Drug Injury Watch

Natrecor: A Definitive Safety Study Is Long Overdue

Off-label Use Of Natrecor Continues To Be A Problem

A year ago two medical journal articles raised serious safety issues about Natrecor; in summary: (1) a 50% increased risk of kidney damage or renal failure; and, (2) a 75% increased risk of Natrecor-associated death within 30 days of use when compared to similar drugs. 

At that point in time Scios, the Johnson & Johnson subsidary which makes Natrecor, convened a panel of experts who told the drug company that a study of these safety issues should be done immediately.

What happened?  According to a May 30, 2006 article in The Wall Street Journal, Johnson and Johnson (J&J) recently provided this update about their new Natrecor safety study:

"There are just a couple of details that we're putting the finishing touches on," said Roger Mills, vice president of medical affairs at Scios, the J&J unit that makes Natrecor. . . . 

[Another] company spokeswoman said the study would be the largest and most comprehensive to date in this group of patients. The study, she said, will demonstrate the "commitment and confidence" the company has in Natrecor.

This one-year delay in launching this Natrecor study, according to the May 30 WSJ article, drew a scathing comment from Milton Packer, a member of the advisory committee convened by J&J a year ago: "I think no one on the panel imagined that the recommendation would be followed by silence for a year. . . .  It's an unacceptably long period of time."

On other fronts, the WSJ's Scott Hensley reported:

J&J said in a recent quarterly securities filing that "there is no new data supporting the conclusions" of the safety critics. And unpublished data from a new study of the drug in patients undergoing heart-bypass surgery indicated that Natrecor might protect kidneys from damage related to the operations. . . .

The FDA hasn't asked J&J for a safety study of Natrecor.

In part, it is the so-called "off-label" prescribing of Natrecor (nesiritde) -- an infusion in outpatient clinics to avoid acute congestive heart failure episodes with severe breating problems vs. use in hospitalized patients whose hearts pump so weakly that they have trouble breathing -- which has contributed to the growing controversy about J&J's Natrecor.

Meanwhile, perhaps due to the Natrecor side effects controvery, according to this May 30, 2006 WSJ article the sales of Natrecor has gone from $375 in 2004 to a projected $100 million in 2006.

The fate of Natrecor remains to be seen.

(Posted by: Tom Lamb)

Merck's New Vioxx Web Site: What Is This About?

The Drug Company Wants You To Know What It Thinks About The Vioxx Litigation

Merck & Co. has turned to the Internet in order to further disseminate their positions concerning the ongoing Vioxx litigation including, among other things, the critical issue of when Merck first learned about the increased cariovascular risks associated with Vioxx.

It may seem odd that in mid-May 2006 Merck went "live" with a new Vioxx web site -- which can be found at www.learnaboutvioxx.com -- given that Vioxx was voluntarily recalled by Merck in September 2004.  Merck appears, however, to be using this "Learn About Vioxx" web site to generously assist those people who want a better understanding of the Vioxx litigation -- from the drug company's perspective.

For that purpose, in the "Merck Responds" section of this new Vioxx site, the drug company presents these four subjects:

1. What Merck Knew
2. Disclosing the Data
3. Marketing of Vioxx
4. Benefits and Risks

One can also read "An Open Letter from Merck", written by Raymond V. Gilmartin, the retired Chairman, President, and CEO of Merck & Co.

Some of the other parts from this new Vioxx web site that provide the Merck perspective concerning the Vioxx litigation are: 

• Behind The Science;
• Litigation Information;
• In The News;
• Timeline; and
• Additional Resources.

In the "Additional Resources" section (for whatever reason) one can find links to these organizations:

Center for Legal Policy at the Manhattan Institute

American Enterprise Institute for Public Policy Research

American Tort Reform Association

American Tort Reform Foundation

On another front, here is an overview of the Vioxx cases that had been filed as of March 31, 2006, according to the April 2006 edition of Mealey's Litigation Report: Arthritis Drugs, Vol.2, Iss. 11 (4/06) at p.15:

". . . 11,500 lawsuits, comprising approximately 23,350 plaintiff groups alleging personal injuries from Vioxx."

". . . 190 putative class actions alleging personal injuries and/or economic loss have also been filed." 

"Some 5,175 actions are or will be in the federal MDL and approximately 5,250 are included in the coordinated proceeding in New Jersey Superior Court that has yielded two trials thus far." 

"An additional 4,450 potential litigants had entered into tolling agreements with the company over alleged injuries from a thrombotic cardiovascular event that results in a myocardial infarction or ischemic stroke."

Anyhow, be sure to visit LearnAboutVioxx.com often in the months and years to come so that you can stay informed about the Vioxx litigation, courtesy of Merck.

(Posted by: Tom Lamb)

Antibiotic Ketek: FDA Staff Recommends "Black-box" Warning

As Of May 1, 2006 There Are 23 Reports Of Serious Liver Injury, Including 12 Cases Of Liver Failure, In U.S.

After finding the antibiotic Ketek (telithromycin) has been associated with 12 cases of liver failure, including four deaths, staff members at the FDA's drug safety office have recommended adding a "black-box" warning to the label, or package insert, for Ketek stating that "severe, life-threatening, and in some cases fatal" liver toxicity has been reported in patients taking Ketek.

This black-box warning recommendation was first reported in a May 19, 2006 Wall Street Journal (WSJ) article by Anna Wilde Mathews, which references "a confidential May 16 memorandum by the FDA's Division of Drug Risk Evaluation reviewed by The Wall Street Journal" as the source of this information.  According to this May 19 WSJ article, "The document concludes that the Ketek rates are 'consistent with an association' between the drug and liver failure."

In more detail, Ms. Wilde reports:

The internal FDA memo analyzes incidents reported through the end of April in people in the U.S. who were prescribed Ketek after the drug won FDA approval. The reviewers found 23 reported cases of serious liver injury, as well as the 12 liver failures, that were "associated" with Ketek. The FDA also got reports of 44 liver-related events that weren't serious. . . .

Calling some of the liver-failure cases "clinically remarkable," the memo describes "profound" liver injury that set in as soon as a few days after some patients took Ketek and had a "signature of rapid onset and tempo." The document says that many of the 12 cases appeared to have few other possible causes and occurred in people who were "generally healthy." Besides the four deaths, one patient had a liver transplant and three others were considered for transplants but recovered.

Ms. Wilde's article also covers the official FDA response to the black-box warning recommendation as well as the reaction from Sanofi-Aventis SA, the drug company that makes Ketek.  Starting with the FDA:

In a statement, an FDA spokeswoman said that the memo reflects the drug-safety office's "interpretation of adverse-event data" and recommends "labeling revisions be considered but not product withdrawal." . . .

The FDA spokeswoman said that the safety reviewers found "the numerical risk appears higher in the Ketek database" but "they are not able to conclude greater risk for liver injury in patients receiving Ketek than other drugs in the category." The finding will be "carefully considered along with all other sources of expert review" in the FDA's final assessment of Ketek, she said.

As for Aventis-Sanofi, the drug company which makes Ketek:

In a statement, Sanofi-Aventis said it "continues to believe that Ketek is safe and effective when used as directed." It said that it is engaged in "ongoing discussions with the FDA regarding a detailed medical evaluation of hepatic events" reported in connection with Ketek use and that it is evaluating the data with leading experts. The company said a detailed response to the findings in the memo would be inappropriate while it is in discussions with the agency.

Regarding the black-box warning, according to Ms. Wilde's article the confidential FDA memo reviewed by The Wall Street Journal:

. . .recommended that the Ketek label carry a warning about liver risk set apart by bold type or a black box, which is reserved for the most serious safety concerns. Among other things, the proposed warning would mention reports of liver necrosis and liver failure, and say that in some cases liver injury "progressed rapidly and occurred after administration of a few doses of Ketek." The suggested labeling would also warn doctors to watch patients for signs of hepatitis.

Ketek's current label includes only some cautionary language that liver dysfunction "has been reported with the use of Ketek" and that "these events were generally reversible."

Last year, Ketek was prescribed 3.35 million times in the U.S. and had sales of $193 million, according to a company that tracks prescription drug sales, IMS Health.

On another aspect, Senator Charles Grassley of Iowa as well as Congressmen Edward Markey of Massachusetts and Henry Waxman of California recently told the FDA that they want to know more about allegations of fraud and irregularities concerning a large clinical trial that was designed to demonstrate the Ketek's safety.  That drug-safety study was being conducted after the FDA initially refused to approve Ketek because of the agency's concerns about liver damage and other serious side effects.  Later, seemingly because of those allegations of improper conduct and procedures, the study was discontinued -- but the FDA approved Ketek in April 2004. Now, Sen. Grassley, Rep. Markey, and Rep. Waxman want to know more about the discontinued study and the FDA approval of Ketek.

(Posted by: Tom Lamb)

Birth Control Patch Lawsuits Being Settled Early By Johnson & Johnson

Ortho Evra Contraceptive Patch Causes Blood Clots Resulting In Strokes, Heart Attacks, Pulmonary Embolism, And Deep Vein Thrombosis 

According to a May 16, 2006 article in the New Jersey Law Journal, Johnson & Johnson has said it wants to settle those lawsuits where a woman who used its skin patch Ortho Evra was hospitalized with any of the following serious side effects: 

• strokes;
• heart attacks;
• pulmonary embolisms; and,
• deep vein thrombosis.

The Ortho Evra patch lawsuits have been designated for multi-district litigation, or MDL, treatment in the federal court system, and designated as a mass tort by the Supreme Court in New Jersey, where Johnson & Johnson has its headquarters.  According to the May 16 New Jersey Law Journal article, lawyers for Johnson & Johnson announced their "quick-settlement strategy" on May 2, 2006 during conferences with the respective judges who are presiding over the Ortho Evra MDL cases and the New Jersey Ortho Evra consolidated cases.

At a May 2 status conference with U.S. District Judge David Katz in Cleveland, where 73 cases from around the country have been consolidated, a Johnson & Johnson lawyer announced that the company is prepared to settle all suits in which plaintiffs were hospitalized for stroke, heart attacks, pulmonary embolisms or deep vein thrombosis. . . .

The same day, Johnson & Johnson lawyer Susan Sharko wrote to Superior Court Judge Peter Bariso in Hudson County that the company had reached confidential settlements with 11 of the 12 plaintiffs who sued there. . . .

The Ortho Evra lawsuits generally allege that this contraceptive patch causes blood clots due to heightened estrogen levels, with the result being that relatively young and healthy women -- mostly in their teens and twenties -- using the Ortho Evra patch have suffered heart attacks, strokes, and even death.

Reportedly, since January 2006 about 30 Ortho Evra lawsuits have already received confidential settlements, and Johnson & Johnson (J&J) has told plaintiffs lawyers that the drug company wants to evaluate their remaining personal injury and wrongful death cases for the purpose of settling those Ortho Evra cases.

The Ortho Evra patch was introduced in 2002 and remains on the market, but reports of birth control patch side effects prompted the FDA in November 2005 to order that J&J put a stronger warning on the Ortho Evra package insert, or label, regarding the increased risk of blood clots for women using this contraceptive patch.

(Posted by: Tom Lamb)

Already Poor Visibility In The Vioxx Litigation Seemingly Gets Worse

What Do The Latest Vioxx Study Results Mean, And What Will Merck Do?

The assertions, claims, and interpretations about what the new data from the so-called "Approve" study means regarding any increased risk of a heart attack or stroke during the first year after a person stopped taking Vioxx, and how it will influence the developing Vioxx litigation, are all over the place -- as you were starting to think after reading different articles.

The Wall Street Journal (WSJ) on May 12, 2006, under the headline "Merck Study Finds A Vioxx Risk After Use Ended", said that data for the fourth-year patients who were followed in the Approve study "suggests patients remained at risk of a heart attack or stroke during the first year after they stopped taking [Vioxx]."  The WSJ article pointed out:

In a follow-up analysis of the 2,587-patient study called Approve that led the company to pull the drug from the market in September 2004, Merck officials said patients who took the drug during a three-year trial were 1.64 times as likely to have a heart attack or stroke during a subsequent year when they weren't taking it, compared with those who had been on a placebo.

But this May 11, 2006 Associated Press (AP) article came at the new Approve data from a different angle, under this banner: "Study: Vioxx Users Not at Increased Risk -- Study Finds Vioxx Users Not at Higher Risk of Heart Attack, Stroke in Year After Stopping Drug".  This AP article showed the other side of the recent Approve data:

Merck said data from a "preliminary safety analysis" of an additional year of patient follow-up, part of the study's original plan, did not show a statistically significant difference in the rate of heart attacks and strokes among patients who had been on Vioxx and those who had taken a dummy pill. That means the differences over that year could have been due to chance.

Merck's general counsel Kenneth Frazier asserts that the new Approve results should help Merck defend itself against those legal cases -- among the more than 11,000 Vioxx lawsuits filed against Merck to date -- where a person blamed Vioxx for their heart attack or stroke event at some time in the year after they had already stopped using Vioxx.  As reported in the May 11 AP Vioxx article, Mr. Frazier told analysts and reporters on a conference call: "We [at Merck] believe that the data don't provide for a claim for a patient who had an event after they stopped taking [Vioxx]."

Perhaps Matthew Herper had the best handle on the situation when he used the headline "Vioxx: More Murk For Merck" for his May 11, 2006 online Forbes piece.

Merck says the data show that the heart risk from Vioxx does not persist, because the difference in outcomes between patients who stopped taking the drug and patients who stopped taking a placebo is not statistically significant. But responses from scientists and a Wall Street analyst were all over the map. . . .

The results do show that there is no statistically significant increase in heart attacks among patients who have stopped taking Vioxx compared to those who have stopped taking placebo. However, the data provide no certainty. The door is left open to arguments that Vioxx may increase the risk of heart attacks and strokes. Whether that is true could be crucial as Merck defends itself against more than 11,000 Vioxx-related lawsuits.

Meanwhile, just one week before this latest development in the Vioxx litigation, from "Vioxx Heart Risk Found to Be Early and Persistent", an online piece posted May 3, 2006 on MedPage Today, we learned that perhaps even very short-term Vioxx use -- as little as a week or two weeks of daily use -- could increase a Vioxx user's risk of heart attack or stroke. Moreover, in direct contradiction to some of the recent takes on the latest Approve data (see above), this MedPage article indicated that the increased risk on having a cardiovascular event ended on day seven after one stopped taking Vioxx.

The possible increased risk of having a heart attack or stroke after only short-term use was emphasized in this May 2, 2006 Bloomberg article, "Vioxx-Linked Heart Attacks May Occur Within 2 Weeks, Study Says", which starts:

Merck & Co.'s Vioxx painkiller may raise the risk of a heart attack within two weeks after patients start taking the drug, earlier than previous studies have shown, according to Canadian researchers.

More than a fourth of 239 elderly patients who had heart attacks while on Vioxx did so within six to 13 days after they first started taking the drug, according to a study published online today by the Canadian Medical Association Journal.

Of course, all of this is under consideration by the various interested parties as the two-year anniversary of the Vioxx recall, and the lawsuit filing deadline for many Vioxx plaintiffs, rolls around in September 2006.

(Posted by: Tom Lamb)

What Is The Better Way To Improve Safety Of New Prescription Drugs?

Five Points For Consideration In May 2006 Circulation Editorial By Jerry Avorn, M.D.

In May 2006 the medical journal Circulation published "Evaluating Drug Effects in the Post-Vioxx World -- There Must Be a Better Way", an editorial piece written by Jerry Avorn, M.D., who is associated with Harvard Medical School and Brigham and Women’s Hospital, in Boston.

Dr. Avorn's editorial takes issue with the idea that "requiring extreme criteria for demonstrating efficacy" is the only way to be sure that we are getting adequate safety information about new prescription drugs in the aftermath of the Vioxx recall.

This Avorn editorial is in the same edition of Circulation that includes the article "Clinical trials in the wake of Vioxx: requiring statistically extreme evidence of benefit to ensure the safety of new drugs", by Michelle D. Roth-Cline, B.S.  While Dr. Avorn reaches the some conclusion that Roth-Cline does in her article -- "that demanding unprecedentedly stringent tests for efficacy is a poor way to fix the nation's drug safety problem", in Avorn's words -- his reasoning differs from that presented in the related article by Roth-Cline.

In his May 2006 editorial, Dr. Avorn raises five points for consideration which, as he explains below, are derived from the lessons of Vioxx:

The delayed "discovery" of the dangers of rofecoxib [i.e., Vioxx] and other high-profile drugs should indeed cause us to ask what additional lessons can be learned from our current debacles and prompt a thorough review of how drug risks are detected. Unfortunately, many of the lessons drawn from such case studies by regulators, clinicians, companies, and the public, including the proposal rightly condemned by Roth-Cline, have led to the wrong conclusions.

Thereafter, in this four-page Circulation editorial, Dr. Avorn briefly discusses each of the following five points:

• Wrong Lesson 1: Preapproval Studies Provide the Only Opportunity to Detect Important Drug Risks 
• Wrong Lesson 2: Either We Can Approve Drugs in a Timely Manner or We Can Learn Enough About Their Risks Before Approval, but We Cannot Do Both 
• Wrong Lesson 3: Rofecoxib Proved That Many Important Adverse Events Are Inherently Unknowable Until It Is Too Late, and Therefore We Are Unlikely to Develop Better Systems for Their Detection 
• Wrong Lesson 4: Greater Scrutiny for Adverse Events Will Impede the Availability of Important New Products and Drive Up Drug Prices 
• Wrong Lesson 5: The Best Strategy Now Is for the FDA to Warn About Everything 

Dr. Avorn concludes his Circulation editorial with both a lament and a call for action:

It is a sad commentary on the current state of drug evaluation and safety surveillance in the United States that some believe that the only way we can be sure of getting adequate safety information is by requiring extreme criteria for demonstrating efficacy. Fortunately, other solutions are possible that are more scientifically rigorous, clinically appropriate, and feasible.  All that is lacking is the political will to implement them.

Let's hope that our lawmakers in Washington heed Dr. Avorn's suggested solutions and, more importantly, act on them before we have another drug-safety debacle like Vioxx.

(Posted by: Tom Lamb)   

FDA's Approval Of Antibiotic Drug Ketek Under Scrutiny

WSJ Investigative Article Revealed Faulty Data And Improper Record-keeping For Key Drug Study

As reported in a May 2, 2006 article by Wall Street Journal reporter Anna Wilde Mathews, Senator Charles Grassley (R-Ill.) as well as Congressmen Edward Markey (D-Mass.) and Henry Waxman (D-Calf.) are asking the FDA for some explanation about the agency's decision to approve the antibiotic Ketek (telithromycin) in 2004.  This scrutiny follows in the wake of Ms. Wilde's May 1, 2006 investigative piece in the Wall Street Journal about how the FDA approved Ketek despite knowing about some problems with a key study -- known as trial 3014 -- which was submitted to the FDA by Ketek's manufacturer, Sanofi-Aventis.

Senator Grassley wrote one letter to the FDA expressing his concerns about the Ketek situation, while Congressmen Markey and Waxman co-wrote a second letter.  In her May 2 article, Ms. Wilde reported the reactions to these letters from the FDA and Sanofi-Aventis:

In a statement, an FDA spokeswoman said the agency will "welcome this opportunity to continue talking about the scientifically rigorous work" of the FDA. She also said agency officials are assessing reports of liver damage in people who took the drug but "still believe when used as directed, Ketek is safe and effective." Sanofi-Aventis said in a statement it is "committed to patient safety" and will address questions from the FDA and Congress. It said it "remains confident that Ketek is a safe and effective therapy when used as directed."

More generally, the two Congressmen's letter also pointed out, and questioned, how the efficacy of antibiotics -- unlike most other prescription drugs seeking approval by the FDA -- is tested.  In summary, instead of being compared to a placebo as is usually done, new antibiotics are typically compared with older antibiotics that have already been approved by the FDA.  For the new antibiotic to gain approval, the drug company needs to prove, only, that its new antibiotic is about as effective as the older drug.  In fact, under the current scheme, the new antibiotic can perform a bit worse than the older antibiotic and still be approvable as for its efficacy.

(Posted by: Tom Lamb)

Phenergan And Similar Drugs Associated With Infant Deaths

FDA Cautions That These Drugs Should Not Be Given To Children Under Two

On April 25, 2006 the FDA issued a drug safety alert about promethazine hydrochloride, warning doctors and parents that drugs containing promethazine hydrochloride (HCl) should not be given to children younger than two years of age, and they should use care in giving those drugs to children older than two years.  The FDA said in this safety alert that seven cases of death and 22 reports of severe breathing problems, all in children younger than two, had been linked to promethazine HCl. The drug, originally approved for use back in 1951, is usually prescribed as an antihistamine or allergy drug.

This April 2006 drug safety alert covers all prescription drugs containing promethazine HCl, and all forms of the drug, including syrups, suppositories, tablets, and injectable liquids.  One of the more popular medications containing promethazine HCl is called Phenergan, which is sold by the drug company Wyeth.  In addition, there are various generic versions of promethazine HCl available in the U.S.

Safety concerns about Phenergan and other drugs containing promethazine HCl -- while getting renewed interest by means of this April 2006 FDA warning -- have been around for some time.  An article by Bloomberg News Service that was published in the Asbury Park Press newspaper on June 23, 2005 provides some background on this issue:

The Food and Drug Administration received 125 reports of adverse reactions in children under age 16 from 1969 through 2003, according to an agency letter that appears in today's New England Journal of Medicine. Problems included 38 cases of respiratory distress and cardiac arrest, 29 cases of involuntary muscle contractions and 15 seizures. Infants had the greatest risk.

The agency added a warning, enclosed by a black box, to the label last year to alert doctors to problems with the drug known chemically as promethazine. The agency detailed the case for its action in today's journal because of fears that doctors might not notice the change on the label of the decades-old drug, said Badrul A. Chowdhury, director of the FDA's division of pulmonary and allergy drug products.

Phenergan, at least, has never been approved by the FDA for use in children under the age of two.

(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)