Drug Injury Watch

FDA Updates Exjade Adverse Drug Reaction Numbers In Its First Drug-Safety Newsletter

FDA Post-Marketing Safety Review Adds Liver Problems To Previous Reports Of Kidney Failure Associated With Exjade

(Posted by Tom Lamb at DrugInjuryWatch.com)

In the first edition of FDA Drug Safety Newsletter (Volume 1, Number 1), which was posted on the FDA's web site September 18, 2007, there is an article about the agency's post-marketing safety review of Exjade (deferasirox).  This medication is an orally active chelating agent that removes excess iron in patients undergoing regular blood transfusions. Marketed in the U.S. by Novartis AG (NVS), Exjade was approved by the FDA for sale in 1995.

Adverse drug reaction reports associated with Exjade were the subject of a May 22, 2007 article in The Wall Street Journal, "FDA Warns Novartis's Exjade Could Cause Kidney Failure", which included this information:

In a May 14 letter to health-care professionals posted Tuesday to the FDA's Web site, Novartis said it received reports of kidney failure, some with a fatal outcome, in postmarketing reports of Exjade....

In a statement, Novartis said there were eight deaths associated with acute renal, or kidney, failure. More than 13,000 patients have been treated with Exjade since the drug was approved in November 2005.

In mid-September 2007 the FDA updated us on the Exjade safety situation, stating in the FDA Drug Safety Newsletter that the agency had received 115 reports of suspected adverse drug reactions (ADR) in association with Exjade use, including 17 deaths in adults.

In more detail, the FDA provided this additional information about the Exjade ADR reports it received from November 2005 through June 20, 2006:

• 108 of the reported Exjade cases were considered serious, with 74 events requiring hospitalization;
• 24 of the Exjade reports involved liver problems and included three reports of liver failure; those patients, however, apparently had a history of liver problems;
• 16 reports concerning Exjade use were associated with kidney problems; and,
• 15 reports to the FDA were associated with Exjade causing various blood disorders.

In closing-out its September 2007 Exjade update article, the FDA said that additional studies are being conducted in order for the agency and Novartis to "determine the longer-term benefits and risks of [Exjade (deferasirox)]."

Of course, we will continue to monitor and report on the safety profile of Exjade.

Sleep Disorder Narcolepsy Drug Provigil Associated With Serious Skin Reactions

FDA Links Cephalon's Provigil To Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, And Erythema Multiforme

(Posted by Tom Lamb at DrugInjuryWatch.com)

According to the Fall 2007 FDA Drug Safety Newsletter (Volume 1, Number 1), which was released in mid-September 2007, the FDA has been monitoring cases of serious skin reactions associated with the sleep disorder drug Provigil (modafinil). This medication, made by the drug company Cephalon, Inc., is prescribed to treat patients with excessive sleepiness (ES) associated with narcolepsy, obstructive sleep apnea / hypopnea syndrome (OSAHS), and shift work sleep disorder.

Based on postmarketing reviews of adverse event reports made to the FDA, the serious skin reactions associated with Provigil are toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and erythema multiforme (EM), as well as drug rash with eosinophilia and systemic symptoms (DRESS).

According to the Provigil article about serious skin reactions published in this first edition of the FDA Drug Safety Newsletter, which is reportedly aimed at healthcare professionals:

From the date of initial marketing, December 1998, to January 30, 2007, FDA received six cases of severe cutaneous adverse reactions associated with [Provigil]....

Although some cases were potentially confounded by drugs known to be associated with serious skin reactions, all cases had features that implicate modafinil. The cases described a temporal relationship with detailed clinical descriptions, relevant laboratory data, dermatologist-substantiated diagnoses, skin biopsy confirmation, positive dechallenges, and/or a positive rechallenge, all of which support an association between modafinil use and serious cutaneous skin reactions.

As a result of these adverse event reports associated with the use of Provigil, Cephalon has changed the package insert, or label, for Provigil to include a bolded warning for serious skin rashes, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug rash with eosinophilia and systemic symptoms (DRESS).

According to this same FDA Drug Safety Newsletter article, a similar bolded warning about serious skin reactions has been added to the package insert, or label, for Nuvigil (armodafinil) -- another drug by Cephalon which has a similar chemical structure to Provigil -- based on these adverse event reports regarding Provigil.

FDA To Finally Study Possible Increased Heart Risks Caused By Attention Deficit Medications

The Safety Profile Of Adderall, Concerta, Ritalin, Dexedrine And All Other ADHD / ADD Drugs Will Be Reviewed

(Posted by Tom Lamb at DrugInjuryWatch.com)

In a September 17, 2007 FDA News article titled "AHRQ and FDA to Collaborate in Largest Study Ever of Possible Heart Risks With ADHD Medications" we learned that the safety of Adderall, Concerta, Ritalin, and Dexedrine -- as well as all other attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD) drugs -- will finally be reviewed.

In more detail, the FDA will collaborate with the Agency for Healthcare Research and Quality (AHRQ) to examine clinical data regarding 500,000 children and adults who have used ADHD / ADD drugs in the past to determine these drugs cause an increased risk of heart attacks, strokes, or other serious cardiovascular problems.  The study is expected to take about two years to complete.

As stated in the September 17 FDA News item:

"Case reports have described adverse cardiovascular events in adult and pediatric patients with certain underlying risk factors who receive drug treatment for ADHD, but it is unknown whether or not these events are causally related to treatment," said Gerald Dal Pan, M.D., director of FDA's Office of Surveillance and Epidemiology. "The goal of this study is to develop better information on this question."

We get the impressions of Steven Nissen, a prominent cardiologist who has been involved previously with the ADHD / ADD safety debate about this new FDA study announcement from the September 17, 2007 post "Feds Studying Risks of ADHD Drugs" by Jacob Goldstein at The Wall Street Journal (WSJ) Health Blog:

... told the Health Blog that the study could be “potentially very helpful,” because it will look at seven years’ worth of data, while earlier studies have looked at shorter periods of time....

Nissen... pointed out both that ADD and ADHD drugs tend to raise blood pressure (which raises cardiovascular risks) and that 10% of those treated for the disorders are over 55 years old — an age group where the risk of heart attack and stroke tends to be higher to begin with.

“We really don’t know what the long-term impact of the drugs is going to be on cardiovascular health,” said Nissen, who is not involved in the federal project. “This would obviously be unique data and potentially very helpful because it’s long-term.”

In August 2006 the FDA approved label changes they had requested from the drug companies that make ADHD / ADD medications -- such as Novartis AG's Ritalin and Shire Plc's Adderall -- to add information about the emerging heart-related issues.  Later, in February 2007, the FDA asked those same drug companies to develop patient guides that explained the possible cardiovascular risks associated with ADHD / ADD drugs.

We will monitor and report the results of this seemingly long overdue ADHD / ADD drug safety study by the FDA and AHRQ.

Natrecor Is Associated With Increased Risk Of Acute Renal Failure And Death

Questions About Safety Of Natrecor Continue, With No Apparent Resolution Any Time Soon

(Posted by Tom Lamb at DrugInjuryWatch.com)

As reported previously, in June 2007 Scios, Inc. announced it had started enrolling patients in a 7,000-patient trial designed to "assess the long-term clinical outcomes and benefit/risk profile of Natrecor (nesiritide) in patients with acutely decompensated heart failure (ADHF)".  At the time, Scios did not mention when this Natrecor safety trial would be completed nor when its results would be available.

As background, the safety profile of Natrecor has been a matter of much debate since a prominent heart doctor, Dr. Jonathan Sackner-Bernstein, published two reports in 2005 warning that Natrecor use was possibly linked to significantly increased rates of kidney problems and death.

Over time, we have monitored developments regarding the safety of Natrecor, including these two reports among other:

Natrecor: Is Controversial J&J Heart Failure Drug Harmful Or Harmless?

Natrecor Safety Controversy Considered In Two May 2007 Medical Journal Articles

While we wait to learn the results of the large-scale Natrecor trial which started-up in June 2007 -- and finally find out whether or not Natrecor is associated with an increased risk of serious kidney problems which could be fatal -- we consider a couple more medical journal articles about the safety of Natrecor.

The first article, "Benefit-risk assessment of nesiritide in the treatment of acute decompensated heart failure", was published by Drug Safety in January 2007 but only recently came to our attention.  Based on research done by the Baylor Heart and Vascular Institute, Baylor University Medical Center, in Dallas, Texas, we get the following information from the Medline Abstract for this January 2007 Natrecor article:

The effect of nesiritide on all-cause mortality is currently unresolved. Recent meta-analyses of existing databases have raised concerns regarding adverse effects of the drug on 30-day mortality. However, reviews of large, observational, registry databases do not suggest an adverse inpatient mortality effect compared with other vasodilator therapies. Further resolution of the mortality question awaits completion of pending randomised controlled clinical trials.When used for approved indications and according to recommended dosage and administration regimens, nesiritide represents a reasonable treatment adjunct for ADHF.

A more recent article, published online on September 5, 2007, from Nephrology Dialysis Transplantation, is "Predictors of mortality in adult patients with congestive heart failure receiving nesiritide—Retrospective analysis showing a potential adverse interaction between neseritide [sic] and acute renal dysfunction".  Drawing from the Abstract for this the Abstract for this September 2007 Natrecor article:

• Univariate analysis revealed that Natrecor usage was associated with increased mortality
• However, Natrecor usage was not an independent predictor of mortality.
• When patients were stratified according to Natrecor usage, acute renal failure emerged as an independent risk factor for mortality only among patients who received Natrecor.
• Among congestive heart failure patients who developed acute renal failure, Natrecor usage emerged as the only independent predictor of mortality.

In turn, these findings led the authors to this Conclusion:

We conclude that, while [Natrecor] per se is not independently associated with an increased risk for mortality, the development of [acute renal failure] in association with [Natrecor] use may confer an increased risk of mortality.

We will continue to report on developments regarding this Natrecor drug-safety issue.

The Use Of Antibiotic Ketek Appears To Significantly Increase Risk Of Liver Damage And Injury

2007 Medical Journal Article Reports That Ketek May Cause A Greater Than 80% Increased Risk Of Hepatotoxicity

(Posted by Tom Lamb at DrugInjuryWatch.com)

In early September 2007 Health Canada issued a MedEffect alert about Ketek which was based upon their review of the available safety information, including reported cases of severe liver injury. In the end, Health Canada determined that the benefit-risk profile for Ketek no longer supported the use of this antibiotic for the treatment of acute exacerbation of chronic bronchitis, acute bacterial sinusitis, tonsillitis, or pharyngitis.

For more information about the extent of the liver injury risk associated with Ketek (telithromycin) we consider a medical article, "Telithromycin use and spontaneous reports of hepatotoxicity", that was published in the January 1, 2007 edition of the medical journal Drug Safety.  Therein the authors' primary aim was to quantify the effect of Ketek on serious liver injury, or hepatotoxicity.  Remarkably, they found that Ketek use may increase a person's risk of hepatotoxicity by more than 80%.

From the Medline Abstract for this 2007 Ketek article in Drug Safety we get these details:

We conducted a spontaneous-report case-control study of hepatotoxicity in telithromycin recipients using reports from the US FDA Adverse Event Reporting System. Reports from between 1 January 2005 and 30 June 2005 were examined. Cases included reports of patients with abnormal liver function tests, hepatocellular damage and hepatic impairment, while patients with reported conditions with similar reporting probabilities were considered as controls. The primary outcome measure of the analysis was the reporting odds ratio (ROR) evaluating the a priori hypothesis that telithromycin use confers an elevated risk of hepatotoxicity relative to other agents.... We estimated an ROR for hepatotoxicity associated with telithromycin compared with other agents of 1.82 (95% CI 1.12, 2.96) after controlling for age and gender, approximating an 82% excess risk in users of telithromycin relative to users of other agents.

With other, safe antibiotics being available in the U.S. -- and in view of the significantly increased risk of Ketek-induced liver damage demonstrated by this study -- one must wonder whether the FDA will eventually decide that there should be a Ketek recall.

Health Canada Issues Ketek MedEffect Alert In Early September 2007

Antibiotic Ketek Restricted To Certain Types Of Pneumonia; No Longer Used For Sinusitis, Bronchitis, Tonsillitis, Pharyngitis

(Posted by Tom Lamb at DrugInjuryWatch.com)

On September 5, 2007 Health Canada issued by email a MedEffect alert about Ketek which included this summary:

Sanofi-aventis Canada, Inc. is informing Canadians that the antibiotic Ketek (telithromycin), should no longer be used to treat sinusitis, bronchitis, tonsillitis or pharyngitis. Ketek can still be used to treat certain types of pneumonia.

More information about these restrictions imposed on Ketek in Canada are set forth in the accompanying "PUBLIC COMMUNICATION Health Canada Endorsed Important Safety Information on KETEK (telithromycin)" and the the so-called "Dear Doctor" letter sent to health care professionals by Sanofi-aventis Canada Inc. on August 30, 2007.

From this Canadian Ketek Dear Doctor letter we get this more in-depth information about this change in indications for Ketek in Canada:

Upon review of the available safety information, including reported cases of severe liver injury, Health Canada has determined that the benefit-risk profile for KETEK® no longer supports its use for the treatment of acute exacerbation of chronic bronchitis (AECB), acute bacterial sinusitis (ABS) or tonsillitis/pharyngitis. These indications will be removed from the label.

KETEK® continues to be indicated only for the treatment of community-acquired pneumonia (CAP) of mild to moderate severity due to Streptococcus pneumoniae, (including multi-drug resistant isolates [MDRSP]), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila (Chlamydia) pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, and Staphylococcus aureus for patients 18 years old and older.

In view of the following developments regarding Ketek in the U.S., however, this action by Health Canada and Sanofi-aventis Canada seems relatively late:

• In December 2006 an FDA advisory panel recommended the use of Ketek should be restricted to treatment of community-acquired pneumonia, only, and should no longer be used as treatment for acute bacterial exacerbation of chronic bronchitis nor acute bacterial sinusitis;
• In February 2007 we learned that the FDA was going to heed this recommendation by its advisory panel when the agency issued a bulletin entitled "FDA Announces Label and Indication Changes for the Antibiotic Ketek"; and,
• In March 2007 Sanofi-Aventis sent a "Dear Doctor" letter in the U.S regarding these prescribing and treatment changes that were being made for Ketek due to its association with severe liver injury.

Meanwhile, several product liability lawsuits regarding cases of serious liver injury allegedly caused by Ketek have been filed in various courts, here, during 2007.  We are not aware of any Ketek lawsuits filed in Canada but that is not to say that there are not any, there.

Current Evidence Of Associations Between Hormone-Replacement Therapy Drugs And Several Serious Side Effects

Drug Safety Update Publishes September 2007 Guide For Doctors To Assess HRT Risks And Benefits

(Posted by Tom Lamb at DrugInjuryWatch.com)

The second issue of Drug Safety Update, an electronic bulletin (PDF file) published by the UK's Medicines and Healthcare products Regulatory Agency (MHRA), was published on September 3, 2007. It includes some important side effects information for doctors who prescribe hormone-replacement therapy (HRT).

As described by Claire Tilstone, the Editor of Drug Safety Update: 

We have prepared digested guide of current evidence for the associations between HRT and coronary heart disease; stroke; venous thromboembolism; and cancers of the breast, endometrium, or ovary. We hope that this updated information, including
revised risk estimates, will help healthcare professionals assess the risks and
benefits associated with HRT for individual women.

Of course, this advisory article from Volume 1, Issue 2 of Drug Safety Update will also be of interest to some of the women who use HRT drugs as well as others who follow the developing safety profile of HRT drugs.