Drug Injury Watch

Novantrone: FDA MedWatch Alert Regarding Heart Damage Risks

April 2005 "Dear Doctor" Letter Also Addressed an Increased Risk of AML

In late May 2005 the FDA warned patients of the risk of heart damage from Serono's multiple sclerosis drug Novantrone.  In a MedWatch alert, the FDA said congestive heart failure, a potentially fatal condition, could occur either during Novantrone therapy, or months to years after termination of Novantrone therapy. The May 2005 MedWatch alert also included information about an increased risk of developing treatment-related leukemia due to Novantrone use.

An April 2005 "Dear Doctor" letter sent out by Serono, the drug company responsible for Novantrone, provided additional information concerning the risks of cardiotoxicity associated with Novantrone.  The April 2005 Serono letter to doctors and other healthcare professionals also provided supplemental information regarding secondary acute myelogenous leukemia (AML) reported in MS patients treated with Novantrone.

A pharmaceutical sector financial analyst, Karl-Heinz Koch, of Lombard Odier Darier Hentsch, opined that this new warning will likely have little impact on Novantrone sales:

The drug is burdensome already because it has a large side effect catalog....  It is only used in very severe cases anyway.  I don't believe it will have a big effect on Serono or a large impact on the use of the drug.

A spokesman for Serono concurred about the impact of this new set of warnings on Novantrone sales; "We believe it is not going to have an effect on the product. The product is for very severe forms of MS, for people who have no choice," the spokesman said.

(Posted by: Tom Lamb)

Pfizer Maintains There is No NAION / Blindness Risk from Viagra

Bayer Has Not Decided Whether to Add NAION Warning for Levitra

On June 27, 2005 Pfizer Inc. issued a press release asserting that there is no evidence of any increased risk of developing non-arteritic anterior ischemic optic neuropathy (NAION), leading to blindness, among patients taking Viagra, Pfizer's erectile dysfunction (ED) drug.

Joseph Feczko, Pfizer's chief medical officer, was quoted in the Viagra press release as stating:

There is no evidence that Viagra causes blindness or any other serious ocular condition....  Several studies specifically looking into the effect of Viagra in the eye by Pfizer as well as independent ophthalmologic experts found Viagra to have no serious adverse effects on the eye.

The Pfizer press release also stated that the drug company is currently negotiating with the FDA about making revisions to the Viagra package insert, or warning label, to inform doctors and patients about the development of NAION, and blindness, in some Viagra users.

Pfizer said in this press release that it believes the FDA has asked other drug companies to add the NAION and blindness information to the warning labels for their respective ED drugs.  For market share as concerns ED drugs, or impotence drugs, Pfizer's Viagra competes with Cialis, sold by Eli Lily & Co. and Icos Corp., as well as Levitra, which is co-promoted by GlaxoSmithKline and Bayer AG.

The day after Pfizer's Viagra press release, Bayer said it had not decided, yet, whether new warning language about NAION and blindness will be added to the package insert for their impotence drug. Levitra.

Meanwhile, Lilly and Icos updated the Cialis warning label last month to add language regarding NAION and blindness.

Previously, the FDA has said while the agency has received 43 reports of NAION and blindness among men who took ED or impotence drugs, the FDA has concluded there is no evidence of a link between the ED drugs and blindness.

Read more about reports of NAION and blindness among users of Viagra and other ED, or impotence, drugs.

(Posted by: Tom Lamb)

European Drug Regulators Want Increased Warnings on All COX-2 Inhibitor Drugs

Bextra: Suspension of Marketing in European Union to Continue

In a June 27, 2005 press release issued by the European Medicines Agency (EMEA), the Agency's Committee for Medicinal Products for Human Use (CHMP) said that additional side effect warnings and prescribing contraindications are necessary for all COX-2 inhibitors due to the cardiovascular risks linked to this class of drugs. 

Further, because the CHMP concluded that the additional risks of serious and potentially fatal skin reactions associated with the use of Bextra outweigh its benefits, it was recommended that the current suspension of the marketing of Bextra should continue.  Bextra's manufacturer, Pfizer, had voluntarily suspended marketing of Bextra in the European Union in April 2005 at the request of the EMEA.  The suspension of Bextra in the E.U. will be reviewed within one year, according to this June 2005 EMEA press release, during which time Pfizer has the opportunity to provide Bextra drug-safety data for consideration by the CHMP.

The CHMP confirmed its February 2005 finding that the probability of suffering a cardiovascular reaction such as a heart attack or stroke from one's use of COX-2 inhibitor drugs like Bextra was a function of dose and duration, i.e., dose-related. The Committee also confirmed its earlier finding that while serious skin reactions such as Stevens-Johnson Syndrome (SJS) occur with the use of other COX-2 inhibitors, the others are not near the relatively high skin reaction incident rate that has been associated with Bextra.

The CHMP recommended several prescribing contraindications and precautions for the remaining COX-2 inhibitors products. 

In concluding its review, the CHMP maintained that when these COX-2 inhibitors are prescribed in accordance with these additional contraindications and precautions, the risk-benefit analysis for this class of drugs remains positive.

(Posted by: Tom Lamb)

Congressman Henry Waxman's June 2005 NEJM Article About Vioxx and Merck's Sales Tactics

Tells How Merck's Drug Reps Did Their Vioxx "Spin" for Concerned Doctors

In the June 23, 2005 issue of The New England Journal of Medicine (NEJM), is "The Lessons of Vioxx -- Drug Safety and Sales", by Henry A. Waxman.  This Congressman from California tells doctors and other readers what he learned recently about how -- during the period from February 2001 up until the September 2004 Vioxx recall -- Merck's sale representatives dealt with the rising level of concern about the increased risk of cardiovascular side effects for patients taking Vioxx.

On May 5, 2005 Congressman Waxman convened the Government Reform Committee of the U.S. House of Representatives for a hearing to seek an answer to a question that has been asked by many doctors and patients, both, since the fall of 2004:  How did Vioxx remain such a widely-prescribed drug given the many serious safety issues that were raised during a period of several years before Vioxx was finally withdrawn from the market?

The NEJM article reveals that Congressman Waxman believes the answer, or lesson, has to do with the promotional and sales practices that Merck used in their dealings with prospective prescribing doctors.

Congressman Waxman realizes that the practices used by Merck and its sales representatives are probably similar in kind to those of other drug manufacturers.  Accordingly, early on in Waxman's NEJM article, a couple of industry-wide statistics are presented to set the stage:

• The pharmaceutical industry spends more than $5.5 billion to promote drugs to doctors each year.
• Major drug companies employ about 90,000 sales representatives — one for every 4.7 doctors in the United States.

Congressman Waxman points out that, because of the public uproar about the Vioxx debacle, the Government Reform Committee's May 5 hearing focused on Merck, the manufacturer of Vioxx.  As a result, Henry Waxman and his fellow Congressmen had an opportunity to learn much about how Merck directed its many Vioxx sales representatives to present doctors who were in a position to prescribe Vioxx with what Waxman calls "a distorted picture of the relevant scientific evidence" concerning the cardiovascular risks of Vioxx.

For example, on February 7, 2001 the FDA's Arthritis Drugs Advisory Committee voted unanimously that doctors should be made aware of the cardiovascular risk information derived from the Vioxx Gastrointestinal Outcomes Research study, more commonly known as the VIGOR study.  According to Congressman Waxman in this June 23 NEJM article:

The next day, Merck sent a bulletin to its [Vioxx] sales force of more than 3000 representatives. The bulletin ordered, "DO NOT INITIATE DISCUSSIONS ON THE FDA ARTHRITIS ADVISORY COMMITTEE . . . OR THE RESULTS OF THE . . . VIGOR STUDY." It advised that if a physician inquired about VIGOR, the sales representative should indicate that the study showed a gastrointestinal benefit and then say, "I cannot discuss the study with you."

Merck further instructed its representatives to show those doctors who asked whether [Vioxx] caused myocardial infarction a pamphlet called "The Cardiovascular Card."... 

The Cardiovascular Card provided a misleading picture of the evidence on [Vioxx]. The card did not include any data from the VIGOR study. Instead, it presented a pooled analysis of preapproval studies, in most of which low doses of [Vioxx] were used for a short time. None of these studies were designed to assess cardiovascular safety, and none included adjudication of cardiovascular events. In fact, FDA experts had publicly expressed "serious concerns" to the agency's advisory committee about using the preapproval studies as evidence of the drug's cardiovascular safety.

In this NEJM article, Congressman Waxman provides additional examples of how, as regards Merck and Vioxx during the period 2001 to 2004, there was generally "a broad disparity between the evidence-based perspective provided by scientific journals and expert committees, on the one hand, and the sales pitch used by the company's field staff, on the other."

All of the Merck documents discussed by Congressman Waxman in his June 2005 NEJM article, and many other compelling documents, are available on this web site:

http://democrats.reform.house.gov/story.asp?ID=848

This NEJM article concludes by encouraging doctors, medical journal editors, and leaders of medical professional associations to review the various drug company documents obtained by the Government Reform Committee.  In giving this encouragement, Congressman Henry Waxman seemingly believes that doctors targeted by the drug company sales representatives must "develop new strategies to keep promotional efforts from distorting clinical care."

This, hopefully, will be the real lesson of Vioxx.

(Posted by: Tom Lamb)

Possible Vioxx "Smoking-gun" Document Provides Basis for June 2005 AP Report

Internal Document: Merck Reportedly Considered Changing Vioxx Drug Formulation in 2000

On June 23, 2005 Theresa Agovino and The Associated Press (AP) reported that in 2000 Merck & Co.'s researchers considered reformulating Vioxx in an attempt to reduce the cardiovascular side effects which ultimately led to the September 2004 Vioxx recall.  The internal company discussions at Merck about changing the Vioxx formula came during the time when the drug company was engaged in a public relations campaign aimed at discounting a March 2000 study that pointed out Vioxx's potential heart attack risk.

The March 2000 Vioxx Gastrointestinal Outcomes Research, or VIGOR, study revealed that patients taking Vioxx were five times more likely to have heart attacks than individuals using the generic medicine naproxen. Following the release of the VIGOR study, Merck contended repeatedly that the study's finding about increased rate of heart attacks was a result of naproxen's cardioprotective properties and was not the result of Vioxx use.

Now, it appears, at the same time as making its "naproxen-not-Vioxx" contentions, Merck had its researchers considering how Vioxx could be reformulated such that the active chemical in Vioxx, rofecoxib, would be combined with a thromboxane inhibitor.  The apparent purpose of adding another agent to Vioxx was an attempt to reduce the risk of heart attacks and strokes in patients using Vioxx, such as the participants in the VIGOR study.

This June 2005 AP article is based on an internal Merck document that was inadvertently produced to plaintiffs' lawyers in the discovery process in one of the hundreds of filed Vioxx lawsuits.  In the AP article, itself, it was reported that a copy of this internal Merck document was provided to The Associated Press on the condition that its source not be identified.  Theresa Agovino, the AP reporter, summarized parts of this so-called "smoking-gun" Merck document in her article:

According to the document, Edward Scolnick, the former head of Merck's research labs, was the first to suggest combining Vioxx with an agent that would block blood platelets from clotting. Such clots can lead to heart attacks and strokes. There are three dates on the document; the first is March 30, 2000.

The document's authors said Vioxx might reduce the production of a substance called prostacyclin, which prevents platelet aggregation. That reduction may alter the ratio of prostacyclin to thromboxane, a substance which can constrict blood vessels and cause clotting. The change may cause increased risk of cardiac and cerebral adverse events, the document said.

The internal Merck document recently became an issue in a New Jersey Vioxx lawsuit when Merck objected to the document's use as evidence in any Vioxx case.  The basis for the legal objection by Merck's lawyers is that the subject document was an attorney-client communication between Merck's researcher and the drug company's in-house patent counsel.  On May 27, 2005 New Jersey Superior Court Judge Carol E. Higbee ruled in favor of Merck as regards this objection, holding that the Merck internal document was privileged and could not be used at trial. 

Thousand of wrongful death claims and personal injury lawsuits have been filed against Merck based on the legal theory that the drug company hid Vioxx's serious side effect risks.  Currently, the first Vioxx trial is scheduled to start July 11, 2005 in a Brazoria County, Texas state court.  The second Vioxx case set for trial is one that will be heard in an Atlantic County, New Jersey state court; the scheduled trial date for the New Jersey Vioxx case is August 1, 2005.

Read more about events leading up to the Vioxx recall:

• http://www.druginjurylaw.com/Vioxx-milestones.html

(Posted by: Tom Lamb)

Drug Watch: FDA's New Early-warning System Web Site

Emerging Side-effect Risk Alerts to be Posted by FDA Online

In May 2005 the FDA announced the establishment of a new web site, called Drug Watch, which will serve as the FDA's new online early-warning system for serious side effects arguably linked to FDA-approved prescription drugs.

The Drug Watch web site is a key part of the FDA's effort to increase public awareness of health risks from prescription drugs, in response to the groundswell of criticism -- which began in the fall of 2004, following the Vioxx recall -- over the agency's apparent poor performance in fulfilling its drug safety monitoring role. 

A main function of the Drug Watch site will be the listing of prescription drugs which FDA reviewers think show emerging serious side effect risks that should be emphasized for the purpose of alerting doctors and patients, alike.

According to John K. Jenkins, director of the FDA's Office of New Drugs, the drug companies probably will not be allowed to edit or challenge the Drug Watch safety information in advance of news about serious side effect associated with their respective prescription drugs being posted on this new early-warning system web site sponsored by the FDA. "We don't expect they will have an opportunity to review the documents or provide comments before they're posted," Jenkins said. He clouded this issue a bit, however, when he went on to state that the drug companies will be notified in advance about a posting to be put on Drug Watch about one of their drugs, and the companies will be allowed to point out any factual errors in the FDA Drug Watch postings.

The all-important decision about which drug safety alerts to post on the Drug Watch web site will be made by members of the new FDA Drug Safety Oversight Board (DSOB).  Susan K. Cummins, the Oversight Board's executive director, said that the DSOB will help "set standards" on when to put new safety warnings about certain prescription drugs on the Drug Watch site.

Essentially, the Drug Watch site is intended to allow the posting of serious side effect  warnings that the FDA deems reliable but which, in fact, may go beyond the current version of a prescription drug's FDA-approved package insert label, or warning label.

Although it had been reported that, on a temporary basis, the Drug Watch alert system could be accessed by means of the FDA's web site -- www.fda.gov -- there is no apparent hyperlink for, nor any user information about, the Drug Watch site showing at present on the FDA homepage.

(Posted by: Tom Lamb)

Black-box Warning for Celebrex and Other NSAIDs

FDA Requires Warning Label Changes for Painkillers

In June 2005 the FDA advised Pfizer, the maker of Celebrex, and several other drug manufacturers that the package insert, or warning label, for their prescription NSAID painkillers must contain a so-called "black-box warning".  Specifically, the new black-box warnings are intended to alert doctors and patients about the association between these painkillers and the increased risks of heart attacks, ischemic strokes, and gastrointestinal bleeding.  Further, the black-box warnings must describe early symptoms of a serious skin reaction, Stevens-Johnson Syndrome, which has been linked to use of certain NSAID painkillers.

Prescription NSAIDs include Vioxx, which was voluntarily taken off the market by Merck in September 2004 because of the increased heart-attack (MI) and stroke (CVA) risks for Vioxx users .

The FDA initially indicated the need for stronger warning labels for prescription NSAIDs in April 2005 after Pfizer suspended sales of its Bextra painkiller.  The Bextra "recall" ordered by Pfizer was precipitated by a growing number of drug study reports which linked Bextra to cardiovascular side effects and serious skin reactions.  The skin disorders, which are relatively rare but potentially fatal, include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Erythema Multiforme (EM).

Beyond the prescription NSAIDs, the FDA said warning labels on over-the-counter (OTC) medications containing ingredients such as generic ibuprofen, ketoprofen, or naproxen must also inform patients about the increased risks of cardiovascular side effects, gastrointestinal (GI) bleeding, and serious skin reactions.

For all prescription drug and OTC products in this class, the FDA has said that the mark "NSAID" must be displayed prominently on the respective package insert label in a contrasting color or in bold type.

Read more about Bextra and its serious side effects:

• http://www.druginjurylaw.com/Bextra-information.html

Read more about Toxic Epidermal Necrolysis:

• http://www.drug-injury.com/druginjurycom/2005/06/toxic_epidemal_.html

(Posted by: Tom Lamb)

FDA's Drug Safety Oversight Board Holds First Meeting

No Specific Drug-safety Issues Discussed at Board's First Meeting

On June 17, 2005 the FDA's Drug Safety Oversight Board (DSOB) held its first meeting, the primary purpose of which was to allow the Board an opportunity to discuss fundamental organizational matters. No specific drug-safety issues were discussed at the Board's first meeting. The FDA said it will post a summary of this first Drug Safety Oversight Board meeting at its primary web site -- www.fda.gov -- in approximately one week, and will do likewise after each future DSOB meeting.

In connection with this first Drug Safety Oversight Board meeting, Dr. Steven Galson, Acting Director for the Center for Drug Evaluation and Research (CDER) made these comments:

The Drug Safety Board is a central component of FDA’s commitment to communicating in a transparent manner emerging and important drug safety information to health care practitioners and the public.  I believe today’s meeting set the stage that will allow the board to conduct timely and comprehensive evaluations of emerging drug safety concerns and assist FDA in ensuring that safe and effective drugs are available for patients. I look forward to working with this Board, comprised of some of the nation’s most experienced drug safety experts, as they come together in this important task.

As background, the FDA announced the identity of Drug Safety Oversight Board members in a May 18, 2005 press release.  Essentially, the Board is comprised of scientists who have been appointed to serve by the FDA's Acting Commissioner from offices throughout the FDA as well as from other federal agencies. The board includes 15 voting members who will meet on a regular basis.  A list of the Board members can be viewed by use of this link:

• www.fda.gov/cder/drug/DrugSafety/DSOBMembers.pdf

On May 4, 2005 the FDA published its internal policy for the Drug Safety Oversight Board -- called the MAPP (manual of policies and procedures).  The MAPP for the Drug Safety Oversight Board is available on the FDA's CDER Web site:

• www.fda.gov/cder/drugSafety.htm

(Posted by: Tom Lamb)

Antipsychotic Risperdal Associated with Benign Tumors in Pituitary Gland

Another Possible Side Effect for Atypical Antipsychotic Class of Drugs

On June 17, 2005 The Wall Street Journal reported that Risperdal, one of the so-called atypical antipsychotic drugs, has been associated with benign tumors in the pituitary gland.  FDA researchers reviewing the MedWatch database of adverse drug reactions found a higher incidence of benign tumors in the pituitary gland among patients taking Johnson & Johnson's antipsychotic Risperdal than for similar drugs.

It is important to keep in mind that this finding is preliminary, and the observed association between Risperdal and the pituitary tumors does not prove whether these tumors were caused by the use of Risperdal or other factors.  Moreover, "Patients should not stop taking their medications before talking to their doctor about all the risks and benefits," said P. Murali Doraiswamy, a psychiatrist at Duke University and co-author on the study.

The atypical antipsychotics are used primarily to treat schizophrenia and bipolar disorder.  Risperdal is one of the most widely prescribed antipsychotics, and it was Johnson & Johnson's second-biggest-selling drug last year, with world-wide sales of $3.1 billion.  A Johnson & Johnson spokesman said the drug company would be analyzing the FDA researchers' study to determine if further study is warranted.

Risperdal competes for market share with several other major drugs in the so-called atypical antipsychotic class, including Eli Lilly & Co.'s Zyprexa, AstraZeneca PLC's Seroquel, and Bristol-Myers Squibb Co.'s Abilify.  Side-effect issues have a big impact on sales in the highly competitive atypical antipsychotic class.  For example, Zyprexa's market share has slipped six percentage points over the past year over concerns about weight gain and diabetes.  Notably, the FDA in 2003 required all the atypical antipsychotic drugs to carry warnings about weight gain and diabetes.

The FDA researchers' study has not been published, yet.  It was presented June 18, 2005 at a University of Pittsburgh conference. The Wall Street Journal published on June 17, however, the following information about the methodology and findings of this FDA researchers' study:

The researchers analyzed 2.5 million adverse events reported by doctors, patients, and individuals since 1968. Of the 307 reports of pituitary tumors, 64, or 21%, occurred in patients taking antipsychotics. Forty-eight reports of pituitary tumors were reported in patients taking Risperdal, six in patients taking Zyprexa, four associated with Pfizer Inc.'s Geodon, and one with Seroquel. Novartis AG's Clozaril, which is also available as a generic clozapine, had three reports, while haloperidol, an older generic antipsychotic, had eight reports. Abilify had zero cases, but hasn't been on the market for as long as the other drugs.

Significantly, Ana Szarfman, a FDA medical officer and lead author of the study, said this kind of study cannot reveal how common the pituitary tumor side effect may be for users of Risperdal and the other atypical antipsychotics because, unfortunately, it is well-known that doctors do not report all suspected adverse drug reactions to the FDA's MedWatch program.

(Posted by: Tom Lamb)

Toxic Epidermal Necrolysis (TEN) is Usually Due to Adverse Drug Reaction

Patients with Toxic Epidermal Necrolysis (TEN) Often Have Fatal Outcome

Toxic epidermal necrolysis (TEN) is an infrequent, yet often fatal, severe systemic and cutaneous disease that is most often the result of an adverse drug reaction.

Toxic epidermal necrolysis (TEN) progresses rapidly and is characterized by severe shedding of the skin and mucous membranes.  This serious skin reaction may involve complete detachment of the skin, and usually affects more than 30% and up to 100% of the body surface. The fatality rate for patients with TEN is 25-75%.

Patients with TEN may suffer one or more of the following complications:

• kidney impairment,
• severe infection,
• difficulty breathing that requires ventilation,
• gastrointestinal bleeding,
• inflammation of the pancreas, and
• inflammation of the cornea or mucus membranes around the eye.

In addition, patients with toxic epidermal necrolysis (TEN) may experience scarring, changes in skin pigmentation, other eye diseases, changes in brain matter, and abnormal nail growth.

Several treatment options have been proposed, with contradictory results. Currently, the best results have been obtained with intravenous drugs known as immunoglobulins.  Some practitioners believe that a short course of corticosteroid therapy is the best treatment, if started early enough.

(Posted by: Tom Lamb)