Drug Injury Watch

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?

Actavis And FDA Criticized Over Their Digitek Recall Conduct In New 2009 Report

ISMP QuarterWatch: Cannot "rule out, or state definitively, whether defective digoxin tablets led to hundreds of patient deaths"

(Posted by Tom Lamb at DrugInjuryWatch.com)

On January 15, 2009 The Institute for Safe Medication Practices (ISMP) released QuarterWatch: 2008 Quarter 2, which includes an analysis of how the Digitek recall has been handled by Actavis, the drug maker, and FDA, the regulatory agency, which demonstrates how ineffectual the FDA has become when it comes it critical issues of drug safety in the U.S.

As background, the IMSP QuarterWatch Project Team consists of the following individuals:

• Thomas J. Moore, Senior Scientist, Drug Safety and Policy, ISMP;
• Michael R. Cohen RPh, MS, ScD, President, ISMP; and,
• Curt D. Furberg, MD, PhD, Professor of Public Health Sciences, Wake Forest University School of Medicine.

The Digitek recall was classified as Class I recall by the FDA, meaning there is “a reasonable probability... a violative product will cause serious adverse health consequences or death." (21 CFR 7.3 Recall Classification). 

This new ISMP QuarterWatch report, however, reveals that the FDA has seemingly taken a back seat and let Actavis determine how the Digitek recall would be done.  To start:

Although this is one of the largest Class I drug recalls we know of—affecting more than 1 million vulnerable heart patients—the FDA allowed the company to manage public notification of consumers, doctors, pharmacies and wholesalers. The public notice from the Center for Drug Evaluation and Research was a reproduction of a brief company statement.

For its Digitek recall analysis, the ISMP QuarterWatch Project Team attempted to get some new information from Actavis and the FDA about what has been learned thus far about the extent of defective Digitek (digoxin) pills that were dispensed to patients in terms of time frame and number of pills.  As can be seen by the following statements, however, both Actavis and the FDA are continuing to be vague, at best, when it comes to divulging that type of information:

• In April 2008 the Actavis Group announced the voluntary Class I, consumer level recall of 800 million digoxin tablets, the entire unexpired production of its Little Falls, NJ plant over a 26-month period, and about 60% of the entire U.S. supply of an important generic heart drug.

• The company stated that it had no evidence that any defective tablets had in fact entered commercial distribution, and that it had recalled nearly 1 billion tablets and closed its plants “out of an abundance of caution.”

• Neither the company nor the FDA will estimate how many tablets actually reached consumers; nor will either party reveal how many tablets have been recovered through the Class I recall. Neither the FDA nor the company has tested the recalled tablets to determine how many might have been defective.

In this new QuarterWatch report, at least, there is no indication by Actavis about the fate of the Digitek pills that have been collected as regards whether those pills are still available for testing in the future.  Another issue that was not addressed is whether the pills that were "returned" by patients through Stericycle are being preserved and kept separate such that any future testing would reveal which patients, if any, had been dispensed Digitek pills that had the "double-thickness" defect and up to twice the active ingredient, thereby putting them at risk for digoxin toxicity (also called digitalis poisoning).

The ISMP analysis contained in this January 2009 QuarterWatch report gives rise to well-deserved criticism of the FDA as regards the Digitek recall -- which, essentially, goes far beyond the Digitek recall:

Because of limitations in the U.S. system for post-market surveillance, the characteristics of the drug, and the nature of the system for recalling defective drugs, it is not possible to estimate how many patients might have died or become seriously injured by defective [Digitek] tablets....

Without extensive testing of distributed and recalled tablets, it is difficult to separate cases caused by defective tablets from other causes, including declining kidney function, decreasing cardiac output and failure to monitor blood levels of the medication.

Largely because of how this Digitek recall has been conducted, i.e., letting the drug company call the shots as opposed to the FDA acting in the interest of patients who took Digitek, the ISMP QuarterWatch report reached this conclusion:

The existing evidence does not permit us to either rule out, or state definitively, whether defective [Digitek] pills led to hundreds of patients deaths.

Of course, while the FDA might feel that is an acceptable endpoint, the attorneys who represent people who developed digoxin toxicity while using Digitek as well as the families of people who died due to an overdose of digitalis in product liability lawsuits will not be as easy on Actavis.

And as for the FDA, let us hope that the Obama Administration will act so as to restore the FDA to its proper role, which is protecting patients and not protecting drug makers.

In closing, a hat tip to Ed Silverman, formerly of the Pharmalot blog and now writing for The RPM Report, where we first read about this ISMP QuarterWatch Digitek analysis in his January 19, 2009 online article, "ISMP Draws Attention to Drug Safety Issues In New Report".

Stay tuned for our future reports on what is learned from Actavis in the discovery aspect of these Digitek lawsuits about the extent of defective Digitek pills dispensed to patients in terms of time frame and number of pills.

Celgene Letter About Revlimid And Serious Skin Reactions In January 2009 Medical Journal

Discusses 16 Cases Of Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Erythema Multiforme (EM) Reported Over Two-and-a-half Years

(Posted by Tom Lamb at DrugInjuryWatch.com)

In an October 1, 2008 article, "FDA Alerts Doctors That Revlimid Can Cause Serious Skin Reactions In Patients", we reported that Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Erythema Multiforme (EM) have been associated with the use of Revlimid (lenalidomide).

A Correspondence item published in the January 1, 2009 edition of the Journal of Clinical Oncology provides some new information about 16 reports of these serious skin rash conditions among patients who used Revlimid from December 2005 -- when this drug was first marketed by Celgene Corporation -- through June 2008.

This letter to the editor was written by several Celgene employees, and is titled "Erythema Multiforme/Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in Lenalidomide-Treated Patients".  From the letter we get this background about the skin reactions known as SJS, TEN, and EM:

Stevens-Johnson syndrome (SJS) is a rare but life-threatening cutaneous adverse reaction. While SJS may sometimes be admixed with diagnoses of erythema multiforme (EM) minor or major, SJS and toxic epidermal necrolysis (TEN) are considered to be severity variants of the same disease with drug exposure the primary etiologic factor. The incidence of SJS has been estimated at 1.1 to 7.1 cases per million person-years, and that of TEN at 0.4 to 1.2 per million person-years.1 Mortality among patients with SJS or TEN has been reported to be between 1% to 3% and 10% to 70%, respectively.  [footnotes omitted]

The letter goes on to discuss in some detail several of the SJS, TEN, and EM case reports that Celgene knows about thus far.

In closing, the authors acknowledge that there is a possible cause-and-effect relationship between Revlimid and previews an upcoming Revlimid label change:

Most cases were postmarketing reports and as such had inadequate information, making confirmation of the reporters’ diagnoses difficult and hampering causality assessment. The temporal relationship between the events and lenalidomide initiation in many reports cannot exclude a causal relationship. The company is updating the prescribing information for lenalidomide to include guidance on these rare events.

We will watch for more reports of Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Erythema Multiforme (EM) in patients using Revlimid.

Please let us know if you are aware of any additional Revlimid-related serious skin reaction cases by submitting a Comment below or sending us a private email.

Fosamax Update January 2009: More Osteonecrosis Of Jaw Cases Reported In Medical Journal

Possible Link Between Fosamax And Esophagus Cancer Surfaces; Merck Disputes This New Side Effect

(Posted by Tom Lamb at DrugInjuryWatch.com)

In January 2009 the Journal of the American Dental Association published an article, "Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw", by Parish P. Sedghizadeh, DDS, MS, and his colleagues at the University of Southern California.

The findings from this 2009 medical journal article about Fosamax and osteonecrosis of the jaw (ONJ) were summarized in a MedPage Today online article, "Osteoporosis Drug Increases Risk of Dental Complications", which also included some remarks by Dr. Sedghizadeh:

Even short-term use of oral alendronate (Fosamax) can increase the risk of osteonecrosis of the jaw as a complication of dental procedures, researchers here said.

In a single-institution, retrospective study, 4% of patients taking oral alendronate developed osteonecrosis, compared with none of a large population of dental patients who didn't take the drug, according to Parish Sedghizadeh, D.D.S., of the dental school at the University of Southern California, and colleagues.

The finding contradicts claims that the rate of osteonecrosis in alendronate patients is about 0.7 cases per 100,000, or less than 0.00001%, the researchers said in the Jan. 1 issue of the Journal of the American Dental Association....

That position is incorrect, Dr. Sedghizadeh said in a statement. "We've been told that the risk with oral bisphosphonates is negligible, but 4% is not negligible," he said.

"Here at the school of dentistry we're getting two or three new patients a week who have bisphosphonate-related ONJ (osteonecrosis of the jaw)," he said, "and I know we're not the only ones seeing it."

A July 2008 article from the Canadian Family Physician, "Bisphosphonate-associated osteonecrosis of the jaw", however, contends that Fosamax and other oral bisphosphonates do not cause ONJ:

In 2003, the first reports describing osteonecrosis of the jaw in patients receiving bisphosphonates were published. About 95% of these cases occurred among cancer patients receiving high-dose intravenous bisphosphonates. Approximately 5% of the reported cases have been in osteoporosis patients receiving low-dose bisphosphonate therapy....

Recently, however, high-dose intravenous bisphosphonates have been identified as a risk factor for osteonecrosis of the jaw among oncology patients. Low-dose bisphosphonate use in patients with osteoporosis or other metabolic bone disease has not been causally linked to the development of osteonecrosis of the jaw. [footnotes omitted]

Lastly as regards Fosamax and ONJ, which is sometimes referred to as "phossy jaw", from the November 2008 edition of the Journal of oral and Maxillofacial Surgery, we have a brief article by Robert E. Marx, DDS, Professor of Surgery and Chief, Division of Oral and Maxillofacial Surgery, University of Miami Miller School of Medicine, Miami, FL.  Dr. Marx first wrote about the bisphosphonate-induced necrosis of the jaws back in 2003 (and it was his reports that were mentioned by the Canadian medical journal article, above).  In his latest article, "Uncovering the Cause of 'Phossy Jaw' Circa 1858 to 1906: Oral and Maxillofacial Surgery Closed Case Files — Case Closed", asserts that:

[T]he cause of phossy jaw in the late 1800s was actually bisphosphonate-induced osteonecrosis of the jaws, long before clever modern pharmaceutical chemists synthesized bisphosphonates. Today's bisphosphonate-induced osteonecrosis represents the second epidemic of “phossy jaw.” Case closed.

This January 2009 update would not be complete without a mention of a January 1, 2009 New England Journal of Medicine (NEJM) Correspondence item, "Reports of Esophageal Cancer with Oral Bisphosphonate Use", by Diane K. Wysowski, Ph.D. -- who is with the FDA -- which suggests a possible link between Fosamax and the development of esophageal cancer.

From an ABC News report about this January 2009 NEJM letter to the editor, "Report Links Osteoporosis Drug to Esophagus Cancer", we get a summary and some comments by Dr. Wykowski:

The report... reveals that the FDA received 23 reports of esophageal cancer possibly linked to the drug between its October 1995 debut and May 2008. Of these patients, eight have died so far, according to the report.

The report also said that "no similar U.S. reports for other oral bisphosphonates were retrieved from the FDA's database for adverse-event reporting" -- a statement that seems to spare other drugs in the same class, such as Boniva, Actonel or Didronel, from similar condemnation. Wysowski, however, says she remains unconvinced that the rest of this class of drugs is definitely not linked to esophageal cancer....

However, Wysowski acknowledged to ABCNews.com that it still remains uncertain whether Fosamax and other oral bisphosphonates can be linked to esophageal cancer.

"It is uncertain if the drugs can cause esophageal cancer," Wysowski said. "However, use of oral bisphosphonates has been linked to inflammation of the esophagus, also called esophagitis, primarily in patients who have not used them according to directions."

This irritation, she says, may set the esophagus up for cancer later on.

This January 1, 2009 ABC News article went on to report that Merck & Co., the drug company that makes Fosamax, denied any link between its osteoporosis drug and esophageal cancer.

All Sprint Fidelis Federal Court MDL Cases Dismissed On Federal Preemption Grounds

U.S. District Court Judge in Minnesota Follows Supreme Court's Riegel vs. Medtronic Ruling As Precedent In Making His January 2009 Ruling

(Posted by Tom Lamb at DrugInjuryWatch.com)

All of the Sprint Fidelis cases that are part of the federal court multi-district litigation (MDL) were dismissed in early January 2009 pursuant to a motion to dismiss that had been filed by the defendant, Medtronic, Inc.

From a January 6, 2009 company press release, "Court Rules in Favor of Medtronic in Fidelis Litigation", we get this summary:

Medtronic, Inc. (NYSE: MDT) reported that on Jan. 5, the United States District Court for the District of Minnesota dismissed with prejudice the Master Consolidated Complaint for Individuals and the Master Consolidated Complaint for Third-Party Payors relating to the multi-district litigation (MDL) involving Medtronic’s Sprint Fidelis defibrillator leads on grounds of federal preemption. The Court issued a companion order that each case in the MDL will be dismissed with prejudice unless an individual plaintiff can establish his or her case survives the Court’s preemption analysis based on claims different from those asserted in the master complaints.

In an exuberant January 6 article, "Sprint Fidelis Preemption Decision - Yessssss", the Drug and Device Law blog -- which typically has an unabashed company / defense perspective on issues like this -- trumpeted this January 2009 medical device preemption ruling:

In what will certainly be an early entry for one of the top ten decisions of 2009, Medtronic just won. The short of it:

Medtronic, the Defendant in this multidistrict litigation, asserts the same doctrine here, arguing that Plaintiffs’ claims – sounding in negligence and strict products liability – are preempted by the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act (“FDCA”), 21 U.S.C. § 301 et seq. Having carefully considered the parties’ voluminous submissions, the Court agrees.

In re Medtronic, Inc. Sprint Fidelis Leads Products Liability Litigation, slip op. at 2.

The Drug and Device Law blog was kind enough to post the Court's ALL CASES MEMORANDUM OPINION AND ORDER (slip opinion) which was filed for the MDL cases that are part of In re Medtronic, Inc. Sprint Fidelis Leads Products Liability Litigation.

In June 2008 we first reported that the U.S. Supreme Court's Riegel preemption ruling would be negated by legislation sponsored by Democrats in Congress which, in effect, permits U.S. patients to sue medical device companies like Medtronic if their product causes harm, such as the alleged injuries caused by the defective Sprint Fidelis lead wires.

With this federal preemption motion to dismiss being granted by the Sprint Fidelis MDL Court in January 2009, we expect there to be a renewed push to get this type of legislation passed in Congress and then to President-elect Obama later this year.

Over time I have expressed consistently my opposition to any federal preemption of patient lawsuits against medical device or pharmaceutical companies. 

Now we want to hear what you think about this federal preemption issue.