Previously, the anti-obesity agent orlistat had been under scrutiny at the FDA for concerns about rectal bleeding.  See: Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between April - June 2008

If you are aware of any cases of drug-induced hepatitis, liver injury, or liver failure involving the use of Xenical or Alli, please let us know by submitting a Comment, below, or you can send me a private email.

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)

2008 Emory Law Journal Article Presents Ketek As A Case Study In FDA Regulatory Failure

Discusses The Dire Consequences Of Fraudulent Science, Federal Preemption, And Corporate Deregulation

(Posted by Tom Lamb at DrugInjuryWatch.com)

Thomas O. McGarity, of the University of Texas School of Law, is uniquely positioned to give us a history of the beleaguered antibiotic Ketek in his 2008 article, "Corporate Accountability for Scientific Fraud: Ketek and the Perils of Aggressive Agency Preemption", which was published in the Emory Law Journal, Volume 58, Number 2 (58 EMORY L.J. 287, 2008).

From an introductory footnote we get this background information about Professor McGarity and this 2008 law review article about Ketek:

This Article lies at the intersection of three major projects on which the author has labored for the past several years and will continue to pursue during the next two years. The first, an inquiry with my colleague Professor Wendy Wagner into the strategies that advocates in the private sector employ to “bend science” to support predetermined policy agendas, resulted in a recently published book....  The second project describes and analyzes the efforts of common law defendants, joined more recently by some regulatory agencies, to persuade courts to find that state common law claims against the manufacturers of federally licensed products and activities are preempted by federal regulatory action....  The final project, a forthcoming book, Freedom to Harm, examines the thirty-year project of free market advocates in corporate America, conservative think tanks, and academia to free companies of “unnecessary and burdensome” regulatory responsibilities and common law obligations.

I understand not many of you may have the appetite nor the time to consume all that Professor McGarity has to offer in his 58-page law review article.  Anyone wanting to learn about the various "irregularities" in how Ketek was approved by the FDA, however, should at least be aware that this McGarity article is available as a resource.

To give one a sense of what this Ketek law review article by Professor McGarity has to offer, I have excerpted the following from the Introduction section:

• Part I briefly describes the new drug approval process through which a manufacturer of a prescription drug must obtain approval from the Food and Drug Administration (FDA) for new products and for new uses of existing products.

• Part II provides a case study of the dramatic failure of this process to protect consumers by using recently uncovered information concerning the antibiotic Ketek.

• Part III briefly describes the role that state common law can play in providing a backup for ensuring that manufacturers behave responsibly during the drug approval process and are held accountable when they do not.

• Part IV describes the Supreme Court’s decision in Buckman Co. v. Plaintiffs’ Legal Committee, in which the Court held, in a fairly unique factual setting, that the plaintiffs’ common law claims based upon the fraud allegedly perpetrated by a consultant for a medical device manufacturer was preempted by federal law.  [footnote omitted]

• Part V analyzes the arguments for and against preemption of fraud-on-the-agency claims in light of the Ketek experience and concludes that, on balance, preemption is a bad idea because federal enforcement alone provides inadequate incentives to companies that, because they face powerful economic pressures to show large profits to their shareholders, are inclined to cut corners.

• Part VI offers suggestions on how the lower courts should react to Buckman, how the Supreme Court can avoid extending Buckman when it next takes up the issue, and how Congress might go about reversing or limiting Buckman and empowering common law courts to reassume the vital backstop role that they have played in the past.

One may wonder why Professor McGarity chose Ketek as his example for depicting what is currently wrong with the FDA and its drug-approval process.  From the Conclusion section:

Why does Ketek matter? Because FDA broke its own rules and allowed Ketek on the market; because dozens of patients have died or suffered needlessly; because FDA allowed Ketek’s maker to experiment with it on children over reviewers’ protests; because FDA ignored warnings about fraud; and because FDA used data it knew was false to reassure the public about Ketek’s safety.  [footnote omitted]

For those of you who are not familiar with Ketek (telithromycin), it is in a class of drugs called ketolide antibiotics and is to be prescribed only for community-acquired pneumonia. Ketek has been associated with adverse side effects such as liver damage, liver disease, liver failure, and hepatitis.

FDA Reports About Eli Lilly's Drug Strattera Being Associated With Serious Liver Injury Cases

While Strattera Label Has Warning About Liver Injury, Does Current Version Serve To Protect The Millions Of Children Who Take This ADHD Drug?

(Posted by Tom Lamb at DrugInjuryWatch.com)

In the most recent FDA Drug Safety Newsletter (Volume 2, Number 1, 2009) we found a report, "Atomoxetine (Marketed as Strattera): Serious Liver Injury", that is rather disturbing insofar that the majority of patients at risk are children.

As background, drug-induced liver injury (DILI) is now the most frequent cause for acute liver failure in the United States.  Furthermore, DILI is one of the main reasons for the FDA not approving new prescription drugs, or for removing previously approved drugs from the U.S. market.

This report about Strattera (atomoxetine) and six cases of serious liver injury was part of the FDA Drug Safety Newsletter which was released in mid-January 2009.  From that report:

FDA continues to receive reports of serious liver injury in patients given [Strattera]. Atomoxetine received FDA approval on November 26, 2002 as the first non-stimulant medication used for the treatment of attention deficit hyperactivity disorder (ADHD) in children (ages 6 years and above) and adults.  Atomoxetine's therapeutic action is believed to be due to its selective inhibition of norepinephrine reuptake. From the year 2002 to 2007, approximately 3.3 million patients received a prescription for [Strattera] in the United States.  Of those, approximately 2.1 million patients (64%) were children ages 17 years and younger.  [footnotes omitted]

The current Strattera package insert, or label, was last revised by Eli Lilly and the FDA in 2007.  This Strattera label advises doctors about the risk for severe liver injury in its Warnings and Precautions section.  In comparison, there is a so-called "Black-Box Warning" for the risk of suicidal ideation in children and adolescents that has been associated with Strattera.

This January 2009 FDA Drug Safety Newsletter report provides an overview of six Adverse Event Reporting System (AERS) cases of Strattera-associated liver injury that the FDA received between January 2005 and March 19, 2008.  Two of these liver injury cases are examined in more depth.

One wonders whether these six new case reports will lead Eli Lilly and the FDA to add a stronger warning in the the Strattera label about the risk of severe liver injury.

Do you think the present warning about liver injury is sufficient, especially given that the majority of patients using Strattera are children?

The Leading Cause Of Drug-Induced Liver Damage Is Use Of Antibiotics Such As Ketek

Two December 2008 Medical Journal Articles Examine Prescription Drug Hepatotoxicity And Reports Of Liver Damage Associated With Ketek

(Posted by Tom Lamb at DrugInjuryWatch.com)

Antibiotics cause drug-induced liver injury (DILI) more often than other prescription drugs according to a recent medical journal article, "Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States", which appeared in the December 2008 edition of Gastroenterology.

This December 2008 article is based on a study done by Dr. Naga P. Chalasani and his colleagues at the Indiana University School of Medicine, in connection with the Drug Induced Liver Injury Network (DILIN).

We get an overview of this new study from the "Results" section of the full-text version of this Gastroenterology article:

[Drug-induced liver injury (DILI)] was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%.

A December 1, 2008 HealthDay News article, "Antibiotics Largest Cause of Drug-Induced Liver Damage", provided a summary of this Gastroenterology article as well as some additional observations from Dr. Chalasani, the lead author:

"DILI is a serious health problem that impacts patients, physicians, government regulators and the pharmaceutical industry. Further efforts are needed in defining its pathogenesis and developing means for the early detection, accurate diagnosis, prevention and treatment," Chalasani said in an American Gastroenterological Association news release.

Picking up on the early detection aspect of that comment, we move next to a December 2008 article from The Annals of Pharmacotherapy, "Risk of Hepatotoxicity Associated with the Use of Telithromycin: A Signal Detection Using Data Mining Algorithms", which was published initially online November 25, 2008, ahead of the print edition of this medical journal.

This second medical journal article focuses on the antibiotic Ketek (telithromycin),with the objective being to determine when there were a sufficient number of reports concerning liver damage associated with Ketek such that a so-called "safety signal" should have first been detected, i.e., early detection.

The Abstract of this article from The Annals of Pharmacotherapy describes how the researchers looked to detect this Ketek safety signal regarding liver damage, or hepatotoxicity, by using four "commonly employed" data mining algorithms (DMAs):

METHODS: Based on the Adverse Events Reporting System (AERS) database of the Food and Drug Administration, 4 DMAs, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the Gamma Poisson Shrinker (GPS), were applied to examine the association between the reporting of hepatotoxicity and the use of telithromycin. The study period was from the first quarter of 2004 to the second quarter of 2006....

RESULTS: A total of 226 reports describing hepatotoxicity associated with the use of telithromycin were recorded in the AERS. A safety problem of telithromycin associated with increased reporting of hepatotoxicity was clearly detected by 4 algorithms as early as 2005, signaling the problem in the first quarter by the ROR and the IC, in the second quarter by the PRR, and in the fourth quarter by the GPS.

In fact, however, the association between Ketek use and hepatotoxicity first received general attention in January 2006 when the Annals of Internal Medicine published online an "early" release version of an article describing the cases of three patients at Carolinas Medical Center, in Charlotte, North Carolina, who developed differing degrees of liver problems after taking Ketek.  It was in connection with this Annals of Internal Medicine article that the FDA issued a MedWatch Alert concerning Ketek and possible liver problems in January 2006.

Almost a year later, in February 2007, the FDA issued a news bulletin entitled "FDA Announces Label and Indication Changes for the Antibiotic Ketek" which announced from that point forward Ketek wasto be prescribed only for community-acquired pneumonia, and that Ketek should no longer be prescribed for two lesser medical conditions, acute bacterial exacerbation of chronic bronchitis and acute bacterial sinusitis.

Possible Avandia Recall: Liver Failure Cases May Tip Balance Of Risk vs. Benefit

October 2008 Public Citizen Petition Wants Glaxo's Diabetes Drug Banned Due To "New" Side Effect, Liver Toxicity

(Posted by Tom Lamb at DrugInjuryWatch.com)

On October 30, 2008 Public Citizen's Health Research Group (HRG) submitted a petition to the FDA requesting that GlaxoSmithKline's diabetes drug Avandia (rosiglitazone) be banned due to the drug's several serious side effects, including some newly found cases of liver failure.

According to this "Petition to Immediately Ban Diabetes Drug Rosiglitazone (AVANDIA) (HRG Publication #1848)":

Our petition is based on [Avandia]’s multiple, serious risks, including one just documented by our new analysis of 14 cases of liver failure, of which 12 resulted in death.

Besides the Avandia-induced liver failure, this Petition by Public Citizen's HRG pointed out several other serious side effects associated with Avandia, including:

Myocardial Ischemia: Three recent meta-analyses have demonstrated an increased risk of myocardial ischemia or myocardial infarction with [Avandia]. The approximate increase in the risk of heart attacks is 40%.

Congestive Heart Failure:... Several meta-analyses estimate the increased risk
to be approximately two-fold.

In this October 2008 document Public Citizen compared Avanida to Rezulin (troglitazone) when it comes to the risk for drug-induced liver failure, as is seen from the following excerpt from the Petition:

[Rezulin], a thiozolidinedione similar in structure to [Avandia], was approved for marketing by the FDA in March 1997, but was withdrawn from the market in March 2000 after 94 cases of [Rezulin]-induced liver failure, the majority of which were fatal, were reported.  Although the premarketing signal for hepatotoxicity with [Avandia] was not as strong as the signal with [Rezulin], one of the most hepatotoxic drugs ever approved by the FDA, several cases of [Avandia]-induced hepatotoxicity have been reported in the literature, and many more via the FDA Adverse Event Reporting System (AERS). [footnotes omitted]

Overall, according to Public Citizen -- taking into account the newly found cases of liver failure together with "the accompanying lack of evidence of any clinical benefit" when Avandia is compared to other diabetes drugs -- the time has come for the FDA to order an immediate Avandia recall.

In October 30, 2008 article, "Glaxo's Avandia Should Be Banned, Public Citizen Says (Update2)", Bloomberg reporter Justin Blum let us know the drug company's initial reaction:

Glaxo hasn't read the petition and "we do not believe there is a connection between liver toxicity and this medicine," according to an e-mail from company spokeswoman Mary Anne Rhyne. She said Avandia is safe "for appropriate type 2 diabetes patients, when used according to the label."

Previously, in the article "Mixed Reactions To Avandia's Revised Warning In November 2007 About Risk Of Heart Attacks"", we reported that in November 2007 the FDA issued a news release entitled "FDA Adds Boxed Warning for Heart-related Risks to Anti-Diabetes Drug Avandia", which carried the sub-heading "Agency says drug to remain on market, while safety assessment continues". 

One wonders, now, whether this apparent new link to liver toxicity will compel the FDA to ban Avandia as requested by Public Citizen.

P.S.  Late in the day on October 30 GlaxoSmithKline issued its formal response to the HRG Avandia Petition submitted to the FDA by means of this press release, "GSK Believes There Is No Liver Safety Issue With AVANDIA; Responds to Public Citizen Petition". 

The main point raised therein:

The safety of patients using our medicine is very important to us. On a continual basis, an external Hepatic Safety Board reviews any adverse event report received by GSK of liver failure, liver-related deaths and liver transplants for possible relationship to AVANDIA. As recently as July 2008, this panel of experts continued to endorse a favorable hepatic safety profile for AVANDIA.

There has been no word from the FDA about how long the agency will need to make a determination on the Avandia recall requested by Public Citizen.  (10/31/08)

New Reports Of Vytorin And Zetia Causing Liver Failure And Liver Disease

2008 Medical Journal Articles Describe Two Cases; Authors Suggest Liver Testing At Start Of Therapy And When Titrating Dosage Is Necessary

(Posted by Tom Lamb at DrugInjuryWatch.com)

In December 2007 we told you about an article by New York Times (NYT) reporter Alex Berenson, "Data About Zetia Risks Was Not Fully Revealed", which revealed that Merck and Schering-Plough had conducted several studies of Zetia that raised the possibility that Zetia can cause liver damage when used long-term with statin drugs.  The drug companies, however, decided not to publish the results of those Zetia studies, according to this NYT article.

Now, in late summer 2008, two medical journal articles have been published which associate Zetia (ezetimibe) with liver failure and liver disease.

From the September 1, 2008 edition of Pharmacotherapy we get an article, "Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation", that discusses a case of liver failure involving Vytorin -- which is a combination of Zetia with the statin drug Zocor.  The article points out that reports liver damage reports involving Zetia or Vytorin have not been widely published to date.  It continues with one particular case report involving liver failure in a patient using Vytorin.  From the abstract from this August 2008 Pharmacotherapy article:

We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin [or Zocor] 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day [i.e., Vytorin]. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. [The Vytorin] and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course....  To our knowledge, this is the first case report of [Vytorin]-induced liver failure that resulted in liver transplantation.

Thereafter, the article authors -- from the Division of Clinical and Administrative Pharmacy, at University of Iowa's College of Pharmacy -- posit a theory on how Vytorin and Zetia can cause liver failure:

[Zetia] undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity....  We postulate that the mechanism of the [Vytorin]-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes.

These authors conclude with the suggestion that liver function tests should be carefully monitored when starting Vytorin therapy and when titrating the Vytorin dosage.

The second article, "Serious drug-induced liver disease secondary to ezetimibe", published in World Journal of Gastroenterology, August 28, 2008 edition, focuses on just Zetia.  It reports the case of a woman who developed a "serious hepatocellular drug-induced liver disease" after taking Zetia 10 mg daily for a four month period, then recovered after she was taken off the Zetia.  Based on this case, the authors concluded:

[Zetia] may produce serious toxic hepatitis and prompt withdrawal is mandatory in case of a significant abnormality in liver testing after beginning or during treatment with [Zetia].

We will continue to watch for reports of liver injury associated with Vytorin and Zetia.  If you are aware of such a case, please share your information with us.

EU Drug Watchdog Wants Avelox Use Limited Mainly Due To Liver Toxicity Concerns

Risk Of Adverse Hepatic Reactions, Including Fatal Liver Injury, Is Cited by European Regulators At July 2008 Meeting

(Posted by Tom Lamb at DrugInjuryWatch.com)

The Committee for Medicinal Products for Human Use (CHMP), a division of the European Medicines Agency (EMEA), concluded at its July 2008 meeting that the benefits of oral moxifloxacin medicines continued to outweigh the risks, but went on to state that these antibiotics should be prescribed on a limited basis, only, going forward.

Moxifloxacin, a fluoroquinolone antibiotic, is marketed by Bayer under the brand name Avalox in Europe and Avelox in the U.S.  According to a July 24, 2008 Reuters article, "EU agency recommends restricting moxifloxacin use": 

Avelox had sales of 445 million euros ($697.3 million) worldwide last year. ($1=.6382 Euro)....

The CHMP opinion will now be forwarded to the European Commission to apply to all oral moxifloxacin-containing medicines authorized in the European Union.

What the limited prescribing of Avelox, as recommended by the CHMP, would do to sales revenues for this Bayer antibiotic remains to be seen.

Details of the CHMP recommendation to restrict Avelox use make clear that the primary reason for their action is the increased risk of liver toxicity associated with Avalox / Avelox.  From the EMEA's July 24, 2008 press release, "European Medicines Agency recommends restricting the use of oral moxifloxacin-containing medicines":

At its July 2008 meeting, the CHMP concluded that the benefits of oral moxifloxacin medicines continue to outweigh its risks. However, due to safety concerns, mainly related to an increased risk of adverse hepatic reactions, the CHMP recommended restricting their use in these indications. For acute bacterial sinusitis and acute exacerbations of chronic bronchitis, they should only be prescribed when other antibiotics cannot be used or have failed. For community acquired pneumonia, they should only be given when treatment with other antibiotics cannot be used.

The CHMP also recommended that the warnings of oral moxifloxacin-containing medicines should be strengthened concerning the risk of diarrhoea, heart failure in women and older patients, severe skin reactions and fatal liver injury.

The July 24 Reuters article includes an apparent "so-what" response from Bayer about this EMEA-CHMP action regarding Avelox:

Responding to the recommendation, Bayer said the review confirmed the positive benefit-risk profile of the drug.

"We would welcome an EMEA assessment of other antibiotics used for treatment of these infections in a similar fashion in the interest of patient care," said Kemal Malik, a member of Bayer HealthCare executive committee and chief medical officer.

Together with its July 24 press release, the EMEA made available an explanatory document, "Questions and answers on the recommendation to restrict the use of oral formulations of moxifloxacin-containing medicines".

In an article posted here earlier this month, "Will There Be An Avelox - Liver Toxicity Warning Letter From Bayer Coming Soon In The U.S., Or Not?", I referred back to the February 2008 "Dear Doctor" letter about Avelox / Avalox that Bayer sent out in Europe, only, and then inquired about any corresponding letter to health care providers in the U.S.

We will continue to wait and see what, if anything, Bayer or the FDA tells American doctors about Avelox and its association with liver toxicity.

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.