Assurance of Care Legal Nurse Consultants

September 12, 2008

FDA; Vytorin, Zetia & Zocor

Filed under: FDA WARNINGS, MEDICAL NEWS YOU CAN USE — aofcarec @ 12:31 pm
Ezetimibe/Simvastatin (marketed as Vytorin)
Simvastatin (marketed as Zocor)
Ezetimibe (marketed as Zetia)
Audience: Endocrinologists, cardiologists, other healthcare professionals, patients
[Posted 08/21/2008] FDA informed healthcare professionals that the Agency is investigating a report from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of a possible association between the use of Vytorin and a potentially increased incidence of cancer. Vytorin is a combination product of simvastatin and ezetimibe used to decrease the production of cholesterol by the liver and inhibit the absorption of cholesterol in the intestine to reduce LDL-cholesterol levels and reduce the risk of cardiovascular events. Recently, FDA obtained preliminary results from the SEAS trial. The clinical trial tested whether lowering LDL-cholesterol with Vytorin would reduce the risk of cardiovascular events in individuals with aortic stenosis. A lower overall cardiovascular risk was not found with Vytorin. However, there was an additional observation that a larger percentage of subjects treated with Vytorin were diagnosed with and died from all types of cancer combined when compared to placebo during the 5-year study.FDA anticipates receiving a final SEAS study report in about 3 months and the Agency’s review and evaluation of the clinical trial data and other relevant information should take approximately 6 months. FDA will communicate its conclusions and recommendations at that time. Healthcare professionals and caregivers should continue to monitor patients taking Vytorin and report side effects from the use of this drug to the Agency. 

[August 21, 2008 - Early Communication about an Ongoing Safety Review - FDA]

October 17, 2007

Title: Byetta (Exenatide) and Postmarketing Reports of Acute Pancreatitis

Filed under: FDA WARNINGS, MEDICAL NEWS YOU CAN USE — aofcarec @ 12:58 pm

 “Byetta (Exenatide) and Postmarketing Reports of Acute Pancreatitis”

BETHESDA, MD — October 16, 2007 — U.S. Food and Drug Administration (FDA) has reviewed 30 postmarketing reports of acute pancreatitis in patients taking Byetta (exenatide), a drug used to treat adults with type 2 diabetes. An association between Byetta and acute pancreatitis is suspected in some of these cases. Amylin Pharmaceuticals, Inc. has agreed to include information about acute pancreatitis in the “Precautions” section of the product label. Healthcare professionals should be alert to the signs and symptoms of acute pancreatitis and instruct patients taking Byetta to seek prompt medical care if they experience unexplained, persistent, severe abdominal pain which may or may not be accompanied by vomiting. If pancreatitis is suspected, Byetta should be discontinued. If pancreatitis is confirmed, Byetta should not be restarted unless an alternative etiology is identified. SOURCE: U.S. Food and Drug Administration

Deadly Bacteria Found to Be More Common

Filed under: MEDICAL NEWS YOU CAN USE, MRSA Bacteria — aofcarec @ 12:50 pm

 

Article Tools Sponsored By
By KEVIN SACK
Published: October 17, 2007
ATLANTA, Oct. 16 — Nearly 19,000 people died in the United States in 2005 after being infected with virulent drug-resistant bacteria that have spread rampantly through hospitals and nursing homes, according to the most thorough study of the disease’s prevalence ever conducted.  

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Ann Johansson for The New York Times

Dr. Elizabeth Bancroft called the findings “astounding.”

Related

Text of the Study (JAMA)

  

 Back Story With The Times’s Kevin Sack (mp3)  

The government study, which is being published Wednesday in The Journal of the American Medical Association, suggests that such infections may be twice as common as previously thought, according to its lead author, Dr. R. Monina Klevens.

If the mortality estimates are correct, the number of deaths associated with the germ, methicillin-resistant Staphylococcus aureus, or MRSA, would exceed those attributed to H.I.V.-AIDS, Parkinson’s disease, emphysema or homicide each year.

By extrapolating data collected in nine places, the researchers estimated that 94,360 patients developed an invasive infection from the pathogen in 2005 and that nearly one of every five, or 18,650 of them, died. The study points out that it is not always possible to determine whether a death is caused by MRSA or merely accelerated by it.

The authors, who work for the Centers for Disease Control and Prevention, cautioned that their methodology differed significantly from previous studies and that direct comparisons were therefore risky. But they said they were surprised by the prevalence of serious infections, which they calculated as 32 cases per 100,000 people.

In an accompanying editorial in the medical journal, Dr. Elizabeth A. Bancroft, an epidemiologist with the Los Angeles County Department of Public Health, characterized that finding as “astounding.”

The prevalence of invasive MRSA — when the bacteria has not merely colonized on the skin, but has attacked a normally sterile part of the body, like the organs — is greater, Dr. Bancroft wrote, than the combined rates for other conditions caused by invasive bacteria, including bloodstream infections, meningitis and flesh-eating disease.

The study also concluded that 85 percent of invasive MRSA infections are associated with health care treatment. Previous research had indicated that many hospitals and long-term care centers had become breeding grounds for MRSA because bacteria could be transported from patient to patient by doctors, nurses and unsterilized equipment.

“This confirms in a very rigorous way that this is a huge health problem,” said Dr. John A. Jernigan, the deputy chief of prevention and response in the division of healthcare quality promotion at the disease control agency. “And it drives home that what we do in health care will have a lot to do with how we control it.”

The findings are likely to stimulate further an already active debate about whether hospitals and other medical centers should test all patients for MRSA upon admission. Some hospitals have had notable success in reducing their infection rates by isolating infected patients and then taking extra precautions, like requiring workers to wear gloves and gowns for every contact.

But other research has suggested that such techniques may be excessive, and may have the unintended consequence of diminishing medical care for quarantined patients. The disease control agency, in guidelines released last year, recommended that hospitals try to reduce infection rates by first improving hygiene and resort to screening high-risk patients only if other methods fail.

Dr. Lance R. Peterson, an epidemiologist with Evanston Northwestern Healthcare, said his hospital system in the Chicago area reduced its rate of invasive MRSA infections by 60 percent after it began screening all patients in 2005.

“This study puts more onus on organizations that don’t do active surveillance to demonstrate that they’re reducing their MRSA infections,” Dr. Peterson said. “Other things can work, but nothing else has been demonstrated to have this kind of impact. MRSA is theoretically a totally preventable disease.”

Numerous studies have shown that busy hospital workers disregard basic standards of hand-washing more than half the time. This week, Consumers Union, the nonprofit publisher of Consumer Reports, called for hospitals to begin publishing their compliance rates for hand-washing.

Lisa A. McGiffert, manager of the “Stop Hospital Infections” campaign at Consumers Union, said, “This study just accentuates that the hospital is ground zero, that this is where dangerous infections are occurring that are killing people every day.”

MRSA, which was first isolated in the United States in 1968, causes 10 percent to 20 percent of all infections acquired in health care settings, according to the disease control agency. Resistant to a number of front-line antibiotics, it can cause infections of surgical sites, the urinary tract, the bloodstream and lungs. Treatment often involves the intravenous delivery of other drugs, causing health officials to worry that overuse will breed further resistance.

The bacteria can be brought unknowingly into hospitals and nursing homes by patients who show no symptoms, and can be transmitted by contact as casual as the brush of a doctor’s lab coat. Highly opportunistic, they can enter the bloodstream through incisions and wounds and then quickly overwhelm a weakened immune system.

On Monday, a Virginia teenager died after a weeklong hospitalization for an MRSA infection that spread quickly to his kidneys, liver, lungs and the muscle around his heart. Local officials promptly closed 21 schools for a thorough cleaning.

A major difference between the new study and its predecessors is that it compiled confirmed cases of MRSA infection, rather than relying on coded patient records that sometimes lack precision. The study found higher prevalence rates and death rates for the elderly, African-Americans and men. The figures also varied by geography, with Baltimore’s incidence rates far exceeding those of the eight other locations: Connecticut; Atlanta; San Francisco; Denver; Portland, Ore.; Monroe County, N.Y.; Davidson County, Tenn.; and Ramsey County, Minn.

Dr. Klevens said further research would be needed to understand the racial and geographic disparities.

July 30, 2007

States Handed Out Poisoned Toothpaste

Filed under: MEDICAL NEWS YOU CAN USE — aofcarec @ 7:02 am

  

  

Boxes of Tianqi toothpaste in China   

AP

Poisoned toothpaste from China was distributed more widely in the U.S. than originally reported.

(June 28) - After federal health officials discovered last month that tainted Chinese toothpaste had entered the United States, they warned that it would most likely be found in discount stores.   

In fact, the toothpaste has been distributed much more widely. Roughly 900,000 tubes containing a poison used in some antifreeze products have turned up in hospitals for the mentally ill, prisons, juvenile detention centers and even some hospitals serving the general population.

The toothpaste was handed out in dozens of state institutions, mostly in Georgia but also in North Carolina, according to state officials. Hospitals in South Carolina and Florida also reported receiving Chinese-made toothpaste, and a major national pharmaceutical distributor said it was recalling tainted Chinese toothpaste.

The Food and Drug Administration has advised consumers to discard all Chinese-made toothpaste, regardless of the brand.

State officials in Georgia and North Carolina said all the tainted tubes were being replaced with brands made outside China. The officials said there had been no reports of illnesses caused by the toothpaste.

Officials of the Food and Drug Administration said toothpaste with even small amounts of the bad ingredient, diethylene glycol, a syrupy poison, had a “low but meaningful risk of toxicity and injury” for children and people with kidney or liver disease.

“This stuff does not belong in toothpaste, period,” a spokesman for the drug agency, Doug Arbesfeld, said. “No Chinese toothpaste has come into the country since the end of May.”

Since the Panamanian government found Chinese toothpaste with diethylene glycol in May, countries from Latin America to West Africa to Japan have seized the toothpaste.

Panama last year inadvertently mixed the poison made in China into 260,000 bottles of cold medicine, killing at least 100 people, prosecutors there said.

Diethylene glycol is often used in Chinese toothpaste in place of its more expensive chemical cousin glycerin. Chinese regulators have said that toothpaste with small amounts of diethylene glycol is not harmful and that international concern is unjustified.

After the drug agency expressed concern about tainted toothpaste, the Georgia Department of Administrative Services checked to see whether Chinese toothpaste was being used by the state. The department found it in 83 prisons, 4 mental health centers and 4 juvenile detention centers, said Rick Beal, contracts manager for the department.

Mr. Beal said officials confiscated 5,877 remaining cases, each with 144 tubes, of the Springfresh brand. Tests showed the toothpaste had a diethylene glycol concentration of about 5 percent, he said.

The state bought the toothpaste for about 9 cents a tube in 2002. Mr. Beal said he did not know how many tubes had been used.

There are no reports of harm resulting from the toothpaste, bought from a distributor, American Amenities in Seattle.

“We do not know who their manufacturer from China was,” Mr. Beal said.

A lawyer for American Amenities, Jesse Lyon, said it had recalled all suspect shipments of the product and had decided to stop importing Chinese toothpaste. Mr. Lyon said he believed that American Amenities had about 30 institutional customers, with Georgia being the largest.

A spokesman for the North Carolina Department of Corrections, George Dudley, said his agency estimated that it bought 22,000 tubes of Pacific brand Chinese toothpaste with a small amount of diethylene glycol from Pacific Care Products in San Francisco.

Pacific Care did not respond to a request for comment, but an executive wrote to North Carolina officials that the toothpaste came from Amercare Products, also in Seattle. A spokeswoman for Amercare declined to comment.

Chinese toothpaste containing “trace amounts” of diethylene glycol has also been recalled from healthcare institutions by McKesson, a major pharmaceutical distributor and health services company, said a spokesman, James Larkin.

Mr. Larkin said although this particular brand, McKesson EverFRESH, was not on the drug agency’s list of contaminated toothpaste, McKesson asked a laboratory to test it. When small amounts of diethylene glycol turned up, the company recalled the product, he said.

“We went back through our records, and every customer that ever bought the product was contacted,” Mr. Larkin said.

He added that on short notice he could not determine how many customers had bought the product.

One institution that did was Florida Hospital Waterman, a 200-bed institution in Tavares, Fla.

“We pulled that product,” Bonnie Zimmerman of the hospital said.

Ms. Zimmerman said that the toothpaste that replaced it also came from China and it had “trace amounts” of diethylene glycol. It, too, was removed, she said.

In South Carolina, four hospitals in the Greenville Hospital System also removed Chinese toothpaste, even though its distributor said it did not have diethylene glycol, said John Mateka, executive director of materials management for the group.

Copyright © 2007 The New York Times Company
2007-06-28 09:16:44

 

Glaxo’s Avandia Should Be Pulled, U.S. Scientist Says

Filed under: MEDICAL NEWS YOU CAN USE — aofcarec @ 7:01 am

(Update2)
By Justin Blum and Michelle Fay Cortez

Enlarge Image 

GlaxoSmithKline’s Avandia pills on display

July 30 (Bloomberg) — GlaxoSmithKline Plc’s diabetes pill Avandia should be removed from the market because of heart risks, a U.S. drug safety scientist said.

There is “no evidence of major clinical health benefits'’ from Avandia and leaving it on the market may “cost thousands of lives,'’ according to slides for a presentation to be given today by David Graham, a Food and Drug Administration safety scientist. Graham is set to speak today to FDA advisers meeting in Gaithersburg, Maryland to review studies of the drug.

Graham’s presentation may raise the likelihood the panel will urge that the drug be removed from the market, or receive a heightened warning. Glaxo’s shares fell 6 pence to 1,219 pence in London, and the company’s American depositary receipts dropped 8 cents to $49.55 at 9:31 a.m. in New York Stock Exchange composite trading. One depositary receipt equals two ordinary shares.

Graham’s slides, released by the FDA before the panel meeting began, question Avandia’s health benefits compared with other treatments. Graham’s recommendation doesn’t represent the FDA’s position and he has disagreed with his superiors in the past. He gained notoriety after calling for Merck & Co.’s painkiller Vioxx to be pulled from the market long before it was withdrawn in 2004 because of heart risks.

“Patients have been scared enough by a lot of snippets of information here and there,'’ said Chris Viehbacher, president of U.S. pharmaceuticals at Glaxo, in an interview today. “The advisory committee’s going to hear a lot of people, including Dr. David Graham, and I think what you’re going to find is that the weight of scientific evidence continues to support the safety of Avandia.'’

Journal Report

Before today, the stock had fallen 16 percent since a May 21 report in the New England Journal of Medicine tied Avandia to a 43 percent increased risk of heart attacks. In February, drug- safety scientists at the FDA concluded Avandia shouldn’t be used with insulin or by patients with heart disease, according to documents posted on the agency’s Web Site July 26.

The FDA often follows the advice of its advisory panels, though the agency isn’t required to do so.

Graham’s recommendation doesn’t mean the FDA will pull the drug from the market, said Navid Malik, an analyst at Collins Stewart in London, in a telephone interview today.

“He obviously made a good call about Vioxx, but these guys, they’re very vocal, they sometimes go against the grain of what the evidence is saying,'’ Malik said. “I’m not sure the reasons he cited for the withdrawal correlate with the evidence. He cites cardiovascular risks but there are data which are contradictory.'’

Glaxo Documents

Numerous studies involving thousands of patients show there is no additional danger with Avandia, Glaxo said in documents it submitted to the FDA before the meeting. The drug remains an important treatment choice for patients with type 2 diabetes, the most common form, the London-based company said.

The question raised by the May report conducted by Cleveland Clinic researchers “has not been confirmed across more robust and definitive data sources,'’ according to Glaxo, the second-biggest drug company in the world after Pfizer Inc.

“There is no consistent or systematic evidence'’ that Avandia increases the risk of heart attacks or death from cardiovascular disease compared with other drugs, it said.

The FDA meeting, composed of nearly two dozen experts from the agency’s diabetes and drug safety advisory committees, will cover more than 600 pages of data and dozens of studies on Avandia. The agency asked the panel to vote on whether existing information “supports the conclusion'’ that Avandia increases cardiac risks like heart attacks and if such a risk is greater than that from other therapies.

Questioning Role

The panel was also asked to consider whether the drug should continue to be sold in the U.S. If the panel rules the drug should stay on the market, the agency wants to know what steps it can take, such as limitations on Avandia’s use, to maximize its benefit while reducing its risk.

“If this drug really does increase the risk of heart attack by 20 or 30 or 40 percent, we really should question its role,'’ said an FDA official, who declined to be named, in a telephone briefing with reporters last week. “We’re asking the committee, do the data tell us that or not?'’

Graham, in his slides, said a similar drug called Actos from Osaka-based Takeda Pharmaceutical Co. doesn’t have the same cardiovascular risks.

A Takeda study comparing Actos to Avandia found patients on Actos had a 22 percent lower risk of heart attacks. The report, expected to be discussed at the advisory committee hearing today, comes from an analysis of a medical claims database including 30,000 diabetics treated from 2003 to 2006.

Higher Risk

Patients taking Avandia had as much as a 3.5-fold increased risk of heart attacks and related complications compared with patients taking Actos in studies analyzed by the FDA, according to Graham’s slides. In addition, Avandia offers no unique advantages and isn’t as good with other outcomes, such as controlling cholesterol levels, he said.

An estimated 246 million people, nearly 6 percent of the world’s adult population, suffer from diabetes and 3.8 million a year die from it, according to the International Diabetes Federation. The most common form is type 2, linked to a sedentary lifestyle and excess weight.

The cells of those patients don’t properly produce and use insulin, the hormone that coverts blood sugar to energy. The disease is progressive, with patients needing more and more aggressive therapy to get their blood sugar under control. Persistently high levels eventually damage the nerves and blood vessels, leading to blindness, kidney failure and death.

Sensitive to Insulin

Avandia and other treatments make the cells more sensitive to the insulin the body produces. Other therapies prompt the body to make more insulin. Eventually, most patients need insulin injections to control their blood sugar.

The advisory committee’s position will help determine whether and to what extent Avandia will contribute to Glaxo’s future earnings. It was the world’s best-selling diabetes pill and London-based Glaxo’s second-biggest drug last year, bringing in $3.3 billion for the company.

After the heart-attack risk was reported in May, Avandia sales fell 22 percent in the second quarter as doctors turned to Actos, a similar drug from Osaka-based Takeda Pharmaceutical Co., and newer medications from Merck & Co. and Eli Lilly & Co.

Before the controversy began, analysts were expecting Avandia to reach peak sales of about $6 billion (3 billion pounds) by 2011. Now many say the chances are slim.

“It will be very difficult to recover from this,'’ Nick Turner, an analyst at Mirabaud Securities in London, said in a telephone interview earlier this month. “Even if the FDA doesn’t can it, it is going to be hard to get patients to take the risk,'’ he said. “Every man and his dog is going to be looking at every trial for heart risk.'’

To contact the reporters on this story: Justin Blum in Washington at jblum4@bloomberg.net ; Michelle Fay Cortez in Minneapolis at mcortez@bloomberg.net

June 18, 2007

Merck & Co. Ordered to Pay Attorneys’ Fees, Costs Following VIOXX(R) Consumer Fraud Finding

Filed under: MEDICAL NEWS YOU CAN USE, VIOXX NEWS — aofcarec @ 11:04 am

Posted : Mon, 18 Jun 2007 16:56:00 GMT

Author : The Lanier Law Firm Category : PressRelease News Alerts by Email click here ) Create your own RSS PressRelease News | Create your own RSS | Home ATLANTIC CITY, N.J., June 18 /PRNewswire/ — New Jersey Superior Court judge Carol E. Higbee has ordered pharmaceutical giant Merck & Co. to pay fees and costs to a group of attorneys who proved in court that Merck committed fraud by deceiving doctors about the cardiovascular risks of the popular painkiller VIOXX(R) and deliberately hiding information about those risks from physicians. Merck could have settled both consumer fraud claims for less than $5,000, but fought the allegations in an April 2006 trial. Similar consumer fraud claims are pending in thousands of additional cases against Merck. Following the trial, jurors awarded $13.5 million in compensatory and punitive damages to 77-year-old John McDarby, who suffered a heart attack after taking VIOXX(R) for four years. Jurors also agreed that Merck committed consumer fraud and awarded an additional $4,013.36 to Mr. McDarby and $45 to second victim Thomas Cona based on the cost of their prescriptions. The order signed June 15 awards approximately $4 million in fees and costs for the attorneys who represented Mr. McDarby and Mr. Cona. “It is a pity that Merck is forcing our nation’s court system to waste thousands of hours of time and millions of dollars to hear these fraud claims after a jury has already said the company committed fraud,” says lead attorney Mark Lanier of The Lanier Law Firm. “This is lawsuit abuse by Merck, plain and simple.” The New Jersey Consumer Fraud Act provides for “reasonable attorneys’ fees, filing fees and reasonable costs of suit” to plaintiffs who prove a consumer fraud claim. The New Jersey statute does not limit counsel fees according to the amount of the original claim. According to the court, the law “provides an incentive to competent counsel to undertake high-risk cases and to represent victims of fraud who suffer relatively minor losses.” The ruling notes that Merck spent $500 million defending VIOXX(R) cases in 2006, and the company has reserved more than $850 million to defend future cases. Prior to the ruling, Merck withdrew any objection to the amount of time expended by attorneys for the plaintiffs or the hourly rate charged by plaintiffs’ counsel. The company acknowledged in a court filing that Merck’s overall fees and costs “were at least as high as plaintiffs corresponding fees and costs.” For more information, contact Mike Androvett at 800-550-4534 or mike@legalpr.com. The Lanier Law Firm CONTACT: Mike Androvett, 1-800-550-4534, mike@legalpr.com, for The Lanier Law Firm

June 12, 2007

Association of Avastin With Tracheoesophageal Fistula

Filed under: FDA WARNINGS, MEDICAL NEWS YOU CAN USE — aofcarec @ 10:35 am

DGNews

    OTTAWA, CANADA — June 12, 2007 — Hoffmann-La Roche Limited, in consultation with Health Canada, would like to inform health professionals of important new safety information regarding the use of Avastin (bevacizumab). 

    Avastin is a recombinant humanized monoclonal antibody that is directed against the vascular endothelial growth factor (VEGF). It is authorized for the first-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with fluoropyrimidine based chemotherapy.

    Based on review of post market and clinical trial reports:

    · Serious adverse events, including fatal events, of tracheoesophageal (TE) fistula have been reported in association with use of Avastin clinical trials of small cell lung cancer (SCLC), non small cell lung cancer (NSCLC) and esophageal cancer.
    · Avastin should be permanently discontinued in patients with TE fistula or any gastrointestinal fistula. There is limited information on the continued use of Avastin in patients with other fistulas.
    · In cases of internal fistula not arising in the GI tract, discontinuation of Avastin should be considered.    There have been two confirmed serious adverse events of TE fistula (one fatal) reported in the first 29 patients enrolled in a U.S. investigator-sponsored multicentre, single-arm phase II trial, in patients with limited-stage small cell lung cancer (SCLC) treated with four cycles of concurrent irinotecan, carboplatin, radiotherapy, and Avastin followed by maintenance Avastin for up to 6 months. A third, fatal event (upper aerodigestive tract hemorrhage and death of unknown cause), was also reported, in which TE fistula was suspected but not confirmed.

    All three events occurred during the Avastin maintenance phase (during continued treatment with Avastin monotherapy) of the study in the presence of persistent (≥ 4 weeks) esophagitis. This study was closed for further recruitment as of March 12, 2007. No Canadian patients were enrolled in this study.

    Avastin is not indicated for use in SCLC or for use in combination with concurrent radiotherapy and chemotherapy for any cancer indication. To date, no cases of TE fistula have been reported in Canada.

    As of March 22, 2007, six additional cases of TE fistula have also been reported world wide in other lung and esophageal cancer studies involving the use of Avastin and chemotherapy alone or with concurrent radiation treatment. A review of all available data from Avastin clinical trials and spontaneous reports revealed that the events of TE fistulas observed to date with Avastin were reported in patients with SCLC, non-small cell lung cancer and esophageal cancer.

    In SCLC patients, it remains unknown if this cluster of events was influenced by the concurrent use of radiotherapy. TE fistulas have not to date been reported in patients with metastatic colorectal cancer, but the possibility that this is a rare adverse drug reaction associated with Avastin in indications other than lung or esophageal cancer cannot be excluded.

    There is limited information in the published literature on the background rate of TE fistula in patients with limited-stage SCLC, but it is estimated to be <1%1. The incidence of TE fistula observed in the U.S. investigator-sponsored trial to date exceeds this rate. Due to the small number of patients treated in the setting of limited-stage SCLC and the non-randomized nature of this trial, it is not possible to distinguish the toxicity observed in this trial from other risk factors for the development of TE fistula, such as intra-thoracic organ sensitivity from chemotherapy and radiotherapy alone.

    In Avastin clinical trials, gastrointestinal fistulas have been reported with the highest incidence of around 2% in patients with metastatic colorectal cancer, but were also reported less commonly in patients with other types of cancers (e.g. breast cancer, lung cancer and others). Uncommon (≥ 0.1% to < 1%) reports of other types of fistulas (e.g. bronchopleural, urogenital and biliary fistulas) were observed across various indications. Fistulas have also been reported in post-marketing experience. Although other risk factors (e.g. diagnosis of cancer, cancer progression, cancer treatments) are known to be associated with an increased risk of development of fistulas, a role for Avastin in increasing this risk cannot be excluded.

    Events were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of Avastin, with most events occurring within the first 6 months of therapy.

    A description of cases of gastrointestinal fistula formation in patients treated with Avastin in clinical studies and post-marketing reports is included in the current Canadian Product Monograph (CPM, see Warnings and Precautions, Gastrointestinal Perforation). Roche intends to revise the Avastin prescribing information to include more detailed information regarding the incidence of all cases of fistula in patients treated with Avastin.

    Managing marketed health product related adverse reactions depends on health care professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any occurrence of serious and/or unexpected adverse reactions in patients receiving Avastin should be reported to Hoffmann-La Roche Limited, or Health Canada.

    SOURCE: Health Canada

May 21, 2007

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes

Filed under: FDA WARNINGS, MEDICAL NEWS YOU CAN USE — aofcarec @ 10:08 am
 

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[ClinicalTrials.gov] ).21 In the DREAM study, 2635 patients were randomly assigned to receive rosiglitazone and 2634 patients were assigned to receive placebo. The DREAM study was designed to determine whether rosiglitazone could prevent the development of type 2 diabetes in patients at high risk for this disorder. In the ADOPT trial, 1456 patients were randomly assigned to receive rosiglitazone and 2895 patients were assigned to receive either metformin or glyburide. The ADOPT study was designed to assess the durability of glycemic control with rosiglitazone therapy, as compared with therapy with metformin or glyburide.

Outcome Measures

We reviewed data summaries provided in the FDA review documents, the GlaxoSmithKline clinical-trial registry Web site, and published trial results and then abstracted from the adverse-event tabulations information on myocardial infarction and death from cardiovascular causes. With the exception of the DREAM study, the included trials did not describe adjudication of myocardial infarction or death from cardiovascular causes. Time-to-event data for cardiovascular events were not available in any of these trials, which precluded the calculation of hazard ratios. Because only summary data were available, it was not possible to discern whether the same patient had both events. Therefore, an outcome measure based on the composite of death or myocardial infarction could not be constructed. Accordingly, these two outcomes are reported separately.

Statistical Analysis

Many trials had few cardiovascular events, so the odds ratios and 95% confidence intervals were calculated with the use of the Peto method.22,23,24 Because all trials had similar durations of follow-up for all treatment groups, the use of odds ratios represents a valid approach to assessing the risk associated with the use of rosiglitazone. Trials in which patients had no adverse cardiovascular events in either group were excluded from analyses. All reported P values are two-sided. Statistical heterogeneity across the various trials was tested with the use of Cochran’s Q statistic. A P value of more than the nominal level of 0.10 for the Q statistic indicated a lack of heterogeneity across trials, allowing for the use of a fixed-effects model. For additional analyses, the active comparator control groups were subgrouped into the following four classes for comparison with rosiglitazone: metformin, sulfonylurea, insulin, and placebo. Odds ratios and 95% confidence intervals were calculated for each subgroup with the use of methods similar to those used in the pooled analyses. Data were analyzed with the use of Comprehensive Meta-Analysis software, version 2.2 (Biostat).

Results

Baseline Characteristics

Table 2 reports the doses of rosiglitazone and comparator drugs, baseline demographic characteristics, study periods, and glycated hemoglobin levels or fasting blood glucose levels for patients enrolled in the trials. The patients were relatively young, averaging less than 57 years of age for both the rosiglitazone group and the control group. Overall, there was a moderate predominance of men. Diabetes control was relatively poor, with a mean baseline glycated hemoglobin level of approximately 8.2% for both study groups.

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http://content.nejm.org/cgi/powerpoint/NEJMoa072761v1/T2
 		 Table 2. Doses, Baseline Demographic Characteristics, Study Periods, and Glycated Hemoglobin Levels. 

Myocardial Infarction and DeathTable 3 reports the myocardial infarction events and deaths from cardiovascular causes that were reported in the 42 clinical trials we reviewed. There were 86 myocardial infarctions in the rosiglitazone group and 72 in the control group. There were 39 deaths from cardiovascular causes in the rosiglitazone group and 22 in the control group. Table 4 lists the odds ratios, 95% confidence intervals, and P values for myocardial infarction and death from cardiovascular causes for the rosiglitazone group and the control group. The summary odds ratio for myocardial infarction was 1.43 in the rosiglitazone group (95% confidence interval [CI], 1.03 to 1.98; P=0.03). The odds ratio for death from cardiovascular causes in the rosiglitazone group, as compared with the control group, was 1.64 (95% CI, 0.98 to 2.74; P=0.06). Table 4 also lists odds ratios and 95% confidence intervals for the pooled group of trials that were smaller and of shorter duration; results for the DREAM and ADOPT studies are shown separately.

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http://content.nejm.org/cgi/powerpoint/NEJMoa072761v1/T3
 		 Table 3. Myocardial Infarctions and Cardiovascular Deaths in Rosiglitazone Trials. 

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 		 Table 4. Rates of Myocardial Infarction and Death from Cardiovascular Causes. 

Table 5 lists odds ratios for myocardial infarction and death from cardiovascular causes associated with rosiglitazone for subgroups defined according to the comparator drug. Similar results were obtained when the analysis excluded trials with an active comparator group. The heterogeneity P values were 0.53 for myocardial infarction and 0.68 for death from cardiovascular causes across subgroups. As compared with placebo or other antidiabetic regimens, the estimated odds ratios in all cases were greater than 1.0, suggesting that observed adverse effects during rosiglitazone treatment were not unique to any specific comparator regimen.

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http://content.nejm.org/cgi/powerpoint/NEJMoa072761v1/T5
 		 Table 5. Risk of Myocardial Infarction and Death from Cardiovascular Causes for Patients Receiving Rosiglitazone versus Several Comparator Drugs. 

In an analysis that was not prespecified, we also studied the effects of rosiglitazone on death from any cause. The odds ratio for death from any cause was 1.18 (95% CI, 0.89 to 1.55; P=0.24). Discussion

Our data show that, as compared with placebo or with other antidiabetic regimens, treatment with rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that was of borderline significance. The similar odds ratio for comparison with placebo suggests that the increased risk associated with rosiglitazone was not a function of the protective effects of active comparator drugs. However, these findings are based on limited access to trial results from publicly available sources, not on patient-level source data. Furthermore, results are based on a relatively small number of events, resulting in odds ratios that could be affected by small changes in the classification of events. Nonetheless, our findings are worrisome because of the high incidence of cardiovascular events in patients with diabetes.4 Because exposure of such patients to rosiglitazone is widespread, the public health impact of an increase in cardiovascular risk could be substantial if our data are borne out by further analysis and the results of larger controlled trials.

Although we did not have access to the source data to construct a composite outcome that included myocardial infarction or death from cardiovascular causes, the increase in the odds ratios for both of these end points suggests that observed adverse effects associated with rosiglitazone were probably not due to chance alone. This meta-analysis included a group of trials that were of relatively short duration (24 to 52 weeks). The odds ratio for these shorter-term trials was similar to the overall results of the meta-analysis. Thus, in susceptible patients, rosiglitazone therapy may be capable of provoking myocardial infarction or death from cardiovascular causes after relatively short-term exposure. In contrast, long-term therapies that improve cardiovascular outcomes, such as statins and antihypertensive drugs, often take several years to provide benefits. Notably, the estimates for the odds ratios for myocardial infarction and death from cardiovascular causes appear elevated for rosiglitazone in comparison with placebo or other commonly prescribed antidiabetic therapies (Table 5).

The mechanism for the apparent increase in myocardial infarction and death from cardiovascular causes associated with rosiglitazone remains uncertain. One potential contributing factor may be the adverse effect of the drug on serum lipids. The FDA-approved rosiglitazone product label reports a mean increase in low-density lipoprotein (LDL) cholesterol of 18.6% among patients treated for 26 weeks with an 8-mg daily dose, as compared with placebo.25 In observational studies and lipid-lowering trials, elevated levels of LDL cholesterol were associated with an increase in adverse cardiovascular outcomes. Thus, an increase in LDL cholesterol of the magnitude observed in the rosiglitazone group may have contributed to adverse cardiovascular outcomes, although the rapidity and magnitude of the apparent hazard was not consistent with an effect produced by lipid changes alone.

Several other properties of rosiglitazone may contribute to adverse cardiovascular outcomes. Rosiglitazone and other thiazolidinediones are known to precipitate congestive heart failure in susceptible patients.26 Congestive heart failure is a physiological state that is associated with an increased intravascular volume. Volume overload increases stress on the left ventricular wall, a factor that determines myocardial oxygen demand. In susceptible patients, an increase in myocardial oxygen demand could theoretically provoke ischemic events. The administration of thiazolidinediones, including rosiglitazone, also produces a modest reduction in the hemoglobin level.25 In susceptible patients, a reduced hemoglobin level may result in increased physiological stress, thereby provoking myocardial ischemia. A study of rosiglitazone that was conducted in rats reported an increase in the rate of death after experimentally induced myocardial infarction.27

Rosiglitazone is not the first PPAR agonist that has been reported to increase adverse cardiovascular events. Muraglitazar, an investigational dual PPAR-{alpha} and PPAR-{gamma} agonist, increased adverse cardiovascular events, including myocardial infarction, during phase 2 and 3 testing.28 After publication of an analysis of cardiovascular outcomes, muraglitazar was not approved by the FDA, and further development was subsequently halted by the manufacturer. Development programs for many other PPAR agonists have been terminated after evidence of toxicity emerged during preclinical studies or initial trials in humans. According to a former FDA official, more than 50 Investigational New Drug applications for novel PPARs have been filed, but no additional drugs have successfully reached the market in more than 6 years.29 In some cases, these drugs have failed because of evidence of direct myocardial toxicity in studies in animals,29 but few data on toxicity are available in the public domain because of the common industry practice of not publishing safety findings for failed products.

PPAR agonists such as rosiglitazone have very complex biologic effects, resulting from the activation or suppression of dozens of genes.30 The patterns of gene activation or suppression differ substantially among various PPAR agonists, even within closely related compounds. The biologic effects of the protein targets for most of the genes influenced by PPAR agonists remain largely unknown. Accordingly, many different and seemingly unrelated toxic effects have emerged during development of other PPAR agents.29 Some drugs have provoked multispecies, multi–organ system cancers; others have resulted in rhabdomyolysis or nephrotoxicity.29 Troglitazone was withdrawn from the market for rare, but sometimes fatal, liver toxicity. Accordingly, it must be assumed that a variety of unexpected toxic effects are possible when PPAR agonists are administered to patients.

The question as to whether the observed risks of rosiglitazone represent a “class effect” of thiazolidinediones must also be considered. Pioglitazone is a related agent also widely used to treat type 2 diabetes mellitus. However, unlike rosiglitazone, pioglitazone has been studied in a prospective, randomized trial of cardiovascular outcomes, called Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE).31 The primary end point, a broad composite that included coronary and peripheral vascular events, showed a trend toward benefit from pioglitazone (hazard ratio, 0.90; P=0.095). A secondary end point consisting of myocardial infarction, stroke, and death from any cause showed a significant effect favoring pioglitazone (hazard ratio, 0.84; P=0.027). Notably, pioglitazone appears to have more favorable effects on lipids, particularly triglycerides, than does rosiglitazone.32

These emerging findings raise an important question about the appropriateness of the current regulatory pathways for the development of drugs to treat diabetes. The FDA considers demonstration of a sustained reduction in blood glucose levels with an acceptable safety profile adequate for approval of antidiabetic agents. However, the ultimate value of antidiabetic therapy is the reduction of the complications of diabetes, not improvement in a laboratory measure of glycemic control. Although reductions in blood glucose levels have been shown to reliably reduce microvascular complications of diabetes, the effect on macrovascular complications has proved to be unpredictable.33 After the failure of muraglitazar and the apparent increase in adverse cardiovascular outcomes with rosiglitazone, the use of blood glucose measurements as a surrogate end point in regulatory approval must be carefully reexamined.

Our study has important limitations. We pooled the results of a group of trials that were not originally intended to explore cardiovascular outcomes. Most trials did not centrally adjudicate cardiovascular outcomes, and the definitions of myocardial infarction were not available. Many of these trials were small and short-term, resulting in few adverse cardiovascular events or deaths. Accordingly, the confidence intervals for the odds ratios for myocardial infarction and death from cardiovascular causes are wide, resulting in considerable uncertainty about the magnitude of the observed hazard. Furthermore, we did not have access to original source data for any of these trials. Thus, we based the analysis on available data from publicly disclosed summaries of events. The lack of availability of source data did not allow the use of more statistically powerful time-to-event analysis. A meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest. Although such a dedicated trial has not been completed for rosiglitazone, the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial may provide useful insights.34

Despite these limitations, our data point to the urgent need for comprehensive evaluations to clarify the cardiovascular risks of rosiglitazone. The manufacturer’s public disclosure of summary results for rosiglitazone clinical trials is not sufficient to enable a robust assessment of cardiovascular risks. The manufacturer has all the source data for completed clinical trials and should make these data available to an external academic coordinating center for systematic analysis. The FDA also has access to study reports and other clinical-trial data not within the public domain. Further analyses of data available to the FDA and the manufacturer would enable a more robust assessment of the risks of this drug. Our data suggest a cardiovascular risk associated with the use of rosiglitazone. Until better precision of the estimates of the risks of this treatment on cardiovascular events can be delineated in patients with diabetes, patients and providers should give careful consideration to the risks and benefits of their overall treatment plans.

Dr. Nissen reports receiving research support to perform clinical trials through the Cleveland Clinic Cardiovascular Coordinating Center from Pfizer, AstraZeneca, Daiichi Sankyo, Roche, Takeda, Sanofi-Aventis, and Eli Lilly. Dr. Nissen consults for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. No other potential conflict of interest relevant to this article was reported. We thank Craig Balog for statistical programming support.
Source Information From the Cleveland Clinic, Cleveland.

This article (10.1056/NEJMoa072761) was published at www.nejm.org on May 21, 2007. It will appear in the June 14 issue of the Journal. Address reprint requests to Dr. Nissen at the Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, or at nissens@ccf.org .

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  6. Center for Drug Evaluation and Research. Medical review(s). Application number: 021071. (Accessed May 15, 2007, at http://www.fda.gov/cder/foi/nda/99/21071_Avandia_medr.pdf.)
  7. Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001;86:280-288. [Erratum, J Clin Endocrinol Metab 2001;86:1659, 2002;2:iv.] [Free Full Text]
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  9. Jones TA, Sautter M, Van Gaal LF, Jones NP. Addition of rosiglitazone to metformin is most effective in obese, insulin-resistant patients with type 2 diabetes. Diabetes Obes Metab 2003;5:163-170. [CrossRef][ISI][Medline]
  10. Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000;283:1695-1702. [Erratum, JAMA 2000;284:1384.] [Free Full Text]
  11. Weissman P, Goldstein BJ, Rosenstock J, et al. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Curr Med Res Opin 2005;21:2029-2035. [CrossRef][ISI][Medline]
  12. Wolffenbuttel BH, Gomis R, Squatrito S, Jones NP, Patwardhan RN. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients. Diabet Med 2000;17:40-47. [CrossRef][ISI][Medline]
  13. St John Sutton M, Rendell M, Dandona P, et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care 2002;25:2058-2064. [Free Full Text]
  14. Raskin P, Rendell M, Riddle MC, et al. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001;24:1226-1232. [Free Full Text]
  15. Vongthavaravat V, Wajchenberg BL, Waitman JN, et al. An international study of the effects of rosiglitazone plus sulphonylurea in patients with type 2 diabetes. Curr Med Res Opin 2002;18:456-461. [CrossRef][ISI][Medline]
  16. Baksi A, James RE, Zhou B, Nolan JJ. Comparison of uptitration of gliclazide with the addition of rosiglitazone to gliclazide in patients with type 2 diabetes inadequately controlled on half-maximal doses of a sulphonylurea. Acta Diabetol 2004;41:63-69. [ISI][Medline]
  17. Barnett AH, Grant PJ, Hitman GA, et al. Rosiglitazone in Type 2 diabetes mellitus: an evaluation in British Indo-Asian patients. Diabet Med 2003;20:387-393. [CrossRef][ISI][Medline]
  18. Kerenyi Z, Samer H, James R, Yan Y, Stewart M. Combination therapy with rosiglitazone and glibenclamide compared with upward titration of glibenclamide alone in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2004;63:213-223. [CrossRef][ISI][Medline]
  19. Zhu XX, Pan CY, Li GW, et al. Addition of rosiglitazone to existing sulfonylurea treatment in Chinese patients with type 2 diabetes and exposure to hepatitis B or C. Diabetes Technol Ther 2003;5:33-42. [CrossRef][Medline]
  20. The DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-1105. [Erratum, Lancet 2006;368:1770.] [CrossRef][Medline]
  21. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-2443. [Erratum, N Engl J Med 2007;356:1387-8.] [Free Full Text]
  22. Bradburn MJ, Deeks JJ, Berlin JA, Localio AR. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 2007;26:53-77. [CrossRef][ISI][Medline]
  23. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 2004;23:1351-1375. [Erratum, Stat Med 2006;25:2700.] [CrossRef][ISI][Medline]
  24. Sutton A, Cooper N, Lambert P, Jones D, Abrams K, Sweeting M. Meta-analysis of rare and adverse event data. Pharmacoeconomics Outcomes Res 2002;2:367.
  25. Avandia (rosiglitazone maleate) tablets: prescribing information. Research Triangle Park, NC: GlaxoSmithKline, 2007 (package insert). (Accessed May 15, 2007, at http://www.fda.gov/cder/foi/label/2007/021071s023lbl.pdf.)
  26. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association: October 7, 2003. Circulation 2003;108:2941-2948. [CrossRef][ISI][Medline]
  27. Lygate CA, Hulbert K, Monfared M, Cole MA, Clarke K, Neubauer S. The PPARgamma-activator rosiglitazone does not alter remodeling but increases mortality in rats post-myocardial infarction. Cardiovasc Res 2003;58:632-637. [CrossRef][ISI][Medline]
  28. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581-2586. [Free Full Text]
  29. El-Hage J. Peroxisome proliferator-activated receptor (PPAR) agonists: preclinical and clinical cardiac safety considerations. Rockville, MD: Center for Drug Evaluation and Research, 2006. (Accessed May 15, 2007, at http://www.fda.gov/cder/present/DIA2006/El-Hage_CardiacSafety.ppt.)
  30. Lemay DG, Hwang DH. Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics. J Lipid Res 2006;47:1583-1587. [Free Full Text]
  31. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-1289. [CrossRef][ISI][Medline]
  32. Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547-1554. [Free Full Text]
  33. Riveline JP, Danchin N, Ledru F, Varroud-Vial M, Charpentier G. Sulfonylureas and cardiovascular effects: from experimental data to clinical use: available data in humans and clinical applications. Diabetes Metab 2003;29:207-222. [ISI][Medline]
  34. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia 2005;48:1726-1735. [CrossRef][ISI][Medline]

April 19, 2007

FDA Seizes All Medical Products From N.J. Device Manufacturer for Significant Manufacturing Violations

Filed under: FDA WARNINGS, MEDICAL NEWS YOU CAN USE — aofcarec @ 8:12 am
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FDA News

FOR IMMEDIATE RELEASE
P07-69
April 17, 2007 

  

Media Inquiries:
Heidi Rebello, 301-827-6242
Consumer Inquiries:
888-INFO-FDA

U.S. Food and Drug Administration (FDA) investigators and U.S. Marshals today seized all implantable medical devices from Shelhigh, Inc., Union, N.J., after finding significant deficiencies in the company’s manufacturing processes. The deficiencies may compromise the safety and effectiveness of the products, particularly their sterility.

The products include pediatric heart valves and conduits (tube-like devices for blood flow), surgical patches, dural patches (to aid in tissue recovery after neurosurgery), annuloplasty rings (to help repair heart valves) and arterial grafts. The tissue-based devices are used in many surgical settings, including open heart surgery in adults, children and infants, and to repair soft tissue during neurosurgery and abdominal, pelvic and thoracic surgery. Critically ill patients, pediatric patients and immuno-compromised patients may be at greatest risk from the use of these devices.

All medical device companies must follow current good manufacturing practice, a set of requirements that help to ensure the safety and effectiveness of all medical products. Shelhigh’s violations include: manufacturing products in a facility with a poorly constructed and poorly maintained clean room where sterilized devices are further processed; failing to adequately monitor critical manufacturing environments for possible microbial contamination; failing to properly test products for sterility and fever-causing contaminants; and failing to scientifically support product expiration dates.

Physicians should consider using alternative devices. Physicians should also monitor patients with a Shelhigh implant for infections and proper device functioning over the expected lifetime of the device. Patients who think they may have received a Shelhigh device during surgery should contact their physician for more information. FDA will issue a Preliminary Public Health Notification to physicians and other health care professionals and a Preliminary Advice for Patients shortly with more information; those documents will be posted to FDA’s Web site.

The seizure follows an FDA inspection of the Shelhigh manufacturing facility last fall, as well as meetings with the company at which FDA warned Shelhigh that failure to correct its violations could result in an enforcement action. FDA also alerted the company to its manufacturing deficiencies and other violations in two warning letters.

Medical devices manufactured by Shelhigh include:

  • Shelhigh Pericardial Patch
  • Shelhigh No-React Pericardial Patch
  • Shelhigh No-React PneumoPledgets
  • Shelhigh No-React VascuPatch
  • Shelhigh No-React Tissue Repair Patch/UroPatch
  • Shelhigh Pulmonic Valve Conduit No-React Treated
  • Shelhigh No-React Dura Shield
  • Shelhigh BioRing (annuloplasty ring)
  • Shelhigh No-React EnCuff Patch
  • Shelhigh No-React Stentless Valve Conduit
  • Shelhigh Internal Mammary Artery
  • Shelhigh Gold perforated patches
  • Shelhigh Pre Curved Aortic Patch (Open)
  • Shelhigh NR2000 SemiStented aortic tricuspid valve
  • Shelhigh BioConduit stentless valve
  • Shelhigh NR900A tricuspid valve
  • Shelhigh MitroFast Mitral Valve Repair System
  • Shelhigh BioMitral tricuspid valve
  • Shelhigh Injectable Pulmonic Valve System

####

Additional Information
FDA Preliminary Public Health Notification
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March 30, 2007

FDA Public Health Advisory

Filed under: MEDICAL NEWS YOU CAN USE — aofcarec @ 8:40 pm

Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)

Recent reports of studies with erythropoiesis-stimulating agents (ESAs) have shown a higher chance of serious and life-threatening side effects and greater number of deaths in patients treated with these agents.  ESAs stimulate the bone marrow to make more red blood cells and are FDA approved for use in reducing the need for blood transfusions in patients with chronic kidney failure, patients with cancer on chemotherapy, patients scheduled for major surgery (except heart surgery) and patients with HIV that are using AZT.  Because all ESAs work the same way, the findings from these studies apply to all ESAs; the FDA is re-evaluating the safe use of this drug class. 

Patients currently using or considering the use of an ESA should know the following:

  • A higher chance of death and an increased rate of tumor growth were reported in patients with advanced head and neck cancer receiving radiation therapy and in patients with metastatic breast cancer receiving chemotherapy, when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
  • A higher chance of death was reported and no fewer blood transfusions were received when ESAs were given to patients with cancer and anemia not receiving chemotherapy.   
  • A higher chance of death was reported and an increased number of blood clots, strokes, heart failure, and heart attacks was reported in patients with chronic kidney failure when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
  • A higher chance of blood clots was reported in patients who were scheduled for major surgery and given ESAs.
  • ESAs are not approved for treatment of the symptoms of anemia, such as fatigue in patients with cancer, surgical patients and patients with HIV. 
  • If you have any questions you should talk with your health care provider.

Important study results include the following:

  • Patients with chronic kidney failure had an increased number of deaths and of non-fatal heart attacks, strokes, heart failure, and blood clots when ESAs were adjusted to maintain higher red blood cell levels (hemoglobin more than 12 g/dL).
  • Patients with head and neck cancer receiving radiation therapy had faster tumor growth when ESAs were adjusted to maintain hemoglobin levels higher than 12 g/dL.
  • Patients with cancer not receiving chemotherapy died sooner and had no fewer blood transfusions when ESAs were given according to the dosing recommendations for cancer patients receiving chemotherapy.
  • Patients scheduled for orthopedic surgery who received ESAs to reduce blood transfusions during and after surgery had more blood clots than those not given an ESA. 

Physicians who prescribe ESAs should consider the important study results above and:

  • Understand that ESAs are given to decrease the need for red blood cell transfusions;
  • Consider both the risks of transfusions and those of ESAs when deciding to prescribe an ESA;
  • Adjust the dose of ESA to maintain the lowest hemoglobin level necessary to avoid the need for transfusions.
  • Monitor patients’ hemoglobin levels to ensure they do not exceed 12 g/dL;
  • Understand that ESAs have not been shown to improve the outcomes of chemotherapy treatment (e.g., better tumor shrinkage, delay in tumor growth or longer time for survival); and
  • Understand that in patients with cancer whose anemia is caused by chemotherapy and in patients with HIV whose anemia is caused by AZT (zidovudine), there are no data to support claims of improvement in health-related quality of life, including effects on fatigue, energy or strength.

FDA and Amgen, the manufacturer of these products, and Ortho Biotech Products, L.P, a Johnson & Johnson Pharmaceuticals Research and Development subsidiary, the distributor of Procrit, have agreed to change the labeling for Aranesp, Epogen, and Procrit to reflect the new safety information and to provide additional instructions for their use. 

FDA-approved uses of ESAs are: for the treatment of anemia in chronic kidney failure patients, in patients with cancer whose anemia is caused by chemotherapy, in patients with HIV whose anemia is caused by AZT (zidovudine), and to reduce the number of transfusions in patients scheduled for major surgery (except heart surgery).

You can find more details about  the use of ESAs in FDA’s Information for Healthcare Professional.

The FDA asks health care professionals and patients to report serious side effects after using ESAs to the FDA through the MedWatch program by phone (1-800-FDA-1088) or by the Internet at  http://www.fda.gov/medwatch

Podcasts Available for this Public Health Advisory

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Filed under: MEDICAL NEWS YOU CAN USE — aofcarec @ 8:22 pm

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MedWatch/TEQUIN - The FDA Safety Information and Adverse Event Reporting Program

Filed under: MEDICAL NEWS YOU CAN USE — aofcarec @ 8:21 pm

TEQUIN

BMS notified FDA and healthcare professionals about proposed changes to the
prescribing information for Tequin, including an updating of the existing
WARNING on hypoglycemia (low blood sugar) and hyperglycemia (high blood
sugar), and a CONTRAINDICATION for use in diabetic patients. The changes
also include information identifying other risk factors for developing low
blood sugar and high blood sugar, including advanced age, renal
insufficiency, and concomitant glucose-altering medications while taking
Tequin. The proposed changes are highlighted in the following “Dear
Healthcare Provider” letter issued by BMS. Specific wording of these
additions and revisions to the labeling is pending FDA review and approval.

Read the complete MedWatch 2006 Safety summary, including links to the Dear
Healthcare Professional letter and proposed revised label at:

http://www.fda.gov/medwatch/safety/2006/safety06.htm#Tequin

MedWatch - The FDA Safety Information and Adverse Event Reporting Program

Filed under: FDA WARNINGS, MEDICAL NEWS YOU CAN USE — aofcarec @ 8:20 pm

KETEK ALERT

The Food and Drug Administration notified healthcare professionals and
patients that it completed its safety assessment of Ketek
(telithromycin), indicated for the treatment of acute exacerbation of
chronic bronchitis, acute bacterial sinusitis and community acquired
pneumonia of mild to moderate severity, including pneumonia caused by
resistant strep infections. The drug has been associated with rare cases
of serious liver injury and liver failure with four reported deaths and
one liver transplant after the administration of the drug. FDA
determined that additional warnings are required and the manufacturer is
revising the drug labeling to address this safety concern. FDA is
advising both patients taking Ketek and their doctors to be on the alert
for signs and symptoms of liver problems. Patients experiencing such
signs or symptoms should discontinue Ketek and seek medical evaluation,
which may include tests for liver function.

Read the complete MedWatch 2006 Safety summary, including links to the
FDA news release and previous alerts, at:

http://www.fda.gov/medwatch/safety/2006/safety06.htm#Ketek2

New Warning for Attention Deficit Drugs

Filed under: MEDICAL NEWS YOU CAN USE — aofcarec @ 8:18 pm
New Warning for Attention Deficit Drugs
AP
WASHINGTON (Feb. 21) - Drugs prescribed to treat attention deficit hyperactivity disorder will include guides to alert patients and parents of the risks of mental and heart problems, including sudden death.

A patient takes part in a study on Attention Deficit Hyperactivity Disorder.

Karen Elshout, St. Louis Post-Dispatch / MCT

A patient takes part in a study on attention deficit hyperactivity disorder. The FDA ordered manufacturers to warn patients that ADHD drugs carry risks, including sudden death.

Jump Below: Drug List | Talk About It: Post Thoughts
The Food and Drug Administration said Wednesday that it directed the manufacturers of Ritalin, Adderall, Strattera and all other ADHD drugs to develop the guides. In May 2006, the agency told manufacturers to revise the labels of the drugs to reflect concerns about the cardiovascular and psychiatric problems.

Draft versions of the guides posted on the FDA Web site include discussion of reports of increased blood pressure and heart rate in ADHD patients, as well as cases of sudden death in some who have heart problems and heart defects. In adult patients, the reported problems also include stroke and heart attack.

The alerts also cover psychiatric problems, such as hearing voices, unfounded suspicions and manic behavior, of which there is a slightly increased risk in patients who take the drugs, the FDA said. The guides also tell patients and their parents of precautions they can take to guard against the risks.
Wednesday’s announcement came roughly a year after two panels of FDA advisers recommended that the drugs include such patient medication guides. The announcement covers 15 drugs, including extended-release, patch and chewable versions of some of them.

Ritalin is manufactured by Novartis Pharmaceuticals Corp. and in generic form by other companies; Adderall is made by Shire Pharmaceuticals Inc.; Strattera by Eli Lilly & Co.

ADHD affects an estimated 3 percent to seven percent of school-age children and four percent of adults, the FDA said.

Copyright 2007 The Associated Press. The information contained in the AP news report may not be published, broadcast, rewritten or otherwise distributed without the prior written authority of The Associated Press. All active hyperlinks

FDA: Zelnorm Being Pulled From Market

Filed under: MEDICAL NEWS YOU CAN USE — aofcarec @ 8:15 pm

FDA: Zelnorm Being Pulled From Market

ROCKVILLE, MD — March 30, 2007 — FDA is issuing this public health advisory to inform patients and health care professionals that the sponsor of Zelnorm (tegaserod maleate), Novartis Pharmaceuticals Corporation, has agreed to stop selling Zelnorm. Zelnorm is being taken off the market because a new safety analysis has found a higher chance of heart attack, stroke, and worsening heart chest pain that can become a heart attack in patients treated with Zelnorm compared to those treated with a sugar pill they thought was Zelnorm.

FDA announces the following, effective immediately:

· At FDA’s request, Novartis Pharmaceuticals Corporation has agreed to stop selling Zelnorm.
· Patients being treated with Zelnorm should contact their physician to discuss alternative treatments for their condition.
· Patients who are taking Zelnorm should seek emergency medical care right away if they experience severe chest pain, shortness of breath, dizziness, sudden onset of weakness or difficulty walking or talking or other symptoms of a heart attack or stroke.
· Physicians who prescribe Zelnorm should work with their patients and transition them to other therapies as appropriate to their symptoms and need.

Zelnorm is a prescription medication approved for short term treatment of women with irritable bowel syndrome with constipation and for patients younger than 65 years with chronic constipation. In late February and early March 2007, Novartis Pharmaceuticals gave FDA the results of new analyses of 29 clinical studies of Zelnorm for treatment of a variety of gastrointestinal tract conditions; the data from all the studies were combined to assess the chance of side effects on the heart and blood vessels. In each study, patients were assigned at random to either Zelnorm or a sugar pill they thought was Zelnorm. These 29 studies included 11,614 patients treated with Zelnorm and 7,031 treated with a sugar pill. The average age of patients in these studies was 43 years and most patients — 88% — were women.

The number of patients who suffered a heart attack, stroke or severe heart chest pain that can turn into a heart attack was small. However, patients treated with Zelnorm had a higher chance of having any of these serious and life-threatening side effects than did those who were treated with a sugar pill. Thirteen patients treated with Zelnorm (0.1%) had serious and life-threatening cardiovascular side effects; among these, four patients had a heart attack (one died), six had a type of severe heart chest pain which can quickly turn into a heart attack, and three had a stroke. Among the patients taking the sugar pill, only one (or 0.01%) had symptoms suggesting the beginning of a stroke that went away without complication.

There may be patients for whom no other treatment options are available and in whom the benefits of Zelnorm treatment outweigh the chance of serious side effects. FDA will work with Novartis to allow access to Zelnorm for those patients through a special program.

FDA has also indicated to Novartis a willingness to consider limited re-introduction of Zelnorm at a later date if a population of patients can be identified in whom the benefits of the drug outweigh the risks. However, before FDA makes a decision about limited re-introduction, any proposed plan would be discussed at a public advisory committee meeting.

SOURCE: FDA

March 10, 2007

Epogen: FDA Issues New Warnings on Anemia Drugs/Death

Filed under: FDA WARNINGS, MEDICAL NEWS YOU CAN USE, WELCOME TO ASSURANCE OF CARE — aofcarec @ 7:09 am
AP
WASHINGTON (March 9) - Federal health officials issued stern new warnings Friday for doctors to more carefully prescribe widely used anemia drugs that can increase the risk of death and other serious problems in patients with cancer and kidney disease.