Drug Injury Watch

David Graham Speaks at May 2005 Event About Need for Change at FDA

FDA was "the single greatest obstacle" as to Vioxx Withdrawal

David Graham says the FDA, itself, was the "single greatest obstacle to doing anything effective" about getting the unsafe prescription drug Vioxx withdrawn from the U.S. market.  Graham, a relatively high-profile FDA official, made his comments in Washington, D.C. on May 15th 2005 to a roundtable event sponsored by the Public Library of Science (PLoS) and the Government Accountability Project.

In his comments, Graham reiterated some of his now infamous testimony to the U.S. Senate Finance Committee, to the effect that the number of people who "probably died from" as a result of Vioxx use -- 60,000 in his estimation -- equals the number of soldiers killed in the Vietnam war. 

Graham's ultimate position is that the FDA had the opportunity and the responsibility to act sooner on Vioxx, but the agency waited until Merck, Inc., the product manufacturer, voluntarily withdrew Vioxx from the U.S. market in September 2004.

"The pharma-FDA complex has to be dismantled," Graham said at the May 2005 roundtable event, "and the American people have to insist on that, otherwise we're going to have disasters like Vioxx that happen in the future."

(Posted by: Tom Lamb)

Natrecor Given Regularly to Outpatients is Focus of Current Safety Controversy

In May 2005 Scios Sent a Natrecor "Dear Doctor" Letter to Heart Doctors

Natrecor is a prescription drug approved by the FDA as a therapy for hospitalized patients or those rushed to emergency rooms in acute heart failure.  The FDA approved Natrecor, also known as nesiritide, in 2001.  Natrecor is at the center of some current controversy, however, because the Natrecor increasingly is being given to outpatients; it is these "off-label" Natrecor treatments that critics say may be dangerous to patients.

The doctors who are critics generally say Natrecor should be used with caution; significantly, they are not calling for the withdrawal of Natrecor from the market. First, the doctors point out that Natrecor can cause serious side effects in hospitalized patients.  Second, and perhaps more the reason for concern, it may prove that Natrecor side effects are even more problematic in patients who are receiving the cardiac drug on a regular, repeated schedule as an outpatient. Notably, Natrecor was not approved by the FDA to be administered to outpatients multiple times per week.

Dr. Jonathan Sackner-Bernstein, director of clinical research at North Shore University Hospital in Manhasset, and chief investigator of two key studies on the Natrecor side effect problems, has recently maintained that Natrecor is a drug that should be used "as a last resort", and not repeatedly.

Natrecor's maker, Scios Inc., a division of Johnson & Johnson, say Natrecor is a drug that is safe and effective when used according to its label. In the first part of May 2005,  Scios sent a Natrecor "Dear Doctor" letter to health heart specialists nationwide, underlining mortality risks which have been associated with Natrecor use.

As for Natrecor's increasing regular, repeated use in outpatient clinics, Johnson & Johnson said the Natrecor package label insert does not say that Natrecor should not be administered on a repeated, outpatient basis.  Moreover, Johnson & Johnson has asserted that it cannot control how doctors prescribe Natrecor to their patients.  The FDA takes the position that doctors are free to prescribe any approved medication "off-label."

• Read more about drug-safety issues regarding Natrecor

http://www.drug-injury.com/druginjurycom/2005/05/may_19_fda_anno.html

(Posted by: Tom Lamb)

Viagra, Other ED Drugs Possibly Linked With Vision Loss and Blindness

FDA To Consider Warning Label Changes for Viagra, Cialis, and Levitra

The FDA is investigating numerous reports of a possible serious side effect from the use of Viagra and other impotence, or erectile dysfunction (ED), drugs.  The primary adverse reaction at issue is nonarteritic ischemic optic neuropathy (NAION), described as "stroke of the eye," in men who used Viagra and other impotence, or erectile dysfunction (ED), drugs.  NAION occurs when blood flow is cut off to the optic nerve, which injures the nerve, causes sudden vision loss, and results in varying degrees of permanent vision loss, including blindness.  An FDA spokesman said that the FDA has 43 reports of NAION among the impotence drug users: 38 for Viagra; four for Cialis; and, one for Levitra.

Complicating the FDA's investigation of these various side effect reports is the fact that NAION is considered one of the most common causes of sudden vision loss in older Americans; it is estimated that there are anywhere from 1,000 to 6,000 new NAION cases a year. Moreover, the risk factors for developing NAION include diabetes and heart disease, which are two of the leading causes of impotence.  Thus the issue becomes whether a man's development of NAION is the result of using the ED drug or due to the underlying medical condition which caused his impotence.

The FDA said on May 27, 2005 that the agency was in discussions with the makers of Viagra, Cialis, and Levitra about what the package insert labels of those ED drugs should say about the rare cases of NAION.  The package insert label for Cialis already has a one-line mention of this vision-loss side effect.  The labels for all three ED drugs currently warn about temporary vision changes -- such as seeing bluish tinges, or having difficulty distinguishing between green and blue.  That warning language, however, has to do with these impotence drugs having a temporary effect on the retina, which is a different medical condition, and not NAION.

The possibility of a link between Viagra and blindness was raised earlier in 2005 by Howard Pomeranz, M.D., associate professor of ophthalmology at the University of Minnesota Medical School.  Dr. Pomeranz reported in the March 2005 issue of the Journal of Neuro-ophthalmology, the cases of seven men, aged between 50 and 69 years, who developed typical features of NAION within 36 hours after their ingestion of Viagra for erectile dysfunction.  Dr. Pomeranz wrote in his article that seven other NAION cases involving Viagra had been previously reported.  The onset of NAION within hours after ingestion of Viagra in 14 patients supports an association between the use of the drug and NAION.  Dr. Pomeranz cautioned, however, "A definite causal relationship cannot be established at this time."

(Posted by: Tom Lamb)

Health Canada Announces Its Adverse Drug Reaction Database is Now Searchable by Public Online

FDA Should Follow Health Canada's Lead and Permit Direct Access to MedWatch Adverse Reaction Reports

Health Canada has announced it is now allowing direct access to the latest reported adverse reactions to prescription drugs and other health products contained in Health Canada's Canadian Adverse Drug Reaction Information System (CADRIS) by means of a new, searchable online database.

The new database can be searched by using one or more of the following criteria: the name of the drug or the drug's active ingredient; the date an adverse reaction report was received by Health Canada; subject patient age and/or gender; and, the medical outcome of the reported adverse drug reaction.

As background, the information source for the new Health Canada database is derived from Health Canada's Adverse Reaction Monitoring Program.  Suspected adverse drug reaction reports which the agency has received from consumers, health care professionals and product manufacturers are entered into the CARDIS database.  With the new, searchable online database which Health Canada announced on May 26, 2005, the public -- patients, advocacy groups, medical professionals, researchers, and pharmaceutical companies -- will now have direct access to the CARDIS adverse reaction reports.

Before the launch of Health Canada's new online database, adverse drug reaction reports from CADRIS were available to the public only by a request submitted to the agency, with responsive information being produced to the requesting party no sooner than two weeks, and often longer.

The adverse drug reactions contained in this new, searchable database will be updated by Health Canada on a quarterly basis. This database can be viewed using this link:

http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/cadrmp-pcseim/index_e.html

During our experimentation with this new Health Canada database, we found that there are still a few bugs and quirks that need to be resolved.  For example, on sporadic occasions the Health Product Name Lookup pop-up box had problems displaying the list of alphabetized drug names by which you can initiate a query.  Regardless of these minor (and, presumably, temporary) flaws, this step by Health Canada to bring an increased degree of transparency to drug-safety monitoring is commendable. 

Hopefully, the FDA will take note of this development in Canada and move toward establishing a similar web site allowing direct and immediate access to adverse drug reaction reports made to the MedWatch program, here.

(Posted by: Tom Lamb)

FDA Drug-safety Oversight Efforts Must Improve to Avoid Another Vioxx Debacle

Dr. Garret FitzGerald's Speech in May 2005 at Edinburgh, Scotland

Dr. Garret FitzGerald, a highly regarded medical doctor at the University of Pennsylvania, told a conference in Edinburgh, Scotland that the problems surrounding the Vioxx recall in the U.S. could happen, again, with a different unsafe drug unless the FDA makes some fundamental changes.  He blamed the Vioxx problems on the FDA's failure to act in a timely manner on emerging evidence of serious side effects risk for prescription drugs with safety issues, such as Vioxx, and suggested that there was an "absence of science" in parts of the FDA.  Dr. FitzGerald said that a much more sophisticated approach by the FDA as regards its drug safety oversight role is necessary in order to avoid a repeat of the Vioxx debacle.  Dr. FitzGerald is one of the doctors who first raised concerns about the serious cardiovascular side effects that have been linked with Vioxx. 

In more detail, Dr. FitzGerald told a medical conference convened by the Royal College of Physicians of Edinburgh in mid-May 2005 that his University of Pennsylvania research team was reporting plausible medical evidence of a Vioxx-related cardiovascular risk as early as 1998 -- a year before Vioxx was first approved by the FDA.  Instead of acting on the concerns and conducting further studies, Dr. FitzGerald said that Merck Inc., the manufacturer of Vioxx, sought to dismiss his team's research findings.  Ultimately, Vioxx was withdrawn by Merck in September 2004 when the company acknowledged that the drug carried "serious cardiovascular risks".

During his speech in Scotland, Dr. FitzGerald called for more rigorous studies to be conducted by pharmaceutical companies like Merck which would integrate the findings of biochemical, pharmocological, and epidemiologcal research so as to produce a more complete safety profile of new prescription drugs seeking approval by the FDA.

Dr. FitzGerald told the Edinburgh audience that he is hopeful that systemic improvements will be made at the FDA insofar that drug safety issues are now being given more priority at the federal agency since the Vioxx recall.

• Read more about the Vioxx recall and the FDA

http://www.drug-injury.com/druginjurycom/2005/05/us_panel_wants_.html

(Posted by: Tom Lamb)

Crestor Side Effects: Reports to FDA MedWatch Analyzed by Tufts Doctors

Crestor-Rhabdomyolysis Link: New Study May Support Allegations by Public Citizen Group

Rhabdomyolysis, proteinuria, nephropathy, and kidney or renal failure are serious side effects which apparently occur more often with the use of Crestor (rosuvastatin) than with other leading cholesterol drugs known as statins.  Moreover, when serious side effects did occur, they tended to be within the first three months of Crestor use and not necessarily associated with higher dosages of Crestor. This analysis comes from a new study done by researchers affiliated with Tufts University School of Medicine and the Tufts-New England Medical Center.  The new analysis supports the mounting concern about the relative safety of Crestor at the range of dosage levels commonly prescribed to patients in the U.S. Intererstingly, this analysis seems to challenge a recent U.S. Food and Drug Administration decision related to the Crestor's safety, and certainly runs contrary to recent safety claims by AstraZeneca, the manufacturer of Crestor.

In March 2005, the FDA had contended Crestor's side effect risks were no greater than the other statins available for use in the U.S., and it rejected consumer efforts to have Crestor pulled from the market. Instead, the FDA ordered AstraZeneca to put a stronger warning on the Crestor label, which now states that Crestor could cause serious muscle problems and kidney damage, especially among Asians.

The lead researcher for this new study is Richard Karas, director of the preventive cardiology at Tufts-New England Medical Center in Boston.  The Tufts study was published May 24, 2005 on an expedited basis by the American Heart Association's journal Circulation by making it available online before the print version was available.  An abstract of this new Crestor study can be viewed by use of this link:

http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.105.555482v1?&searchid=1116892479272_18705&usestrictdates=yes&journalcode=circulationaha&ct

For this Crestor study, the Tufts researchers analyzed adverse event reports (AERs) regarding alleged Crestor serious side effects which had been sent to the FDA MedWatch program for the first year that Crestor was available for use in the U.S.  The primary analysis examined MedWatch reports concerning Crestor AERs of rhabdomyolysis, proteinuria, nephropaty, and renal or kidney failure.  Secondary analyses by the Tufts researchers examined ohter categories of Crestor AERs, including adverse events with serious outcomes, liver toxicity, and muscle toxicity such as myopathy without rhabdomyolysis.  In turn, this FDA data was compared to those MedWatch reports of serious side effects made by doctors and patients to the FDA during the same time period for three other statins: Lipitor (atorvastatin), Zocor (simvastatin), and Pravachol (pravastatin).  Comparison was also made to adverse events reported to the FDA for the first year of marketing of Baycol (cerivastatin), a statin which was recalled in August 2001 due to an unacceptable high-incidence rate of rhabdomyolysis among patients taking Baycol.

The year after Crestor came on the market in October 2003, more than 5 million prescriptions were filled for the drug.  An estimated 20 million Americans are believed to be taking drugs called statins, which researchers say are still the best drugs for lowering high cholesterol and reducing the risk of heart disease and stroke.

An expert and the study's authors agree there were practical, real-world limitations to the new Tufts study.  On one side, there is the possible underreporting of Crestor side effects. On the other side, some theorized that the removal of Baycol from the market likely heightened public awareness of safety concerns involving statins, resulting in an increased reporting rate.  This situation was summed up by Benjamin Ansell, co-director of the cholesterol treatment program at UCLA medical center in Los Angeles.  He acknowledged that is there a general tendency to underreport prescription drug side effects to the FDA; however, there is also a tendency to overreport when controversial prescription drug, like Crestor, has gotten a lot of media attention.

In the wake of this new Crestor safety report being published, the consumer advocacy group Public Citizen announced it would try, again, to get the drug off the market.  "This will be further reason to take the drug off the market," said Sidney M. Wolfe, M.D., director of the Health Research Group at Public Citizen.  A March 2005 letter by Public Citizen to the FDA regarding Public Citizen's allegation that Crestor has higher rates of rhabdomyolysis compared to other statins can be viewed here:

http://www.citizen.org/publications/release.cfm?ID=7370

• Read more about the Crestor safety controversy

http://www.drug-injury.com/druginjurycom/2005/05/crestor_safety_.html

http://www.druginjurylaw.com/Crestor-information.html

(Posted by: Tom Lamb)

SSRI Drugs Can Increase Risk of Gastrointestinal Bleeding

Increased Risk of Acute Gastrointestinal Bleeding When Taking Both SSRIs and NSAIDs

Long-term use of selective serotonin re-uptake inhibitors, or SSRIs, increases the risk of gastrointestinal bleeding to a degree similar to that caused by regular use of non-steroidal anti-inflammatory drugs (NSAIDs).  These findings, which come from a new Northwestern University Medical School report, were first presented on May 16, 2005 during Digestive Diseases Week meetings. 

In more detail, the report was based upon a study involving 549 patients who had been admitted to various hospitals for acute gastrointestinal bleeding.  Researchers affiliated with Northwestern's Medical School reviewed the medical records for these patients to determine which prescription drugs were used in the time period leading up to the subject admission.  The underlying study was sponsored by TAP Pharmaceuticals Products, Inc., a U.S. joint venture of Japan's Takeda Pharmaceutical Co. Ltd. and Abbott Laboratories Inc.  As a matter of disclosure, it should be pointed out that TAP Pharmaceuticals is the company which makes Prevacid, a heartburn drug.

Eli Lilly and Co., which makes Prozac -- one brand name drug in the SSRI category -- has commented on the report and its findings.  In relevant part, Eli Lilly said that Prozac users are already being cautioned about the possibility of acute gastrointestinal bleeding insofar that such bleeding is currently listed as a potential side effect of Prozac use.  Notably, the Northwestern Medical School report presented in May 2005 did not name any specific brand names of the several drugs in the SSRI category.

Dr. Michael Jones, the Northwestern report's chief author, provided some observations following its presentation at the Digestive Diseases Week meetings.  "While more research needs to be conducted ... physicians must closely monitor for this serious adverse event, especially in patients who are taking both SSRIs and NSAIDs", Dr. Jones said.  More generally, he added: "This is a potent example of the need for doctors to be particularly conscious about potential side effects when prescribing multiple medications for their patients."

(Posted by: Tom Lamb)

FDA Advisory Panel Wants To Review Agency's Drug-safety Monitoring Efforts

Concern Over FDA's Handling of Serious Side Effects Issues, Including Recent Drug Recalls Involving Vioxx and Bextra

Members of an FDA advisory panel have voted unanimously in favor of having the federal agency provide this panel of outside consultants with detailed information about actions leading up to the recalls of Merck & Co. Inc.'s Vioxx and Pfizer Inc.'s Bextra painkillers.  This action came on May 19, 2005 during the second day of a two-day meeting convened by the FDA so that the outside consultants could help identify areas for improvement as regards how the agency has handled drug recalls and serious safety issues in the recent past.

In more detail, the purpose of last week's two-day meeting of outside consultants was to advise the FDA on how it could improve its work in the drug safety realm.  Significantly, however, this panel of outside experts is only in a position to provide non-binding recommendations to the FDA.

In comments regarding the advisory panel May 19 vote, Anne Trontell, deputy director of the FDA's Office of Drug Safety, said that the agency will consider the panel's suggestion.  Ms. Trontell stressed, however, that FDA officials were already looking at ways to improve its drug-safety oversight efforts; "It's already an area of active interest," she said.  For example, Ms. Trontell pointed out, the FDA has asked the Institute of Medicine to review its post-approval reviews of drug safety.

At least one of the panelists, Dr. Curt Furberg, an epidemiologist at Wake Forest University, expressed some doubt after the May 19 vote about whether the FDA would acquiesce to the advisory panel's request for detailed information concerning the agency's action, and inaction, as it relates to the Vioxx and Bextra recalls as well as other drug-safety issues.

As has been widely reported, the FDA's drug-safety monitoring work has come under intense scrutiny from all quarters following the Bextra recall in April 2005 and the Vioxx recall in September 2004.

• Read more about the FDA advisory panel meeting

http://www.drug-injury.com/druginjurycom/2005/05/fdas_adverse_ev.html

(Posted by: Tom Lamb)

Natrecor "Dear Doctor" Letter Seeks to Address Recent Safety Concerns

Letter Includes New Natrecor Label Revised in April 2005

Natrecor is a treatment, administered by injection, for patients with acutely decompensated congestive heart failure (ADHF) with dyspnea.  Recent reports in medical journals have raised drug-safety concerns about Natrecor, in particular whether Natrecor might have serious side effects involving kidney function which could result in patient death.

On May 19, 2005 the FDA posted on its web site for MedWatch -- The FDA Safety Information and Adverse Event Reporting Program -- this announcement about Natrecor:

Scios and FDA notified healthcare professionals of revisions to the ADVERSE REACTIONS/Effect on Mortality section of the prescribing information for Natrecor [nesiritide], indicated for patients with acutely decompensated congestive heart failure. The Dear Healthcare Professional letter also provided information from Scios on several published reports that raise the question of whether the product may have adverse effects on survival and kidney function compared to control agents (generally nitroglycerin and diuretics).

The Dear Healthcare Professional letter -- also known informally in the medical community as a "Dear Doctor" letter -- is seemingly intended to accomplish the following objectives:

1. Point out the new information  which Scios has added to the Prescribing Information, or package insert label, for Natrecor;
2. Address the meta-analyses published in the April 20, 2005 issue of The Journal of the American Medical Association (JAMA) and in the March 29, 2005 issue of Circulation; and,
3. Announce that Scios has requested that an independent panel of experts, led by a distinguished cardiologist, Eugene Braunwald (affiliated with Harvard Medical School as well as the Brigham and Women's Hospital in Boston), review all available studies for Natrecor, with a focus of the drug's safety profile.

One can read the complete MedWatch 2005 Natrecor safety summary, which includes links to Scios' Dear Healthcare Professional letter and their revised Natrecor label.  In addition, one can read more about events leading up to this Natrecor Dear Doctor letter.

(Posted by: Tom Lamb)

Medication Errors in Hospitals Involve Pharmacy-dispensing Errors in Estimated 10-20% of Incidents

Drug Name Confusion is a Common Cause of Drug-related Errors

A medication error is generally defined as a deviation from the prescription drug order written by the prescribing physician on the patient's chart.  In the hospital setting, it is estimated that medication errors occur at a rate of about one per patient per day.

A sub-set of medication errors is pharmacy dispensing errors.  In the hospital setting, errors made by pharmacists or pharmacy staff in the cart-filling process is one example of a pharmacy mistake.

Medication errors in the hospital setting can be attributed to a failure to follow the basic techniques and guidelines of medication ordering, preparation, and administration.  Combined, these failures result in medication errors affecting 3% to 6.9% of hospital inpatients, according to some controlled studies of medication errors in hospitals.  Moreover, one such study determined that 11% of medication errors in hospitals are pharmacy-dispensing errors in which the wrong drug or incorrect strength is dispensed by the hospital pharmacist.  A different report on hospital medication errors from 1999 found that 17% of medication errors in a hospital setting were due to dispensing errors by the hospital pharmacy.

Drug name confusion is among the most common causes of drug-related errors.  One example of sound-alike drug names involves Lamictal, the antiepileptic drug, and Lamisil, the antifungal drug.  The volume of dispensing errors involving these two drugs caused the manufacturer of Lamictal, Glaxo Wellcome Inc. (as it was known at the time), to launch a campaign warning pharmacists of the potential confusion.  Staying with this example, the possible consequences of dispensing the wrong drug can be grave.  Epileptic patients receiving the antifungal drug Lamisil by mistake could experience continuous seizures.  Patients erroneously receiving the antiepileptic drug Lamictal might experience a serious skin rash, blood pressure changes, or other unwanted side effects.

(Posted by: Tom Lamb)