Drug Injury Watch

Generic Drug Manufacturer ETHEX Corp. Is Being Shut Down By KV Pharmaceuticals

Troubled Company Pleads Guilty To Criminal Charges, Pays $27.6 Million In Fines And Restitution For Its Conduct Related To Quality-Control Issues

(Posted by Tom Lamb at DrugInjuryWatch.com)

We last wrote about the troubled generic drug manufacturer ETHEX Corp. a little more than a year ago, when we posted this article: "January 2009: ETHEX Corp. Issues Voluntary Recall Of All Pills Due To Suspected Manufacturing Problems".

Now, in February 2010, we know how the story ends for ETHEX -- for the most part, at least.

From a February 25, 2010 article, "KV Pharmaceutical to plead guilty, pay $27.6M, close generics business", published by the St. Louis Business Journal:

KV Pharmaceutical Co. must pay $27.6 million in fines and restitution, and plans to cease its generic drugs business after pleading guilty to criminal charges for not disclosing problems with two of its drugs.....

Bridgeton, Mo.-based KV said Thursday its subsidiary, Ethex Corp., plans to plead guilty to two felony counts of failure in 2008 to file field alerts for the generic drugs Dextroamphetamine, a stimulant used to treat ADHD, and Propafenone, which treats rapid heart beats. The company then plans to cease operations of Ethex. The U.S. Food and Drug Administration requires that companies file field alerts to quickly identify drugs that pose potential safety threats from problems such as contamination or mislabeling.

KV’s interim Chief Executive David Van Vliet declined to disclose the specifics of what the problems with the drugs exactly were.

Van Vliet said the company will now focus on regaining FDA compliance so it can return to making both branded and generic drugs under Ethex's parent company, KV, which retains all related intellectual property, including drug applications and the ability to conduct marketing and distribution of all of its previously approved products.  [Emphasis added]

It remains to be seen whether the U.S. Attorney for the Eastern District of Missouri, the U.S. Department of Justice (DOJ), or the U.S. Food and Drug Administration (FDA) will release details about the extent of the quality control problems at ETHEX and whether those problems resulted in any known-cases of harm to patients using any of the sub-standard generic drugs made by ETHEX.

If you are aware of a drug injury case involving an ETHEX generic drug, we would be interested in hearing about it.  You can do so by posting a Comment below or sending me a private email.

For more articles about quality-control issues at various generic drug companies, view our collection of stories at the Generic Drug Safety part of our blog Archives.

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When Considering A Possible Avandia Recall, Liver Injury Side Effects Should Be A Factor

Heart Risk Is Current Focus Due To GlaxoSmithKline Past Conduct; But Public Citizen Has Pointed The Liver Failure Case Reports Linked To Avandia, Also

(Posted by Tom Lamb at DrugInjuryWatch.com)

As some of you may recall, in October 2008 Public Citizen petitioned the FDA to ban the sale of the diabetes drug Avandia (rosiglitazone) in the U.S. because its risks, which include heart attack and heart failure in addition to liver toxicity, far outweigh its benefits and because much safer alternatives exist for treating Type 2 diabetes.

To our knowledge, there is still no word from the FDA about how long the agency will need to make a determination on the Avandia recall requested by Public Citizen.

More recently, in late July 2009, a new medical journal article about Avandia and liver failure was published in Pharmacoepidemiology and Drug Safety.  This article, "Case series of liver failure associated with rosiglitazone and pioglitazone." -- by James S. Floyd, MD, Elizabeth Barbehenn, PhD, Peter Lurie, MD, MPH, and Sidney M. Wolfe, MD, of Public Citizen's Health Research Group -- seemingly adds further support to the contention that Avandia can cause liver failure and should be recalled by the FDA.

Soon thereafter a July 22, 2009 press release, "Rigorous Study Adds to Case That FDA Should Ban the Diabetes Drug", was issued by Public Citizen in connection with this new Avandia medical journal article.

Those few items, above, suggest that the serious liver injury risk associated with Avandia could (and should) be a factor in the FDA's determination about whether to order an Avandia recall, or not.

As far as when any Avandia recall determination will be made by the FDA, currently it seems this issue will have to wait until a joint public meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees in July 2010. At that FDA meeting, the Advisory Committee will provide an updated assessment of the risks and benefits of Avandia.

Returning to the present, during this past week almost all (if not all) of the Avandia safety debate has had to do with the cardiac risks linked to Avandia, namely heart attacks and heart failure.

First, there was a February 19, 2010 New York Times (NYT) article, "Research Ties Diabetes Drug to Heart Woes", by Gardiner Harris, which was based on "internal FDA reports" and a January 2010 Senate Committee on Finance staff report about Avandia which concludes: "The totality of evidence suggests that [GlaxoSmithKline] was aware of the possible cardiac risks associated with Avandia years before such evidence became public."

Immediately afterward, in two separate press releases, GlaxoSmithKline (GSK) disputed the reports set forth in the February 19 NYT article and took issue with the conclusions of the Senate Committee's Avandia report.  Essentially, the party line for GSK is that "the scientific evidence simply does not establish that Avandia increases ischemic cardiovascular risk or causes myocardial ischemic events."

And then there is renowned cardiologist Steven Nissen, of the Cleveland Clinic, who has been vocal critic of Avandia due to safety reasons.  To learn more about Dr. Nissen's position on Avandia, we refer you to these two items:

1)  A February 23, 2010 New York Times (NYT) story, "A Face-Off on the Safety of a Drug for Diabetes", by Gardiner Harris, again; and,

2)  This recent medical journal article from European Heart Journal, "The rise and fall of rosiglitazone", by Steven E. Nissen -- Advance Access published February 12, 2010 (includes a 1999-2009 timeline).

Our law firm is continuing to investigate Avandia injury and death cases involving liver failure as well as heart attack or heart failure.

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Some Fosamax Users Have Had Their Femur Fracture Without Any Fall Or Other Trauma

Reports About Sudden Breaking Of Thigh Bone In Patients Using Fosamax For Five Years Or More

(Posted by Tom Lamb at DrugInjuryWatch.com)

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UPDATE:   Fosamax Femur Fracture Warning Label Change By Merck Seems Likely After Task Force Report -- FDA Considering Issue Due To September 2010 American Society of Bone And Mineral Research Report About Bisphosphonate Side Effects    

(9/21/10)

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The side effects of Fosamax include osteonecrosis of the jaw (ONJ), esophageal irritation, and musculoskeletal pain. In addition, cases of femur fractures associated with prolonged Fosamax (alendronate) use have been reported.

In the December 18, 2009 edition of the medical journal Clinical Orthopaedics and Related Research (CORR), there is an article about the Fosamax-related femur fractures, "Case Reports: Subtrochanteric Femoral Stress Fractures after Prolonged Alendronate Therapy". 

From this December 2009 CORR article about Fosamax:

CASE DESCRIPTION: We report the cases of four women who sustained low-energy subtrochanteric or femoral shaft stress fractures while being on alendronate therapy for more than 5 years. All radiographs showed typical patterns consisting of a transverse fracture line with external cortical bone reaction and medial cortical spike. Alendronate discontinuation along with nonoperative treatment was sufficient for one patient, whereas surgical stabilization was required in three patients.

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Free Fosamax Case Evaluation 

Strictly Confidential, No Obligation.

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A February 18, 2010 TV news report, "Sudden bone breaks reported in patients taking Fosamax", provides us with some insight about these femur fractures which might be caused by Fosamax.  For this report, WCBD elicited the following comments and observations from rheumatologist Dr. Robert Bunnin, of the National Rehabilitation Hospital in Washington, DC:

"The drugs are supposed to work by shutting down the cells that re-absorb the bone, the osteoclasts. The ones that make the bone, the osteoblasts, are supposed to keep working. However in biopsies of patients who have had the fracture, it shows that both are shut down."

Bunning calls it "frozen bone," which is brittle and more susceptible to these types of clean fractures. He says in the U.S. There have been 50 to 60 reported cases of this.

"Even thought [sic] it’s rare, I think we’re going to be seeing quite a few more cases."

Dr. Bunning says that in all of the reported cases, most patients had been taking Fosamax or another type of bisphosphonate for more than 5 years.

"The drugs clearly were designed to make the bones stronger and I think they do for the first few years. They make them denser."...

Dr. Bunning says typically, patients with that condition will suffer breaks in the hip area—and that usually occurs after a fall.

With all of these patients, the breaks are occurring in the thigh and without any sort of trauma.

Dr. Bunning says that in many of these patients they had experienced vague thigh pain before their femur broke.

So Dr. Bunning says if you or someone you know is taking one of these drugs, make sure to see your doctor right away if something doesn’t feel right.

Our law firm is currently handling Fosamax injury cases involving osteonecrosis of the jaw (ONJ), or jaw bone death, as well as low-stress leg fractures of the femur, or thigh.

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Drug Injury Case Evaluation - Free & Confidential

How Electronic Medical Records Review Might Help FDA Identify Unsafe Drugs Sooner

Study Says Using Such Data Would Have Resulted In Faster Safety Signal Detection For Increased Risk Of Heart Attacks With Avandia Use

(Posted by Tom Lamb at DrugInjuryWatch.com)

A recent medical journal article suggests that a systematic review of electronic medical records may have allowed the FDA and others to identify the increased risk for heart attack, or myocardial infarction (MI), with Avandia use as early as 18 months after Avandia came on the market in the U.S.

The December 15, 2009 edition of Diabetes Care included the article "Rapid identification of myocardial infarction risk associated with diabetic medications using electronic medical records".  From the Abstract for that article:

Objective: To assess the ability to identify potential association(s) of diabetic medications with myocardial infarction (MI) using usual care clinical data obtained from the electronic medical record.

Results: ... After adjustment for potential MI risk factors, relative risk for MI with rosiglitazone was 1.3 (95% CI, 1.1-1.6) compared to sulfonylurea, 2.2 (95% CI, 1.6-3.1) compared to metformin, and 2.2 (95% CI 1.5-3.4) compared to pioglitazone. Prospective surveillance using these data would have identified increased risk for MI with rosiglitazone compared to metformin within 18 months of its introduction with a risk ratio of 2.1 (95% CI 1.2-3.8).

Conclusions: ... Our use of usual care electronic data sources from a large hospital network represents an innovative approach to rapid safety signal detection that may enable more effective post-marketing drug surveillance.

We have reported over time about the FDA's Sentinel Initiative project for monitoring medical product safety, the goal of which is to develop an active electronic safety monitoring system to strengthen FDA's ability to track the postmarket performance of medical products.

This recent study about identifying the heart attack risk associated with Avandia by use of electronic medical records seemingly indicates that the Sentinel Initiative will be a good means by which to augment existing drug safety monitoring systems.

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Factors In Assessing Association Between Valvular Heart Disease And Use Of Dostinex Or Permax

Two Medical Journal Articles Review The Published Research And Suggest Ways To Avoid Cardiac Valve Side Effects

(Posted by Tom Lamb at DrugInjuryWatch.com)

In March 2007 the FDA announced that Permax (pergolide) would be voluntarily removed from the U. S. market because it had been linked to serious heart valve damage.

In August 2007 Health Canada followed suit and announced the sales of Permax must cease in their country, also.

Pfizer's Dostinex (cabergoline), however, 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 September 2008 a so-called "Dear Doctor" letter about Dostinex was sent by Pfizer Ltd., but apparently only to doctors in the U.K.

More recently, there have been two medical journal articles which reviewed and summarized the published research regarding the cardiac valve side effects that have been associated with Permax and Dostinex.

The first article, "Dopamine agonists and valvular heart disease", published in June 2009, we get this information:

RECENT FINDINGS: Off-target action of dopamine agonists at 5-hydroxytryptamine 2B receptors is now recognized to cause cardiac valve disease in several studies in Parkinson's disease patients who received high daily dopamine agonist doses, including [Dostinex (cabergoline)] and [Permax (pergolide)]. Generally, dopamine agonist doses in prolactinoma therapy are 10-fold lower than those employed in Parkinson's disease, although occasionally dopamine agonist-resistant patients require higher doses. Most studies of dopamine agonist use in prolactinoma have not observed valvular abnormalities.

SUMMARY: Dopamine agonists are effective in treating prolactinomas. At typical doses, the risk for valvulopathy appears low. Increased risk of cardiac valvulopathy should be considered in patients requiring higher doses or long duration of therapy. Echocardiography should be performed in these high-risk patients, drug holidays implemented and patients withdrawn from these agents if possible.

The second article, "Potential Cardiac Valve Effects of Dopamine Agonists in Hyperprolactinemia", first published online in February 2010, reinforces the findings and guidance of the earlier article:

Evidence Synthesis: The majority of studies showed no risk of valvular regurgitation associated with [Dostinex (cabergoline)]. However, an increased risk of mild to moderate regurgitation, usually at the tricuspid valve, was reported in a few studies. Only one study suggested a relationship with the mean cumulative dose of [Dostinex (cabergoline)].

Conclusions: Although most reports do not show an association between use of dopamine agonists and valvulopathy, caution must be exercised, especially in patients requiring long-term, high-dose medication regimens. Clinicians should recommend the lowest possible doses of dopamine agonists and address the question of echocardiographic monitoring on an individual basis.

We continue to investigate possible drug injury cases involving Permax and Dostinex.

P.S.  Excerpt from the Abstract for Cabergoline therapy for prolactinomas: is valvular heart disease a real safety concern?  (Expert Rev Cardiovasc Ther, January 1, 2010):

The clinical significance of the present findings has yet to be confirmed by future larger prospective studies with rigorous echocardiographic protocols and prolonged duration of follow-up.

(2/15/10)

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Case Report: Man Using Diabetes Medication Januvia Develops Elevated Hepatic Enzymes

Authors Suggest That Certain Patients Starting Januvia Should Have Their Liver Function Monitored

(Posted by Tom Lamb at DrugInjuryWatch.com)

In the recent past we considered whether Januvia (sitagliptin) can cause pancreatitis in patients using this relatively new diabetes medication.

Now, a new medical journal "To The Editor" letter suggests that Januvia may have a negative effect on the liver for certain patients, specifically "individuals with a history of nonalcoholic steatohepatitis or elevated hepatic enzymes".

From this letter titled "Elevated Hepatic Enzymes Potentially Associated with Sitagliptin"-- published online January 26, 2010 by The Annals of Pharmacotherapy -- we get the following case report concerning a patient who developed elevated hepatic enzyme levels after starting Januvia:

A 58-year-old male with a history of type 2 diabetes and nonalcoholic steatohepatitis (diagnosed in 2006) presented to the clinic for diabetes management. At the time, the patient's aspartate aminotransferase (AST) was 53 U/L (normal <40 U/L) and alanine aminotransferase (ALT) was 102 U/L (normal <40 U/L). The patient was started on rosuvastatin 10 mg once daily....  One month following therapy, AST and ALT had declined to 35 U/L and 64 U/L, respectively.

Two months after the initiation of rosuvastatin, the patient was started on sitagliptin 100 mg once daily due to elevated hemoglobin A1C of 8.2%. The patient's other medications included amlodipine 5 mg once daily, benazepril 20 mg once daily, aspirin 81 mg once daily, glucosamine 500 mg once daily, chondroitin 400 mg once daily, and indomethacin 25 mg once daily as needed. One month after initiation of sitagliptin, liver enzymes were monitored and revealed an AST and ALT of 71 U/L and 127 U/L, respectively. Four days later the AST and ALT levels were 70 U/L and 137 U/L, respectively. All other corresponding hepatic function results were within normal range for the patient. A full medication review was performed. Sitagliptin was discussed as a possible cause of increased liver enzyme levels and promptly discontinued. Reexamination of liver enzymes a month after discontinuing sitagliptin revealed a significant decrease in AST and ALT (48 U/L and 90 U/L, respectively). Most recently, 6 months after discontinuation, AST and ALT were 35 U/L and 62 U/L, respectively.

The authors of this letter about Januvia acknowledge that prior studies have not found any liver-related side effects associated with Januvia, and they list several articles concerning those earlier safety studies.  They go on, however, to make this important point:

Although no significant elevation of hepatic enzymes has been reported in the literature, most of the trials involving the safety of sitagliptin were small and short in duration.

As such, in conclusion, they offer that certain patients starting Januvia should perhaps be monitored for possible liver side effects.

We will continue to monitor the safety profile of Januvia, and we welcome any information or insight you may have about this drug safety issue.

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There Is Disagreement Over The Three-Year Failure Rate For Sprint Fidelis Lead Wires

Medtronic Says 4.6 Percent Of Leads Failed, While Reports From Some Hospitals Indicate 9.2 Percent Of Sprint Fidelis Wires Failed

(Posted by Tom Lamb at DrugInjuryWatch.com)

In our December 30, 2009 article, "Sprint Fidelis Lead Wire Failure Rate Could Rise To 30 Percent By Four Years", we provided the little bit of information we could find, then, about the future failure rates for the Medtronic Sprint Fidelis lead wires that were removed from the market back in 2007:

A report by UBS Investment Research Monday said lead failures could accelerate over time, citing independent studies that predict failure rates could hit 30 percent by four years. Medtronic’s own data suggests a 3 percent failure rate at three years.

Now we have some additional data regarding the three-year failure rate, or survival rate, of these Sprint Fidelis leads thanks to a February 4, 2010 article, "Hospitals Dispute Medtronic Data on Wires", by Wall Street Journal (WSJ) reporter Thomas M. Burton.

From this February 2010 WSJ article we get the following numbers:

Medtronic says its own research shows the Sprint Fidelis leads survive for three years at least 95.4% of the time, for a failure rate of 4.6%. Reports from hospitals including the University of Rochester in New York state, the Minneapolis Heart Institute, the Mayo Clinic and the University of Ottawa, say the overall failure rate for Sprint Fidelis leads is as much as two times as great as the company's own data indicate. Some of the hospitals also report that the rate of fracture accelerates as the leads age.

"The hazard of [Sprint] Fidelis lead fracture is increasing exponentially with time and, based on our data, occurring at a higher rate than the latest manufacturer's performance update," doctors at the University of Rochester concluded in findings published in January's American Journal of Cardiology. The report said the three-year survival rate of 426 Medtronic leads inserted in the hospital's patients was 90.8%, meaning 9.2% failed.

Mr. Burton also looked back at a number of other studies that have been performed since the 2007 Sprint Fidelis recall, and he reports:

Last February, a joint report from the Minneapolis Heart Institute and the Mayo Clinic, published in the journal HeartRhythm, said the estimated rate of failure among 848 leads at three years of use was 12.1%. An October 2008 study by the University of Ottawa Heart Institute, also published in HeartRhythm, found that the fracture rate of Sprint Fidelis leads "increased significantly with time."

In November, a separate Mayo Clinic study showed the failure rate for Sprint Fidelis leads after two years was higher in patients younger than 50, at 20.4%, than in older patients, with a rate of 3.5%. There were 89 patients under 50 who received the leads, and 362 patients who were 50 or above.

Our law firm continues to review possible Sprint Fidelis lawsuits involving incidents of harmful unnecessary shocks in anticipation that the Medical Device Safety Act (MDSA; HR 1346 / S 540) will become law in 2010 and, thereafter, lawsuits can be filed against Medtronic on behalf of those injured patients.

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February 2010: Fosamax Federal Court MDL Litigation Update; Next Trial Starts In Mid-April

Merck Lost Its Attempt To Have Louise Maley's Fosamax Lawsuit Dismissed Before Her April 19, 2010 Trial Date

(Posted by Tom Lamb at DrugInjuryWatch.com)

We have been reporting about the three bellwether trial cases for the federal court Fosamax MDL and, in this article, we continue to do so.

To start, Louise H. Maley v. Merck & Co. Inc. is the next Fosamax case set for trial in the federal court MDL, and this trial will start as scheduled on April 19, 2010.

Recent efforts by Defendant Merck to avoid this Maley Fosamax trial were summarized in a January 28, 2010 news article, "Merck Loses Dismissal Bid in Third Fosamax Case", by Bloomberg reporter Thom Weidlich:

Merck & Co. lost its bid to dismiss the third case scheduled for trial over claims its osteoporosis drug Fosamax caused so-called jaw death.

The claim of the plaintiff, Louise Maley, “does not fail as a matter of law from a lack of evidence of exposed necrotic bone,” U.S. District Judge John Keenan in Manhattan wrote in a ruling entered into the case docket today. “Specific causation remains a material issue of fact for the jury.”

A trial is scheduled for April 19. Maley, of Muncie, Indiana, said she developed osteonecrosis of the jaw, or ONJ, by taking Fosamax, according to her complaint filed in May 2006....

Keenan declined to grant Merck’s request for a so-called summary judgment on Maley’s claim that the drugmaker failed to warn about Fosamax’s dangers. [Maley] didn’t contest Merck’s dismissal request on her strict-liability and warranty claims, and the judge tossed those.

This January 28 Bloomberg article also provides an overview of the Fosamax litigation in terms of the number of Fosamax lawsuits filed and the money Merck has reserved for the defense of those Fosamax cases:

Merck, based in Whitehouse Station, New Jersey, as of Sept. 30 faced about 953 Fosamax cases, including suits with multiple patients, the company said in a Nov. 2 regulatory filing. About 700 lawsuits have been consolidated before Keenan for evidence gathering....

As of Sept. 30, Merck set aside $48 million for defending the litigation, according to the regulatory filing. It hasn’t earmarked any money for damages.

In closing, the next scheduled Fosamax trial is Maley v. Merck & Co., 06-cv-4110, which is one of the hundreds of pending Fosamax lawsuits in In Re Fosamax Products Liability Litigation, MDL 1789, U.S. District Court, Southern District of New York (Manhattan).

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