Elizabeth Mechcatie

SILVER SPRING, MD. — The majority of a Food and Drug Administration advisory panel agreed that the mu-opioid receptor antagonist alvimopan hastened gastrointestinal recovery in patients undergoing bowel resection and receiving opioids for pain. But when the panel weighed the benefits of the drug against its risks, panel members only narrowly voted in favor of the drug.

The FDA's Gastrointestinal Drugs Advisory Committee voted 13–0, with 2 abstentions, that clinical studies evaluating the effects of the drug on postoperative ileus (POI) were “clinically meaningful,” and agreed that reductions in recovery time of 12 and 24 hours were significant.

However, the panel voted by a narrower margin of 9–6 that the beneficial effects of the drug outweighed its potential risks.

The manufacturer, Adolor Corp., has proposed that alvimopan, an oral medication, be approved for “acceleration of time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.” If approved, alvimopan would be the first drug approved for this indication, although surgeons use several drugs off-label for this use. The FDA usually follows the recommendations of its advisory panels, which are not binding.

According to Adolor, alvimopan is a “peripherally acting mu-opioid receptor antagonist that reverses opioid-induced changes in the GI tract without affecting opioid-induced analgesia.” The company plans to market the drug under the trade name Entereg if approved. The recommended dose is one 12-mg capsule taken before surgery, then 12 mg twice daily until discharge for a maximum of 15 doses.

Because of safety concerns raised in a 12-month study of alvimopan as a chronic treatment for opioid-induced bowel dysfunction in patients with chronic, noncancer pain, Adolor has proposed that the drug be limited to short-term, in-hospital use in patients receiving open bowel surgery. The company has proposed a risk management plan aimed at preventing off-label use, long-term use, and use outside acute care hospitals.

In the long-term study of 750 patients, 500 patients received alvimopan 0.5 mg twice daily and 250 received placebo. Compared with the placebo group, the alvimopan group had a greater number of serious cardiovascular events (mostly MI), benign and malignant neoplasms, and bone fractures over a period of 1 year.

However, in short-term POI studies, where patients were treated for 7 days or less, the number of adverse cases was small, and there was no imbalance of these events between placebo and treatment groups, according to Adolor.

In another vote, eight panelists said they remained concerned about the potential risk of cardiovascular events with short-term use, while six panelists, including the cardiologists, said they were not concerned with the risks associated with short-term use. (There was one abstention.)

The nine panel members voting in favor of the overall-risk benefit profile of the drug in this population included the cardiologists and surgeons on the panel, but panelists supported long-term monitoring of cardiovascular effects of the drug and agreed that the risk management plan as proposed by the company was not adequate for monitoring its safety potential.

Cardiologist Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic Foundation, said that in his view, there was no hint of any cardiovascular signal in the short-term follow-up and that he was not concerned about the cardiovascular risks for the short-term indication, even though patients would be taking a higher dose than was used in the long-term trials.

The acting chair of the panel, Dr. Alan L. Buchman, professor of medicine and surgery, division of gastroenterology at Northwestern University, Chicago, said that even though the drug had some physiologic and clinical beneficial effects, they were marginal and POI is a benign condition, so “the risk potential does at a minimum slightly outweigh the potential benefit for the patient.”

Panel members cited the economic benefits of reducing hospital stays by 24 and even 12 hours, opening up more hospital beds for other patients.

The company presented pooled data from four phase III North American studies of more than 1,400 patients undergoing bowel resection (714 on alvimopan 12 mg twice daily and 695 on placebo). The mean age of the patients was about 60 years, and they received opioids via intravenous patient-controlled anesthesia. Alvimopan treatment accelerated GI recovery and reduced the time for the discharge order to be written by about 1 day (18–26 hours).

The proportion of those on alvimopan who met the GI recovery end point, defined as time to tolerating first food (upper GI recovery) and time to first bowel movement (lower GI recovery) by the fifth postsurgical day was 12%–18% higher among those on alvimopan over placebo. The GI recovery time, using this definition, was 13–26 hours faster than with placebo. In addition, the hospital discharge order was written for 85%–89% of those on alvimopan before the seventh day after surgery, compared with 68%–76% for placebo. Moreover, 12% of those on placebo had a nasogastric tube placed, compared with 7% of those on alvimopan, a highly significant difference.

Studies of the drug for chronic opioid-induced bowel dysfunction, conducted by GlaxoSmithKline Inc., are on hold.

SILVER SPRING, MD. — The majority of a Food and Drug Administration advisory panel agreed that the mu-opioid receptor antagonist alvimopan hastened gastrointestinal recovery in patients undergoing bowel resection and receiving opioids for pain. But when the panel weighed the benefits of the drug against its risks, panel members only narrowly voted in favor of the drug.

The FDA's Gastrointestinal Drugs Advisory Committee voted 13–0, with 2 abstentions, that clinical studies evaluating the effects of the drug on postoperative ileus (POI) were “clinically meaningful,” and agreed that reductions in recovery time of 12 and 24 hours were significant.

However, the panel voted by a narrower margin of 9–6 that the beneficial effects of the drug outweighed its potential risks.

The manufacturer, Adolor Corp., has proposed that alvimopan, an oral medication, be approved for “acceleration of time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.” If approved, alvimopan would be the first drug approved for this indication, although surgeons use several drugs off-label for this use. The FDA usually follows the recommendations of its advisory panels, which are not binding.

According to Adolor, alvimopan is a “peripherally acting mu-opioid receptor antagonist that reverses opioid-induced changes in the GI tract without affecting opioid-induced analgesia.” The company plans to market the drug under the trade name Entereg if approved. The recommended dose is one 12-mg capsule taken before surgery, then 12 mg twice daily until discharge for a maximum of 15 doses.

Because of safety concerns raised in a 12-month study of alvimopan as a chronic treatment for opioid-induced bowel dysfunction in patients with chronic, noncancer pain, Adolor has proposed that the drug be limited to short-term, in-hospital use in patients receiving open bowel surgery. The company has proposed a risk management plan aimed at preventing off-label use, long-term use, and use outside acute care hospitals.

In the long-term study of 750 patients, 500 patients received alvimopan 0.5 mg twice daily and 250 received placebo. Compared with the placebo group, the alvimopan group had a greater number of serious cardiovascular events (mostly MI), benign and malignant neoplasms, and bone fractures over a period of 1 year.

However, in short-term POI studies, where patients were treated for 7 days or less, the number of adverse cases was small, and there was no imbalance of these events between placebo and treatment groups, according to Adolor.

In another vote, eight panelists said they remained concerned about the potential risk of cardiovascular events with short-term use, while six panelists, including the cardiologists, said they were not concerned with the risks associated with short-term use. (There was one abstention.)

The nine panel members voting in favor of the overall-risk benefit profile of the drug in this population included the cardiologists and surgeons on the panel, but panelists supported long-term monitoring of cardiovascular effects of the drug and agreed that the risk management plan as proposed by the company was not adequate for monitoring its safety potential.

Cardiologist Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic Foundation, said that in his view, there was no hint of any cardiovascular signal in the short-term follow-up and that he was not concerned about the cardiovascular risks for the short-term indication, even though patients would be taking a higher dose than was used in the long-term trials.

The acting chair of the panel, Dr. Alan L. Buchman, professor of medicine and surgery, division of gastroenterology at Northwestern University, Chicago, said that even though the drug had some physiologic and clinical beneficial effects, they were marginal and POI is a benign condition, so “the risk potential does at a minimum slightly outweigh the potential benefit for the patient.”

Panel members cited the economic benefits of reducing hospital stays by 24 and even 12 hours, opening up more hospital beds for other patients.

The company presented pooled data from four phase III North American studies of more than 1,400 patients undergoing bowel resection (714 on alvimopan 12 mg twice daily and 695 on placebo). The mean age of the patients was about 60 years, and they received opioids via intravenous patient-controlled anesthesia. Alvimopan treatment accelerated GI recovery and reduced the time for the discharge order to be written by about 1 day (18–26 hours).

The proportion of those on alvimopan who met the GI recovery end point, defined as time to tolerating first food (upper GI recovery) and time to first bowel movement (lower GI recovery) by the fifth postsurgical day was 12%–18% higher among those on alvimopan over placebo. The GI recovery time, using this definition, was 13–26 hours faster than with placebo. In addition, the hospital discharge order was written for 85%–89% of those on alvimopan before the seventh day after surgery, compared with 68%–76% for placebo. Moreover, 12% of those on placebo had a nasogastric tube placed, compared with 7% of those on alvimopan, a highly significant difference.

Studies of the drug for chronic opioid-induced bowel dysfunction, conducted by GlaxoSmithKline Inc., are on hold.

SILVER SPRING, MD. — The majority of a Food and Drug Administration advisory panel agreed that the mu-opioid receptor antagonist alvimopan hastened gastrointestinal recovery in patients undergoing bowel resection and receiving opioids for pain. But when the panel weighed the benefits of the drug against its risks, panel members only narrowly voted in favor of the drug.

The FDA's Gastrointestinal Drugs Advisory Committee voted 13–0, with 2 abstentions, that clinical studies evaluating the effects of the drug on postoperative ileus (POI) were “clinically meaningful,” and agreed that reductions in recovery time of 12 and 24 hours were significant.

However, the panel voted by a narrower margin of 9–6 that the beneficial effects of the drug outweighed its potential risks.

The manufacturer, Adolor Corp., has proposed that alvimopan, an oral medication, be approved for “acceleration of time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.” If approved, alvimopan would be the first drug approved for this indication, although surgeons use several drugs off-label for this use. The FDA usually follows the recommendations of its advisory panels, which are not binding.

According to Adolor, alvimopan is a “peripherally acting mu-opioid receptor antagonist that reverses opioid-induced changes in the GI tract without affecting opioid-induced analgesia.” The company plans to market the drug under the trade name Entereg if approved. The recommended dose is one 12-mg capsule taken before surgery, then 12 mg twice daily until discharge for a maximum of 15 doses.

Because of safety concerns raised in a 12-month study of alvimopan as a chronic treatment for opioid-induced bowel dysfunction in patients with chronic, noncancer pain, Adolor has proposed that the drug be limited to short-term, in-hospital use in patients receiving open bowel surgery. The company has proposed a risk management plan aimed at preventing off-label use, long-term use, and use outside acute care hospitals.

In the long-term study of 750 patients, 500 patients received alvimopan 0.5 mg twice daily and 250 received placebo. Compared with the placebo group, the alvimopan group had a greater number of serious cardiovascular events (mostly MI), benign and malignant neoplasms, and bone fractures over a period of 1 year.

However, in short-term POI studies, where patients were treated for 7 days or less, the number of adverse cases was small, and there was no imbalance of these events between placebo and treatment groups, according to Adolor.

In another vote, eight panelists said they remained concerned about the potential risk of cardiovascular events with short-term use, while six panelists, including the cardiologists, said they were not concerned with the risks associated with short-term use. (There was one abstention.)

The nine panel members voting in favor of the overall-risk benefit profile of the drug in this population included the cardiologists and surgeons on the panel, but panelists supported long-term monitoring of cardiovascular effects of the drug and agreed that the risk management plan as proposed by the company was not adequate for monitoring its safety potential.

Cardiologist Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic Foundation, said that in his view, there was no hint of any cardiovascular signal in the short-term follow-up and that he was not concerned about the cardiovascular risks for the short-term indication, even though patients would be taking a higher dose than was used in the long-term trials.

The acting chair of the panel, Dr. Alan L. Buchman, professor of medicine and surgery, division of gastroenterology at Northwestern University, Chicago, said that even though the drug had some physiologic and clinical beneficial effects, they were marginal and POI is a benign condition, so “the risk potential does at a minimum slightly outweigh the potential benefit for the patient.”

Panel members cited the economic benefits of reducing hospital stays by 24 and even 12 hours, opening up more hospital beds for other patients.

The company presented pooled data from four phase III North American studies of more than 1,400 patients undergoing bowel resection (714 on alvimopan 12 mg twice daily and 695 on placebo). The mean age of the patients was about 60 years, and they received opioids via intravenous patient-controlled anesthesia. Alvimopan treatment accelerated GI recovery and reduced the time for the discharge order to be written by about 1 day (18–26 hours).

The proportion of those on alvimopan who met the GI recovery end point, defined as time to tolerating first food (upper GI recovery) and time to first bowel movement (lower GI recovery) by the fifth postsurgical day was 12%–18% higher among those on alvimopan over placebo. The GI recovery time, using this definition, was 13–26 hours faster than with placebo. In addition, the hospital discharge order was written for 85%–89% of those on alvimopan before the seventh day after surgery, compared with 68%–76% for placebo. Moreover, 12% of those on placebo had a nasogastric tube placed, compared with 7% of those on alvimopan, a highly significant difference.

Studies of the drug for chronic opioid-induced bowel dysfunction, conducted by GlaxoSmithKline Inc., are on hold.

A patient's gender and ethnicity, as well as the presence of metabolic syndrome, affect the risk of death after bariatric surgery but not the risk of in-hospital complications, according to a retrospective study of more than 30,000 patients.

The findings “suggest that the presence of the metabolic syndrome negatively affects interethnic and gender-specific outcomes after bariatric surgery,” Dr. Javier Esteban Varela said in an interview.

Dr. Varela of the University of Texas at Dallas was the lead investigator of the study and presented the results at the Academic Surgical Congress.

The investigators evaluated in-hospital clinical data on 30,954 patients with and without metabolic syndrome, who underwent bariatric surgery over a 5-year period (2003–2007). The data were obtained from the University HealthSystem Consortium database. The procedures performed included laparoscopic gastric bypass, open gastric bypass, and laparoscopic gastric banding. Most of the patients (85%) were women, 81% were white, 14% were black, and 5% were Hispanic. The researchers defined metabolic syndrome as morbid obesity plus two or more of the following: hypertension, diabetes, and hyperlipidemia.

The main results of the study—which analyzed gender, ethnicity, morbidity, and mortality—were the following:

▸The prevalence of metabolic syndrome among bariatric surgery patients was higher than previously reported by the National Health and Nutrition Examination Survey (NHANES) III study (27% vs. 23%).

▸Overall morbidity after bariatric surgery was significantly higher in patients with metabolic syndrome than in morbidly obese patients without metabolic syndrome (8.6% vs. 5.8%). Mortality was similar between the two groups (0.04% vs. 0.01%).

▸Hispanics with metabolic syndrome had the highest morbidity rates, followed by blacks and whites. Males had higher mortality than females.

▸In-hospital bariatric surgery outcomes were significantly better in patients who had laparoscopic gastric banding than in those who had gastric bypass. Laparoscopic gastric banding was associated with fewer complications (3% vs. 10%), shorter length of stay (1 vs. 3 days), and lower in-hospital costs ($9,000 vs. $13,000) than was gastric bypass.

The higher complication rates in patients with metabolic syndrome indicate that these patients might benefit from less-invasive procedures, such as laparoscopic gastric banding, said Dr. Varela, who also is director of minimally invasive surgery for the VA North Texas Health Care System. He added, however, that this hypothesis needs to be tested further before any clinical recommendations can be made. Long-term studies evaluating the efficacy of these bariatric procedures in resolving metabolic syndrome in morbidly obese patients are warranted, he said.

The finding that metabolic syndrome was higher among the Hispanic population had been observed previously, he noted.

Asked to comment on the results, Dr. Myriam Curet, a bariatric surgeon and professor of surgery at Stanford (Calif.) University, said that common obesity-related comorbidities—components of what is now called metabolic syndrome—have previously been recognized as risk factors for increased complications after any type of surgery, including bariatric surgery. But the findings of this study are helpful because they demonstrate the association using a large clinical database, and are therefore more translatable to a broad range of practices than are the results of studies from single institutions with a few hundred patients.

She also found the ethnic differences noteworthy. It has been recognized that after bariatric surgery, men do worse than women, and black women tend to do worse than white women, so the data on the ethnic differences are “pretty powerful,” she said.

These results reveal other issues that need to be investigated, Dr. Curet said in an interview. For example, it is important to determine whether something can be done before surgery to reduce risk and to properly counsel patients with the risk factors identified in the study.

“Defining who are the appropriate candidates [and] who are high-risk candidates, and deciding what we can do for those high-risk candidates to make them lower-risk candidates are clearly important issues,” Dr. Curet said. She cautioned against assuming that less-invasive procedures are more appropriate for higher-risk patients, however, pointing out that although some complications with laparoscopic banding are less severe than with gastric bypass procedures, other complications and the need for reoperation are the same as or higher than they are with laparoscopic banding.

In-hospital outcomes were better and costs were lower with gastric banding, Dr. Javier Esteban Varela said. University of Texas Southwestern Medical Center

A patient's gender and ethnicity, as well as the presence of metabolic syndrome, affect the risk of death after bariatric surgery but not the risk of in-hospital complications, according to a retrospective study of more than 30,000 patients.

The findings “suggest that the presence of the metabolic syndrome negatively affects interethnic and gender-specific outcomes after bariatric surgery,” Dr. Javier Esteban Varela said in an interview.

Dr. Varela of the University of Texas at Dallas was the lead investigator of the study and presented the results at the Academic Surgical Congress.

The investigators evaluated in-hospital clinical data on 30,954 patients with and without metabolic syndrome, who underwent bariatric surgery over a 5-year period (2003–2007). The data were obtained from the University HealthSystem Consortium database. The procedures performed included laparoscopic gastric bypass, open gastric bypass, and laparoscopic gastric banding. Most of the patients (85%) were women, 81% were white, 14% were black, and 5% were Hispanic. The researchers defined metabolic syndrome as morbid obesity plus two or more of the following: hypertension, diabetes, and hyperlipidemia.

The main results of the study—which analyzed gender, ethnicity, morbidity, and mortality—were the following:

▸The prevalence of metabolic syndrome among bariatric surgery patients was higher than previously reported by the National Health and Nutrition Examination Survey (NHANES) III study (27% vs. 23%).

▸Overall morbidity after bariatric surgery was significantly higher in patients with metabolic syndrome than in morbidly obese patients without metabolic syndrome (8.6% vs. 5.8%). Mortality was similar between the two groups (0.04% vs. 0.01%).

▸Hispanics with metabolic syndrome had the highest morbidity rates, followed by blacks and whites. Males had higher mortality than females.

▸In-hospital bariatric surgery outcomes were significantly better in patients who had laparoscopic gastric banding than in those who had gastric bypass. Laparoscopic gastric banding was associated with fewer complications (3% vs. 10%), shorter length of stay (1 vs. 3 days), and lower in-hospital costs ($9,000 vs. $13,000) than was gastric bypass.

The higher complication rates in patients with metabolic syndrome indicate that these patients might benefit from less-invasive procedures, such as laparoscopic gastric banding, said Dr. Varela, who also is director of minimally invasive surgery for the VA North Texas Health Care System. He added, however, that this hypothesis needs to be tested further before any clinical recommendations can be made. Long-term studies evaluating the efficacy of these bariatric procedures in resolving metabolic syndrome in morbidly obese patients are warranted, he said.

The finding that metabolic syndrome was higher among the Hispanic population had been observed previously, he noted.

Asked to comment on the results, Dr. Myriam Curet, a bariatric surgeon and professor of surgery at Stanford (Calif.) University, said that common obesity-related comorbidities—components of what is now called metabolic syndrome—have previously been recognized as risk factors for increased complications after any type of surgery, including bariatric surgery. But the findings of this study are helpful because they demonstrate the association using a large clinical database, and are therefore more translatable to a broad range of practices than are the results of studies from single institutions with a few hundred patients.

She also found the ethnic differences noteworthy. It has been recognized that after bariatric surgery, men do worse than women, and black women tend to do worse than white women, so the data on the ethnic differences are “pretty powerful,” she said.

These results reveal other issues that need to be investigated, Dr. Curet said in an interview. For example, it is important to determine whether something can be done before surgery to reduce risk and to properly counsel patients with the risk factors identified in the study.

“Defining who are the appropriate candidates [and] who are high-risk candidates, and deciding what we can do for those high-risk candidates to make them lower-risk candidates are clearly important issues,” Dr. Curet said. She cautioned against assuming that less-invasive procedures are more appropriate for higher-risk patients, however, pointing out that although some complications with laparoscopic banding are less severe than with gastric bypass procedures, other complications and the need for reoperation are the same as or higher than they are with laparoscopic banding.

In-hospital outcomes were better and costs were lower with gastric banding, Dr. Javier Esteban Varela said. University of Texas Southwestern Medical Center

A patient's gender and ethnicity, as well as the presence of metabolic syndrome, affect the risk of death after bariatric surgery but not the risk of in-hospital complications, according to a retrospective study of more than 30,000 patients.

The findings “suggest that the presence of the metabolic syndrome negatively affects interethnic and gender-specific outcomes after bariatric surgery,” Dr. Javier Esteban Varela said in an interview.

Dr. Varela of the University of Texas at Dallas was the lead investigator of the study and presented the results at the Academic Surgical Congress.

The investigators evaluated in-hospital clinical data on 30,954 patients with and without metabolic syndrome, who underwent bariatric surgery over a 5-year period (2003–2007). The data were obtained from the University HealthSystem Consortium database. The procedures performed included laparoscopic gastric bypass, open gastric bypass, and laparoscopic gastric banding. Most of the patients (85%) were women, 81% were white, 14% were black, and 5% were Hispanic. The researchers defined metabolic syndrome as morbid obesity plus two or more of the following: hypertension, diabetes, and hyperlipidemia.

The main results of the study—which analyzed gender, ethnicity, morbidity, and mortality—were the following:

▸The prevalence of metabolic syndrome among bariatric surgery patients was higher than previously reported by the National Health and Nutrition Examination Survey (NHANES) III study (27% vs. 23%).

▸Overall morbidity after bariatric surgery was significantly higher in patients with metabolic syndrome than in morbidly obese patients without metabolic syndrome (8.6% vs. 5.8%). Mortality was similar between the two groups (0.04% vs. 0.01%).

▸Hispanics with metabolic syndrome had the highest morbidity rates, followed by blacks and whites. Males had higher mortality than females.

▸In-hospital bariatric surgery outcomes were significantly better in patients who had laparoscopic gastric banding than in those who had gastric bypass. Laparoscopic gastric banding was associated with fewer complications (3% vs. 10%), shorter length of stay (1 vs. 3 days), and lower in-hospital costs ($9,000 vs. $13,000) than was gastric bypass.

The higher complication rates in patients with metabolic syndrome indicate that these patients might benefit from less-invasive procedures, such as laparoscopic gastric banding, said Dr. Varela, who also is director of minimally invasive surgery for the VA North Texas Health Care System. He added, however, that this hypothesis needs to be tested further before any clinical recommendations can be made. Long-term studies evaluating the efficacy of these bariatric procedures in resolving metabolic syndrome in morbidly obese patients are warranted, he said.

The finding that metabolic syndrome was higher among the Hispanic population had been observed previously, he noted.

Asked to comment on the results, Dr. Myriam Curet, a bariatric surgeon and professor of surgery at Stanford (Calif.) University, said that common obesity-related comorbidities—components of what is now called metabolic syndrome—have previously been recognized as risk factors for increased complications after any type of surgery, including bariatric surgery. But the findings of this study are helpful because they demonstrate the association using a large clinical database, and are therefore more translatable to a broad range of practices than are the results of studies from single institutions with a few hundred patients.

She also found the ethnic differences noteworthy. It has been recognized that after bariatric surgery, men do worse than women, and black women tend to do worse than white women, so the data on the ethnic differences are “pretty powerful,” she said.

These results reveal other issues that need to be investigated, Dr. Curet said in an interview. For example, it is important to determine whether something can be done before surgery to reduce risk and to properly counsel patients with the risk factors identified in the study.

“Defining who are the appropriate candidates [and] who are high-risk candidates, and deciding what we can do for those high-risk candidates to make them lower-risk candidates are clearly important issues,” Dr. Curet said. She cautioned against assuming that less-invasive procedures are more appropriate for higher-risk patients, however, pointing out that although some complications with laparoscopic banding are less severe than with gastric bypass procedures, other complications and the need for reoperation are the same as or higher than they are with laparoscopic banding.

In-hospital outcomes were better and costs were lower with gastric banding, Dr. Javier Esteban Varela said. University of Texas Southwestern Medical Center

Postmarketing reports of an increased risk of first trimester loss and congenital malformations associated with the use of mycophenolate mofetil during pregnancy has prompted a pregnancy category label change for the immunosuppressant drug.

Mycophenolate mofetil, marketed as CellCept by Roche, is approved for preventing organ rejection in allogenic kidney, heart, or liver transplant recipients, and is used with cyclosporine and corticosteroids.

CellCept also has been used off-label to treat some dermatologic and rheumatologic conditions.

Based on postmarketing data from the U.S. National Transplantation Pregnancy Registry and other postmarketing data in women exposed to systemic CellCept during pregnancy, the pregnancy category label has been changed from a category C, in which the risk of fetal harm cannot be ruled out, to category D, in which there is positive evidence of fetal risk.

Exposure to CellCept during pregnancy has been associated with an increased risk of first trimester loss, and an increased risk of congenital malformations, “especially external ear and facial abnormalities, including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney,” according to Roche and the Food and Drug Administration.

The pregnancy category change was announced on the FDA's MedWatch site, and in a letter to health care professionals issued by Roche.

The letter refers to the December 2006 publication of reports from the transplant registry of 33 pregnancies in 24 female transplant patients exposed to regimens containing CellCept. Of the 33 cases, there were 15 spontaneous abortions (45%). Of the 18 live-born infants, 4 (22%) had structural malformations. There were also postmarketing reports, collected between 1995 and 2007, of 77 women exposed to systemic CellCept during pregnancy, of whom 25 (33%) had spontaneous abortions and 14 (18%) had a malformed infant or fetus.

The Roche letter advised that women of childbearing potential–including pubescent girls and perimenopausal women–should have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 1 week before starting treatment and they should receive contraceptive counseling. Unless abstinence is chosen, women in this category should start using two contraceptive methods 4 weeks before starting treatment with CellCept, and should continue using those two methods for 6 weeks after stopping treatment. CellCept should not be used in a woman who plans to become pregnant “unless she cannot be successfully treated with other immunosuppressant drugs,” according to the letter.

Roche encourages health care professionals to register pregnant women exposed to CellCept in the transplant registry by calling 877-955-6877.

For the MedWatch announcement, Roche letter, and revised label, go to: www.fda.gov/medwatch/safety/2007/safety07.htm#CellCept2www.fda.gov/medwatch

Postmarketing reports of an increased risk of first trimester loss and congenital malformations associated with the use of mycophenolate mofetil during pregnancy has prompted a pregnancy category label change for the immunosuppressant drug.

Mycophenolate mofetil, marketed as CellCept by Roche, is approved for preventing organ rejection in allogenic kidney, heart, or liver transplant recipients, and is used with cyclosporine and corticosteroids.

CellCept also has been used off-label to treat some dermatologic and rheumatologic conditions.

Based on postmarketing data from the U.S. National Transplantation Pregnancy Registry and other postmarketing data in women exposed to systemic CellCept during pregnancy, the pregnancy category label has been changed from a category C, in which the risk of fetal harm cannot be ruled out, to category D, in which there is positive evidence of fetal risk.

Exposure to CellCept during pregnancy has been associated with an increased risk of first trimester loss, and an increased risk of congenital malformations, “especially external ear and facial abnormalities, including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney,” according to Roche and the Food and Drug Administration.

The pregnancy category change was announced on the FDA's MedWatch site, and in a letter to health care professionals issued by Roche.

The letter refers to the December 2006 publication of reports from the transplant registry of 33 pregnancies in 24 female transplant patients exposed to regimens containing CellCept. Of the 33 cases, there were 15 spontaneous abortions (45%). Of the 18 live-born infants, 4 (22%) had structural malformations. There were also postmarketing reports, collected between 1995 and 2007, of 77 women exposed to systemic CellCept during pregnancy, of whom 25 (33%) had spontaneous abortions and 14 (18%) had a malformed infant or fetus.

The Roche letter advised that women of childbearing potential–including pubescent girls and perimenopausal women–should have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 1 week before starting treatment and they should receive contraceptive counseling. Unless abstinence is chosen, women in this category should start using two contraceptive methods 4 weeks before starting treatment with CellCept, and should continue using those two methods for 6 weeks after stopping treatment. CellCept should not be used in a woman who plans to become pregnant “unless she cannot be successfully treated with other immunosuppressant drugs,” according to the letter.

Roche encourages health care professionals to register pregnant women exposed to CellCept in the transplant registry by calling 877-955-6877.

For the MedWatch announcement, Roche letter, and revised label, go to: www.fda.gov/medwatch/safety/2007/safety07.htm#CellCept2www.fda.gov/medwatch

Postmarketing reports of an increased risk of first trimester loss and congenital malformations associated with the use of mycophenolate mofetil during pregnancy has prompted a pregnancy category label change for the immunosuppressant drug.

Mycophenolate mofetil, marketed as CellCept by Roche, is approved for preventing organ rejection in allogenic kidney, heart, or liver transplant recipients, and is used with cyclosporine and corticosteroids.

CellCept also has been used off-label to treat some dermatologic and rheumatologic conditions.

Based on postmarketing data from the U.S. National Transplantation Pregnancy Registry and other postmarketing data in women exposed to systemic CellCept during pregnancy, the pregnancy category label has been changed from a category C, in which the risk of fetal harm cannot be ruled out, to category D, in which there is positive evidence of fetal risk.

Exposure to CellCept during pregnancy has been associated with an increased risk of first trimester loss, and an increased risk of congenital malformations, “especially external ear and facial abnormalities, including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney,” according to Roche and the Food and Drug Administration.

The pregnancy category change was announced on the FDA's MedWatch site, and in a letter to health care professionals issued by Roche.

The letter refers to the December 2006 publication of reports from the transplant registry of 33 pregnancies in 24 female transplant patients exposed to regimens containing CellCept. Of the 33 cases, there were 15 spontaneous abortions (45%). Of the 18 live-born infants, 4 (22%) had structural malformations. There were also postmarketing reports, collected between 1995 and 2007, of 77 women exposed to systemic CellCept during pregnancy, of whom 25 (33%) had spontaneous abortions and 14 (18%) had a malformed infant or fetus.

The Roche letter advised that women of childbearing potential–including pubescent girls and perimenopausal women–should have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 1 week before starting treatment and they should receive contraceptive counseling. Unless abstinence is chosen, women in this category should start using two contraceptive methods 4 weeks before starting treatment with CellCept, and should continue using those two methods for 6 weeks after stopping treatment. CellCept should not be used in a woman who plans to become pregnant “unless she cannot be successfully treated with other immunosuppressant drugs,” according to the letter.

Roche encourages health care professionals to register pregnant women exposed to CellCept in the transplant registry by calling 877-955-6877.

For the MedWatch announcement, Roche letter, and revised label, go to: www.fda.gov/medwatch/safety/2007/safety07.htm#CellCept2www.fda.gov/medwatch

SILVER SPRING, MD. — For the third time since 2000, Merck & Co. failed to convince Food and Drug Administration advisory panelists that lovastatin should be made available over the counter.

At a joint meeting, the FDA's Nonprescription Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee voted 10–2, with one abstention, that lovastatin should not be approved as a nonprescription drug, based on the data provided by the company. The data included the results of a trial evaluating how consumers self-select for treatment with lovastatin. The panelists voted 11–2 that the results of the study did not show that OTC consumers could make an appropriate self-selection decision.

Merck filed for approval for OTC use of a fixed daily 20-mg dose of lovastatin, marketed as Mevacor, “to help lower cholesterol, which may prevent a first heart attack,” focusing on a moderate-risk population. This population, identified using National Cholesterol Education Program (NCEP) ATP III guidelines, comprised men aged at least 45 years and women aged at least 55 years with moderately high LDL cholesterol (130 mg/dL to 170 mg/dL) and one additional CHD risk factor. Merck's main argument was that the OTC availability of lovastatin would increase access and use among the large, undertreated population of people with high cholesterol, and would result in significant public health benefits.

The panel generally agreed that lovastatin was a safe and effective medication. But they were concerned that the results of the study indicated that a substantial proportion of patients who were actually high risk and should have been on a prescription statin, under a physician's supervision, would self-select for a statin. Likewise, a substantial proportion of people who were low risk and not candidates for therapy would also self-select for a statin. Other concerns were the lack of actual use studies in real-world situations.

“Patients couldn't figure out whether the drug was for them,” said Dr. William Shrank of the division of pharmacoepidemiology and pharmacoeconomics at Harvard Medical School, Boston.

“In my view, the benefits greatly outweigh the risks,” said Dr. Thomas Pickering, director of the behavioral cardiovascular health and hypertension program at Columbia University, New York. Dr. Pickering voted in favor of approval. Describing the statins as an “incredibly safe” group of drugs, he said there is “a huge, unmet need for people who should be taking statins and who are not, and this offers a plausible way for getting them all to take them.”

The FDA usually follows the advice of its advisory panels. This is the third time that the advisory panels have met to vote on approval since 2000. At the second meeting in January 2005, the panels voted 20–3 against approval for the OTC switch, citing problems with the label comprehension study and doubts about whether patients could properly self-select for treatment.

Since then, Merck made substantial changes to the label and accompanying materials, and conducted another self-selection study of more than 1,400 participants at 14 U.S. sites, in a simulated retail setting in which a pharmacist was available to answer questions. The Self-Evaluation of Lovastatin to Enhance Cholesterol Treatment (SELECT) study evaluated two labels (one with LDL cholesterol information and one with total cholesterol information as eligibility criteria) that patients used to determine whether the drug was appropriate for them and whether they would buy the product. Labels also included information on absolute and relative safety warnings and a decision tree.

About 72% of the participants were correct in determining whether lovastatin was appropriate for them, with either label. Most of the correct decisions were that the drug was not appropriate. For example, of the 662 participants who were in the LDL cholesterol label arm, 439 correctly determined that the drug was not appropriate and 34 correctly determined that it was appropriate, for a total of 71.5%.

The materials included in the redesigned package were a refrigerator magnet reminding people to call their physicians if they experienced muscle pains, a “heart healthy” living guide, and cards for consumers to give to pharmacists and physicians saying they were taking lovastatin.

The FDA is expected to make a decision by the end of January.

SILVER SPRING, MD. — For the third time since 2000, Merck & Co. failed to convince Food and Drug Administration advisory panelists that lovastatin should be made available over the counter.

At a joint meeting, the FDA's Nonprescription Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee voted 10–2, with one abstention, that lovastatin should not be approved as a nonprescription drug, based on the data provided by the company. The data included the results of a trial evaluating how consumers self-select for treatment with lovastatin. The panelists voted 11–2 that the results of the study did not show that OTC consumers could make an appropriate self-selection decision.

Merck filed for approval for OTC use of a fixed daily 20-mg dose of lovastatin, marketed as Mevacor, “to help lower cholesterol, which may prevent a first heart attack,” focusing on a moderate-risk population. This population, identified using National Cholesterol Education Program (NCEP) ATP III guidelines, comprised men aged at least 45 years and women aged at least 55 years with moderately high LDL cholesterol (130 mg/dL to 170 mg/dL) and one additional CHD risk factor. Merck's main argument was that the OTC availability of lovastatin would increase access and use among the large, undertreated population of people with high cholesterol, and would result in significant public health benefits.

The panel generally agreed that lovastatin was a safe and effective medication. But they were concerned that the results of the study indicated that a substantial proportion of patients who were actually high risk and should have been on a prescription statin, under a physician's supervision, would self-select for a statin. Likewise, a substantial proportion of people who were low risk and not candidates for therapy would also self-select for a statin. Other concerns were the lack of actual use studies in real-world situations.

“Patients couldn't figure out whether the drug was for them,” said Dr. William Shrank of the division of pharmacoepidemiology and pharmacoeconomics at Harvard Medical School, Boston.

“In my view, the benefits greatly outweigh the risks,” said Dr. Thomas Pickering, director of the behavioral cardiovascular health and hypertension program at Columbia University, New York. Dr. Pickering voted in favor of approval. Describing the statins as an “incredibly safe” group of drugs, he said there is “a huge, unmet need for people who should be taking statins and who are not, and this offers a plausible way for getting them all to take them.”

The FDA usually follows the advice of its advisory panels. This is the third time that the advisory panels have met to vote on approval since 2000. At the second meeting in January 2005, the panels voted 20–3 against approval for the OTC switch, citing problems with the label comprehension study and doubts about whether patients could properly self-select for treatment.

Since then, Merck made substantial changes to the label and accompanying materials, and conducted another self-selection study of more than 1,400 participants at 14 U.S. sites, in a simulated retail setting in which a pharmacist was available to answer questions. The Self-Evaluation of Lovastatin to Enhance Cholesterol Treatment (SELECT) study evaluated two labels (one with LDL cholesterol information and one with total cholesterol information as eligibility criteria) that patients used to determine whether the drug was appropriate for them and whether they would buy the product. Labels also included information on absolute and relative safety warnings and a decision tree.

About 72% of the participants were correct in determining whether lovastatin was appropriate for them, with either label. Most of the correct decisions were that the drug was not appropriate. For example, of the 662 participants who were in the LDL cholesterol label arm, 439 correctly determined that the drug was not appropriate and 34 correctly determined that it was appropriate, for a total of 71.5%.

The materials included in the redesigned package were a refrigerator magnet reminding people to call their physicians if they experienced muscle pains, a “heart healthy” living guide, and cards for consumers to give to pharmacists and physicians saying they were taking lovastatin.

The FDA is expected to make a decision by the end of January.

SILVER SPRING, MD. — For the third time since 2000, Merck & Co. failed to convince Food and Drug Administration advisory panelists that lovastatin should be made available over the counter.

At a joint meeting, the FDA's Nonprescription Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee voted 10–2, with one abstention, that lovastatin should not be approved as a nonprescription drug, based on the data provided by the company. The data included the results of a trial evaluating how consumers self-select for treatment with lovastatin. The panelists voted 11–2 that the results of the study did not show that OTC consumers could make an appropriate self-selection decision.

Merck filed for approval for OTC use of a fixed daily 20-mg dose of lovastatin, marketed as Mevacor, “to help lower cholesterol, which may prevent a first heart attack,” focusing on a moderate-risk population. This population, identified using National Cholesterol Education Program (NCEP) ATP III guidelines, comprised men aged at least 45 years and women aged at least 55 years with moderately high LDL cholesterol (130 mg/dL to 170 mg/dL) and one additional CHD risk factor. Merck's main argument was that the OTC availability of lovastatin would increase access and use among the large, undertreated population of people with high cholesterol, and would result in significant public health benefits.

The panel generally agreed that lovastatin was a safe and effective medication. But they were concerned that the results of the study indicated that a substantial proportion of patients who were actually high risk and should have been on a prescription statin, under a physician's supervision, would self-select for a statin. Likewise, a substantial proportion of people who were low risk and not candidates for therapy would also self-select for a statin. Other concerns were the lack of actual use studies in real-world situations.

“Patients couldn't figure out whether the drug was for them,” said Dr. William Shrank of the division of pharmacoepidemiology and pharmacoeconomics at Harvard Medical School, Boston.

“In my view, the benefits greatly outweigh the risks,” said Dr. Thomas Pickering, director of the behavioral cardiovascular health and hypertension program at Columbia University, New York. Dr. Pickering voted in favor of approval. Describing the statins as an “incredibly safe” group of drugs, he said there is “a huge, unmet need for people who should be taking statins and who are not, and this offers a plausible way for getting them all to take them.”

The FDA usually follows the advice of its advisory panels. This is the third time that the advisory panels have met to vote on approval since 2000. At the second meeting in January 2005, the panels voted 20–3 against approval for the OTC switch, citing problems with the label comprehension study and doubts about whether patients could properly self-select for treatment.

Since then, Merck made substantial changes to the label and accompanying materials, and conducted another self-selection study of more than 1,400 participants at 14 U.S. sites, in a simulated retail setting in which a pharmacist was available to answer questions. The Self-Evaluation of Lovastatin to Enhance Cholesterol Treatment (SELECT) study evaluated two labels (one with LDL cholesterol information and one with total cholesterol information as eligibility criteria) that patients used to determine whether the drug was appropriate for them and whether they would buy the product. Labels also included information on absolute and relative safety warnings and a decision tree.

About 72% of the participants were correct in determining whether lovastatin was appropriate for them, with either label. Most of the correct decisions were that the drug was not appropriate. For example, of the 662 participants who were in the LDL cholesterol label arm, 439 correctly determined that the drug was not appropriate and 34 correctly determined that it was appropriate, for a total of 71.5%.

The materials included in the redesigned package were a refrigerator magnet reminding people to call their physicians if they experienced muscle pains, a “heart healthy” living guide, and cards for consumers to give to pharmacists and physicians saying they were taking lovastatin.

The FDA is expected to make a decision by the end of January.

Medtronic Inc.'s decision to voluntarily recall all Sprint Fidelis defibrillator leads was announced “because of the potential for lead fractures,” but recommended against replacing leads with no apparent problems.

The company identified five deaths “in which a Sprint Fidelis lead fracture may have been a possible or likely contributing factor,” Medtronic said in a statement announcing the recall. The clinical signs of lead fractures can include audible alerts, inappropriate shocks, and/or loss of output.

The leads are used with defibrillators, including implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-Ds). Patients with Medtronic pacemakers are not affected. About 268,000 of these leads (models 6930, 6931, 6948, and 6949) have been implanted worldwide, the company said.

Medtronic has data showing that at 30 months, the viability of the Sprint Fidelis lead is lower than that of the company's Sprint Quattro lead (97.7% vs. 99.1%), which is not statistically different. However, “if the current lead fracture rates become constant,” the difference will become significant over time, the statement said.

The Medtronic statement explains that the company, its independent panel of physicians, and Dr. Bruce Lindsay, professor of medicine and director of cardiac electrophysiology at Washington University, St. Louis, who is also president of the Heart Rhythm Society, “do not recommend that patients seek prophylactic replacement of Sprint Fidelis leads, as the risks of removal or insertion of another lead exceed the small risk to patients of a lead fracture.”

The letter to physicians points out that lead extraction carries risks “that should be considered in patient management,” and that published literature “suggests major complications (death or surgical intervention) from lead extraction range from 1.4% [to] 7.3%. As always, with confirmed lead failure, the risk of extraction should be weighed against the risk of adding an additional lead.”

In a statement issued by the Food and Drug Administration, Dr. Daniel Schultz, director of the FDA's Center for Devices and Radiological Health, said that based on the agency's initial review of reported adverse events, some deaths and major complications have occurred after the leads have fractured.

Although this can be frightening to patients, Dr. Schultz added that “patients can be assured that the likelihood of fracture is very low.”

The currently available adverse event data for the leads indicate that fractures have occurred in less than 1% of the approximately 268,000 leads implanted, but whether the rate will increase or remain constant over the life of the leads is unknown, the FDA statement said.

The day after the Medtronic announcement, Sen. Chuck Grassley (R-Iowa) sent a letter to the FDA and Medtronic requesting more information about the recalled leads. And in another letter to the FDA, the public advocacy group, Public Citizen's Health Research Group, requested that the agency conduct an investigation into why the FDA did not compel Medtronic to recall the Sprint Fidelis defibrillator leads earlier this year, when the FDA was aware of “the rapidly mounting number of injury reports” associated with these leads, according to the letter.

The FDA statement says that Medtronic first notified physicians about the lead fracture rate and about the proper method of implantation of the leads in March, and that the decision to suspend marketing of the leads was prompted by “additional data on adverse events” that had accumulated since that time.

Medtronic has posted information for physicians and patients at www.medtronic.com/fidelis

Medtronic Inc.'s decision to voluntarily recall all Sprint Fidelis defibrillator leads was announced “because of the potential for lead fractures,” but recommended against replacing leads with no apparent problems.

The company identified five deaths “in which a Sprint Fidelis lead fracture may have been a possible or likely contributing factor,” Medtronic said in a statement announcing the recall. The clinical signs of lead fractures can include audible alerts, inappropriate shocks, and/or loss of output.

The leads are used with defibrillators, including implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-Ds). Patients with Medtronic pacemakers are not affected. About 268,000 of these leads (models 6930, 6931, 6948, and 6949) have been implanted worldwide, the company said.

Medtronic has data showing that at 30 months, the viability of the Sprint Fidelis lead is lower than that of the company's Sprint Quattro lead (97.7% vs. 99.1%), which is not statistically different. However, “if the current lead fracture rates become constant,” the difference will become significant over time, the statement said.

The Medtronic statement explains that the company, its independent panel of physicians, and Dr. Bruce Lindsay, professor of medicine and director of cardiac electrophysiology at Washington University, St. Louis, who is also president of the Heart Rhythm Society, “do not recommend that patients seek prophylactic replacement of Sprint Fidelis leads, as the risks of removal or insertion of another lead exceed the small risk to patients of a lead fracture.”

The letter to physicians points out that lead extraction carries risks “that should be considered in patient management,” and that published literature “suggests major complications (death or surgical intervention) from lead extraction range from 1.4% [to] 7.3%. As always, with confirmed lead failure, the risk of extraction should be weighed against the risk of adding an additional lead.”

In a statement issued by the Food and Drug Administration, Dr. Daniel Schultz, director of the FDA's Center for Devices and Radiological Health, said that based on the agency's initial review of reported adverse events, some deaths and major complications have occurred after the leads have fractured.

Although this can be frightening to patients, Dr. Schultz added that “patients can be assured that the likelihood of fracture is very low.”

The currently available adverse event data for the leads indicate that fractures have occurred in less than 1% of the approximately 268,000 leads implanted, but whether the rate will increase or remain constant over the life of the leads is unknown, the FDA statement said.

The day after the Medtronic announcement, Sen. Chuck Grassley (R-Iowa) sent a letter to the FDA and Medtronic requesting more information about the recalled leads. And in another letter to the FDA, the public advocacy group, Public Citizen's Health Research Group, requested that the agency conduct an investigation into why the FDA did not compel Medtronic to recall the Sprint Fidelis defibrillator leads earlier this year, when the FDA was aware of “the rapidly mounting number of injury reports” associated with these leads, according to the letter.

The FDA statement says that Medtronic first notified physicians about the lead fracture rate and about the proper method of implantation of the leads in March, and that the decision to suspend marketing of the leads was prompted by “additional data on adverse events” that had accumulated since that time.

Medtronic has posted information for physicians and patients at www.medtronic.com/fidelis

Medtronic Inc.'s decision to voluntarily recall all Sprint Fidelis defibrillator leads was announced “because of the potential for lead fractures,” but recommended against replacing leads with no apparent problems.

The company identified five deaths “in which a Sprint Fidelis lead fracture may have been a possible or likely contributing factor,” Medtronic said in a statement announcing the recall. The clinical signs of lead fractures can include audible alerts, inappropriate shocks, and/or loss of output.

The leads are used with defibrillators, including implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-Ds). Patients with Medtronic pacemakers are not affected. About 268,000 of these leads (models 6930, 6931, 6948, and 6949) have been implanted worldwide, the company said.

Medtronic has data showing that at 30 months, the viability of the Sprint Fidelis lead is lower than that of the company's Sprint Quattro lead (97.7% vs. 99.1%), which is not statistically different. However, “if the current lead fracture rates become constant,” the difference will become significant over time, the statement said.

The Medtronic statement explains that the company, its independent panel of physicians, and Dr. Bruce Lindsay, professor of medicine and director of cardiac electrophysiology at Washington University, St. Louis, who is also president of the Heart Rhythm Society, “do not recommend that patients seek prophylactic replacement of Sprint Fidelis leads, as the risks of removal or insertion of another lead exceed the small risk to patients of a lead fracture.”

The letter to physicians points out that lead extraction carries risks “that should be considered in patient management,” and that published literature “suggests major complications (death or surgical intervention) from lead extraction range from 1.4% [to] 7.3%. As always, with confirmed lead failure, the risk of extraction should be weighed against the risk of adding an additional lead.”

In a statement issued by the Food and Drug Administration, Dr. Daniel Schultz, director of the FDA's Center for Devices and Radiological Health, said that based on the agency's initial review of reported adverse events, some deaths and major complications have occurred after the leads have fractured.

Although this can be frightening to patients, Dr. Schultz added that “patients can be assured that the likelihood of fracture is very low.”

The currently available adverse event data for the leads indicate that fractures have occurred in less than 1% of the approximately 268,000 leads implanted, but whether the rate will increase or remain constant over the life of the leads is unknown, the FDA statement said.

The day after the Medtronic announcement, Sen. Chuck Grassley (R-Iowa) sent a letter to the FDA and Medtronic requesting more information about the recalled leads. And in another letter to the FDA, the public advocacy group, Public Citizen's Health Research Group, requested that the agency conduct an investigation into why the FDA did not compel Medtronic to recall the Sprint Fidelis defibrillator leads earlier this year, when the FDA was aware of “the rapidly mounting number of injury reports” associated with these leads, according to the letter.

The FDA statement says that Medtronic first notified physicians about the lead fracture rate and about the proper method of implantation of the leads in March, and that the decision to suspend marketing of the leads was prompted by “additional data on adverse events” that had accumulated since that time.

Medtronic has posted information for physicians and patients at www.medtronic.com/fidelis

The Food and Drug Administration has approved a thrombin product derived from human plasma to help control bleeding during surgery.

Evithrom, is the first human thrombin approved since 1954 and is the only such product currently licensed by the agency, according to an FDA statement announcing the approval. The approved indication is “as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical.”

The approval “offers an important additional option for surgeons and their patients to help control surgical bleeding,” and provides surgeons the choice between human thrombin and bovine-derived thrombin, Dr. Jesse L. Goodman, director of the FDA's Center for Biologics Evaluation and Research, said in the statement.

Evithrom is applied to the surface of bleeding tissue and can be used with an absorbable gelatin sponge. The safety and efficacy of Evithrom were “comparable” with those of cattle-derived thrombin in a study of 305 patients, according to the FDA. In the study, 63 patients who received Evithrom were over age 65. No differences in product safety or efficacy were documented between elderly and younger patients, according to the product's label.

The label cites immunogenicity data from the study, which compared the presence of antibodies to bovine thrombin, bovine Factor V/Va, human thrombin, and human factor V/Va at baseline and 5 weeks after surgery in most of the patients. About 3% of those who received Evithrom developed antibodies to any of these four antigens, compared with nearly 13% of those who received bovine-derived thrombin. Nearly 8% of those in the latter group developed antibodies to bovine thrombin, and nearly 10% developed antibodies to bovine factor V/Va, while none of those treated with Evithrom had detectable antibodies to human thrombin or to human factor V/Va.

Manufactured by Omrix Biopharmaceuticals Ltd., based in Ramat Gan, Israel, Evithrom is made from pooled human plasma derived from U.S.-licensed plasma collection centers, using carefully screened donors. Johnson & Johnson Wound Management (a division of Ethicon Inc.) will be distributing it in the United States.

Evithrom contraindications include treatment of severe or brisk arterial bleeding.

The Food and Drug Administration has approved a thrombin product derived from human plasma to help control bleeding during surgery.

Evithrom, is the first human thrombin approved since 1954 and is the only such product currently licensed by the agency, according to an FDA statement announcing the approval. The approved indication is “as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical.”

The approval “offers an important additional option for surgeons and their patients to help control surgical bleeding,” and provides surgeons the choice between human thrombin and bovine-derived thrombin, Dr. Jesse L. Goodman, director of the FDA's Center for Biologics Evaluation and Research, said in the statement.

Evithrom is applied to the surface of bleeding tissue and can be used with an absorbable gelatin sponge. The safety and efficacy of Evithrom were “comparable” with those of cattle-derived thrombin in a study of 305 patients, according to the FDA. In the study, 63 patients who received Evithrom were over age 65. No differences in product safety or efficacy were documented between elderly and younger patients, according to the product's label.

The label cites immunogenicity data from the study, which compared the presence of antibodies to bovine thrombin, bovine Factor V/Va, human thrombin, and human factor V/Va at baseline and 5 weeks after surgery in most of the patients. About 3% of those who received Evithrom developed antibodies to any of these four antigens, compared with nearly 13% of those who received bovine-derived thrombin. Nearly 8% of those in the latter group developed antibodies to bovine thrombin, and nearly 10% developed antibodies to bovine factor V/Va, while none of those treated with Evithrom had detectable antibodies to human thrombin or to human factor V/Va.

Manufactured by Omrix Biopharmaceuticals Ltd., based in Ramat Gan, Israel, Evithrom is made from pooled human plasma derived from U.S.-licensed plasma collection centers, using carefully screened donors. Johnson & Johnson Wound Management (a division of Ethicon Inc.) will be distributing it in the United States.

Evithrom contraindications include treatment of severe or brisk arterial bleeding.

The Food and Drug Administration has approved a thrombin product derived from human plasma to help control bleeding during surgery.

Evithrom, is the first human thrombin approved since 1954 and is the only such product currently licensed by the agency, according to an FDA statement announcing the approval. The approved indication is “as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical.”

The approval “offers an important additional option for surgeons and their patients to help control surgical bleeding,” and provides surgeons the choice between human thrombin and bovine-derived thrombin, Dr. Jesse L. Goodman, director of the FDA's Center for Biologics Evaluation and Research, said in the statement.

Evithrom is applied to the surface of bleeding tissue and can be used with an absorbable gelatin sponge. The safety and efficacy of Evithrom were “comparable” with those of cattle-derived thrombin in a study of 305 patients, according to the FDA. In the study, 63 patients who received Evithrom were over age 65. No differences in product safety or efficacy were documented between elderly and younger patients, according to the product's label.

The label cites immunogenicity data from the study, which compared the presence of antibodies to bovine thrombin, bovine Factor V/Va, human thrombin, and human factor V/Va at baseline and 5 weeks after surgery in most of the patients. About 3% of those who received Evithrom developed antibodies to any of these four antigens, compared with nearly 13% of those who received bovine-derived thrombin. Nearly 8% of those in the latter group developed antibodies to bovine thrombin, and nearly 10% developed antibodies to bovine factor V/Va, while none of those treated with Evithrom had detectable antibodies to human thrombin or to human factor V/Va.

Manufactured by Omrix Biopharmaceuticals Ltd., based in Ramat Gan, Israel, Evithrom is made from pooled human plasma derived from U.S.-licensed plasma collection centers, using carefully screened donors. Johnson & Johnson Wound Management (a division of Ethicon Inc.) will be distributing it in the United States.

Evithrom contraindications include treatment of severe or brisk arterial bleeding.

A study using national health survey data has found varying associations between body mass index and mortality, depending on the cause.

Using data on cause-specific relative risks of mortality from the National Health and Nutrition Examination Survey (NHANES) from 1971–2002, Katherine M. Flegal, Ph.D., and colleagues looked at the association between body mass index (BMI) and excess deaths associated with three different BMI categories: underweight (BMI less than 18.5), overweight (BMI of 25 to less than 30), and obesity (BMI of 30 and over). Deaths were divided into three major categories: cardiovascular disease (CVD), cancer, and all other causes (noncancer, non-CVD causes). The normal-weight category was used as the reference group.

The underweight category was associated with significantly increased mortality from noncancer and non-CVD causes, but was not associated with increased cancer or CVD mortality.

The overweight category, however, was associated with significantly decreased mortality from noncancer and non-CVD causes. This category was not associated with cancer or CVD mortality, but was associated with significant increased mortality from diabetes and kidney disease. The net result was that the overweight category was associated with significantly decreased all-cause mortality overall, the authors reported.

The obese category was associated with significantly increased mortality from CVD, some cancers, and diabetes and kidney disease. There was no significant association between obesity and cancer mortality overall, or with noncancer, non- CVD mortality. But it was associated with increased mortality from obesity-related cancers such as colon, breast, esophageal, uterine, ovarian, kidney, and pancreatic cancer (JAMA 2007;298:2028–37).

These data “indicate that the association of BMI with mortality varies considerably by cause of death,” the authors concluded. These results also help clarify their findings in an earlier study, which found “excess overall mortality associated with underweight and obesity but not with overweight.”

In an interview, Dr. Flegal, senior research scientist at the National Center for Health Statistics, Hyattsville, Md., and lead author of the study, said the study's results were similar to those in other studies and are not intended for clinical use. Instead, they are intended to make estimates of the contribution of obesity and overweight to excess deaths.

The current study is an extension of a study, published in 2005, which determined that, based on national survey data from 2000, all-cause mortality was significantly increased in the underweight and obese categories and significantly decreased in the overweight category when compared with normal-weight categories.

Dr. Flegal said although some media coverage of that study suggested the findings were unusual, the association of overweight with mortality that is similar to or lower than that for normal weight, as well as the idea that being overweight may offer some survival benefits, have been found in other studies.

She emphasized that the relationship between BMI and mortality is complex. The study is not “the arbiter of whether it's OK to be overweight or not.”

Asked to comment on the study's findings, Dr. Jeffrey I. Mechanick said its implications could “easily and dangerously” be distorted and should not be interpreted to mean that the results support allowing oneself to remain overweight or that dieting to achieve a “normal” BMI may not be medically indicated. Overweight people are at risk for diseases associated with a higher morbidity and mortality rate, including diabetes, obesity, and metabolic syndrome, said Dr. Mechanick, director of metabolic support and clinical professor of medicine at Mount Sinai School of Medicine, New York.

A study using national health survey data has found varying associations between body mass index and mortality, depending on the cause.

Using data on cause-specific relative risks of mortality from the National Health and Nutrition Examination Survey (NHANES) from 1971–2002, Katherine M. Flegal, Ph.D., and colleagues looked at the association between body mass index (BMI) and excess deaths associated with three different BMI categories: underweight (BMI less than 18.5), overweight (BMI of 25 to less than 30), and obesity (BMI of 30 and over). Deaths were divided into three major categories: cardiovascular disease (CVD), cancer, and all other causes (noncancer, non-CVD causes). The normal-weight category was used as the reference group.

The underweight category was associated with significantly increased mortality from noncancer and non-CVD causes, but was not associated with increased cancer or CVD mortality.

The overweight category, however, was associated with significantly decreased mortality from noncancer and non-CVD causes. This category was not associated with cancer or CVD mortality, but was associated with significant increased mortality from diabetes and kidney disease. The net result was that the overweight category was associated with significantly decreased all-cause mortality overall, the authors reported.

The obese category was associated with significantly increased mortality from CVD, some cancers, and diabetes and kidney disease. There was no significant association between obesity and cancer mortality overall, or with noncancer, non- CVD mortality. But it was associated with increased mortality from obesity-related cancers such as colon, breast, esophageal, uterine, ovarian, kidney, and pancreatic cancer (JAMA 2007;298:2028–37).

These data “indicate that the association of BMI with mortality varies considerably by cause of death,” the authors concluded. These results also help clarify their findings in an earlier study, which found “excess overall mortality associated with underweight and obesity but not with overweight.”

In an interview, Dr. Flegal, senior research scientist at the National Center for Health Statistics, Hyattsville, Md., and lead author of the study, said the study's results were similar to those in other studies and are not intended for clinical use. Instead, they are intended to make estimates of the contribution of obesity and overweight to excess deaths.

The current study is an extension of a study, published in 2005, which determined that, based on national survey data from 2000, all-cause mortality was significantly increased in the underweight and obese categories and significantly decreased in the overweight category when compared with normal-weight categories.

Dr. Flegal said although some media coverage of that study suggested the findings were unusual, the association of overweight with mortality that is similar to or lower than that for normal weight, as well as the idea that being overweight may offer some survival benefits, have been found in other studies.

She emphasized that the relationship between BMI and mortality is complex. The study is not “the arbiter of whether it's OK to be overweight or not.”

Asked to comment on the study's findings, Dr. Jeffrey I. Mechanick said its implications could “easily and dangerously” be distorted and should not be interpreted to mean that the results support allowing oneself to remain overweight or that dieting to achieve a “normal” BMI may not be medically indicated. Overweight people are at risk for diseases associated with a higher morbidity and mortality rate, including diabetes, obesity, and metabolic syndrome, said Dr. Mechanick, director of metabolic support and clinical professor of medicine at Mount Sinai School of Medicine, New York.

A study using national health survey data has found varying associations between body mass index and mortality, depending on the cause.

Using data on cause-specific relative risks of mortality from the National Health and Nutrition Examination Survey (NHANES) from 1971–2002, Katherine M. Flegal, Ph.D., and colleagues looked at the association between body mass index (BMI) and excess deaths associated with three different BMI categories: underweight (BMI less than 18.5), overweight (BMI of 25 to less than 30), and obesity (BMI of 30 and over). Deaths were divided into three major categories: cardiovascular disease (CVD), cancer, and all other causes (noncancer, non-CVD causes). The normal-weight category was used as the reference group.

The underweight category was associated with significantly increased mortality from noncancer and non-CVD causes, but was not associated with increased cancer or CVD mortality.

The overweight category, however, was associated with significantly decreased mortality from noncancer and non-CVD causes. This category was not associated with cancer or CVD mortality, but was associated with significant increased mortality from diabetes and kidney disease. The net result was that the overweight category was associated with significantly decreased all-cause mortality overall, the authors reported.

The obese category was associated with significantly increased mortality from CVD, some cancers, and diabetes and kidney disease. There was no significant association between obesity and cancer mortality overall, or with noncancer, non- CVD mortality. But it was associated with increased mortality from obesity-related cancers such as colon, breast, esophageal, uterine, ovarian, kidney, and pancreatic cancer (JAMA 2007;298:2028–37).

These data “indicate that the association of BMI with mortality varies considerably by cause of death,” the authors concluded. These results also help clarify their findings in an earlier study, which found “excess overall mortality associated with underweight and obesity but not with overweight.”

In an interview, Dr. Flegal, senior research scientist at the National Center for Health Statistics, Hyattsville, Md., and lead author of the study, said the study's results were similar to those in other studies and are not intended for clinical use. Instead, they are intended to make estimates of the contribution of obesity and overweight to excess deaths.

The current study is an extension of a study, published in 2005, which determined that, based on national survey data from 2000, all-cause mortality was significantly increased in the underweight and obese categories and significantly decreased in the overweight category when compared with normal-weight categories.

Dr. Flegal said although some media coverage of that study suggested the findings were unusual, the association of overweight with mortality that is similar to or lower than that for normal weight, as well as the idea that being overweight may offer some survival benefits, have been found in other studies.

She emphasized that the relationship between BMI and mortality is complex. The study is not “the arbiter of whether it's OK to be overweight or not.”

Asked to comment on the study's findings, Dr. Jeffrey I. Mechanick said its implications could “easily and dangerously” be distorted and should not be interpreted to mean that the results support allowing oneself to remain overweight or that dieting to achieve a “normal” BMI may not be medically indicated. Overweight people are at risk for diseases associated with a higher morbidity and mortality rate, including diabetes, obesity, and metabolic syndrome, said Dr. Mechanick, director of metabolic support and clinical professor of medicine at Mount Sinai School of Medicine, New York.

A randomized, controlled trial that followed overweight children who had successfully participated in a university-based weight control clinic found that two different family-based maintenance programs were significantly more effective than the use of no maintenance program at helping sustain their weight loss.

However, the positive effects of the interventions waned over a 2-year follow-up, Denise E. Wilfley, Ph.D., of the department of psychiatry, Washington University, St. Louis, and her associates wrote.

The authors stated that, to the best of their knowledge, this was the first large-scale study to examine the effect of weight loss interventions in overweight children (JAMA 2007;298:1661–73).

A total of 204 healthy 7- to 12-year-olds (mean age of about 10 years), who were 20%–100% above the median body mass index (BMI) for age and sex and had at least one parent with a BMI (kg/m

At the program's completion, 150 of the children and at least one of their parents or a guardian were randomized to one of three groups: a control group (n=49), which involved no follow-up, or one of two maintenance programs. The behavioral skills maintenance (BSM) program (n=51) has a cognitive-behavioral approach that emphasizes self-regulation behaviors and relapse-prevention strategies; the social-facilitation maintenance (SFM) program (n=50) involves using techniques to help parents “facilitate child peer networks that support healthy eating and physical activity” and targets factors, such as teasing from peers or body image, that may impede children from engaging in physical activity. The programs lasted for 4 months, for a total of 16 weekly sessions.

At the end of the 4 months, the children in the two maintenance programs had maintained their weight significantly better than did children in the control group, based on the two outcome measures in the study: BMI z score (determined using age-specific and sex-specific median BMI), and the percentage overweight (percentage above median BMI).

The results of children in the BSM group, of those in the SFM group, and of these two groups combined indicated that these participants maintained their BMI z score and percentage overweight significantly better than did those in the control group.

Over the 2-year follow-up, which was initiated after completion of the active weight-loss program, both outcome measures were significantly higher among participants in the SFM group, and also when the SFM and BSM groups were combined, compared with controls, but the results for the BSM group alone were not significantly different than were those of the controls.

At 2 years, for the percentage overweight measure, the SFM group had better results than did the control group, and these results approached statistical significance. But there were no significant differences between the results of the BSM group or the pooled results, compared with those of controls.

The results in the BSM or the SFM groups were not significantly different for either of the outcomes measures at any of the time points.

Among participants with a lower level of social problems, long-term weight maintenance was better among those in the two maintenance programs, compared with those in the control group.

Although the investigators acknowledged some limitations to the study, their results indicate that extended contact with either the BSM or SFM approach in a maintenance program “improves weight loss maintenance in a childhood overweight population in comparison with a weight loss program at least in the short-term, with some evidence for sustained long-term efficacy among more socially adept children receiving an SFM treatment,” they concluded.

“The general decline in effects following extended treatment suggests the need for the development of continuous care models for children, as in the adult weight loss field, which finds that longer ongoing contact helps maintain initial weight loss and improves health outcomes.”

A randomized, controlled trial that followed overweight children who had successfully participated in a university-based weight control clinic found that two different family-based maintenance programs were significantly more effective than the use of no maintenance program at helping sustain their weight loss.

However, the positive effects of the interventions waned over a 2-year follow-up, Denise E. Wilfley, Ph.D., of the department of psychiatry, Washington University, St. Louis, and her associates wrote.

The authors stated that, to the best of their knowledge, this was the first large-scale study to examine the effect of weight loss interventions in overweight children (JAMA 2007;298:1661–73).

A total of 204 healthy 7- to 12-year-olds (mean age of about 10 years), who were 20%–100% above the median body mass index (BMI) for age and sex and had at least one parent with a BMI (kg/m

At the program's completion, 150 of the children and at least one of their parents or a guardian were randomized to one of three groups: a control group (n=49), which involved no follow-up, or one of two maintenance programs. The behavioral skills maintenance (BSM) program (n=51) has a cognitive-behavioral approach that emphasizes self-regulation behaviors and relapse-prevention strategies; the social-facilitation maintenance (SFM) program (n=50) involves using techniques to help parents “facilitate child peer networks that support healthy eating and physical activity” and targets factors, such as teasing from peers or body image, that may impede children from engaging in physical activity. The programs lasted for 4 months, for a total of 16 weekly sessions.

At the end of the 4 months, the children in the two maintenance programs had maintained their weight significantly better than did children in the control group, based on the two outcome measures in the study: BMI z score (determined using age-specific and sex-specific median BMI), and the percentage overweight (percentage above median BMI).

The results of children in the BSM group, of those in the SFM group, and of these two groups combined indicated that these participants maintained their BMI z score and percentage overweight significantly better than did those in the control group.

Over the 2-year follow-up, which was initiated after completion of the active weight-loss program, both outcome measures were significantly higher among participants in the SFM group, and also when the SFM and BSM groups were combined, compared with controls, but the results for the BSM group alone were not significantly different than were those of the controls.

At 2 years, for the percentage overweight measure, the SFM group had better results than did the control group, and these results approached statistical significance. But there were no significant differences between the results of the BSM group or the pooled results, compared with those of controls.

The results in the BSM or the SFM groups were not significantly different for either of the outcomes measures at any of the time points.

Among participants with a lower level of social problems, long-term weight maintenance was better among those in the two maintenance programs, compared with those in the control group.

Although the investigators acknowledged some limitations to the study, their results indicate that extended contact with either the BSM or SFM approach in a maintenance program “improves weight loss maintenance in a childhood overweight population in comparison with a weight loss program at least in the short-term, with some evidence for sustained long-term efficacy among more socially adept children receiving an SFM treatment,” they concluded.

“The general decline in effects following extended treatment suggests the need for the development of continuous care models for children, as in the adult weight loss field, which finds that longer ongoing contact helps maintain initial weight loss and improves health outcomes.”

A randomized, controlled trial that followed overweight children who had successfully participated in a university-based weight control clinic found that two different family-based maintenance programs were significantly more effective than the use of no maintenance program at helping sustain their weight loss.

However, the positive effects of the interventions waned over a 2-year follow-up, Denise E. Wilfley, Ph.D., of the department of psychiatry, Washington University, St. Louis, and her associates wrote.

The authors stated that, to the best of their knowledge, this was the first large-scale study to examine the effect of weight loss interventions in overweight children (JAMA 2007;298:1661–73).

A total of 204 healthy 7- to 12-year-olds (mean age of about 10 years), who were 20%–100% above the median body mass index (BMI) for age and sex and had at least one parent with a BMI (kg/m

At the program's completion, 150 of the children and at least one of their parents or a guardian were randomized to one of three groups: a control group (n=49), which involved no follow-up, or one of two maintenance programs. The behavioral skills maintenance (BSM) program (n=51) has a cognitive-behavioral approach that emphasizes self-regulation behaviors and relapse-prevention strategies; the social-facilitation maintenance (SFM) program (n=50) involves using techniques to help parents “facilitate child peer networks that support healthy eating and physical activity” and targets factors, such as teasing from peers or body image, that may impede children from engaging in physical activity. The programs lasted for 4 months, for a total of 16 weekly sessions.

At the end of the 4 months, the children in the two maintenance programs had maintained their weight significantly better than did children in the control group, based on the two outcome measures in the study: BMI z score (determined using age-specific and sex-specific median BMI), and the percentage overweight (percentage above median BMI).

The results of children in the BSM group, of those in the SFM group, and of these two groups combined indicated that these participants maintained their BMI z score and percentage overweight significantly better than did those in the control group.

Over the 2-year follow-up, which was initiated after completion of the active weight-loss program, both outcome measures were significantly higher among participants in the SFM group, and also when the SFM and BSM groups were combined, compared with controls, but the results for the BSM group alone were not significantly different than were those of the controls.

At 2 years, for the percentage overweight measure, the SFM group had better results than did the control group, and these results approached statistical significance. But there were no significant differences between the results of the BSM group or the pooled results, compared with those of controls.

The results in the BSM or the SFM groups were not significantly different for either of the outcomes measures at any of the time points.

Among participants with a lower level of social problems, long-term weight maintenance was better among those in the two maintenance programs, compared with those in the control group.

Although the investigators acknowledged some limitations to the study, their results indicate that extended contact with either the BSM or SFM approach in a maintenance program “improves weight loss maintenance in a childhood overweight population in comparison with a weight loss program at least in the short-term, with some evidence for sustained long-term efficacy among more socially adept children receiving an SFM treatment,” they concluded.

“The general decline in effects following extended treatment suggests the need for the development of continuous care models for children, as in the adult weight loss field, which finds that longer ongoing contact helps maintain initial weight loss and improves health outcomes.”

Microbubble ultrasound contrast agents used in patients with suboptimal echocardiograms have been linked to serious cardiopulmonary reactions and several deaths, according to the Food and Drug Administration.

In October, the agency issued a notice on its MedWatch site alerting health care professionals that the agency had received reports of deaths and cardiopulmonary reactions after ultrasound microbubble contrast agents had been administered to patients undergoing echocardiography. Of the 11 deaths reported, 4 were due to cardiac arrest during the infusion or within 30 minutes of administration, and most of the serious, nonfatal reactions also occurred during this time period.

The manufacturers of Definity (perflutren lipid microsphere) injectable suspension and Optison (perflutren protein-type A microspheres for Injection), the only microbubble ultrasound contrast agents approved in the United States, have agreed to add a black box warning and other warnings to the product labels describing these risks. A contraindication against their use in patients at a particular risk for cardiopulmonary reactions will also be added to the label. These patients include with those with known cardiac shunts, clinically unstable or recent worsening of heart failure, symptomatic arrhythmias, or those at high risk for arrhythmias due to QT prolongation, respiratory failure, severe emphysema, pulmonary emboli “or other conditions that compromise pulmonary arterial vasculature.”

These agents are a sterile suspension of perflutren gas microspheres that are indicated for use in patients with suboptimal echocardiograms, and are used to “opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border,” according to the FDA.

Most of the reports have been associated with Definity, approved in 2001. There have been 10 postmarketing deaths reported with Definity and 1 following the administration of Optison, which was approved in 1997; marketing of Optison was temporarily suspended in 2005. In most of the deaths, the patient had a severe underlying condition: Some patients were on other medications the FDA statement said “could have contributed to their death.” Four of the deaths that followed cardiac arrest occurred during administration of Definity or within the 30 minutes that followed; two patients had severe heart failure and one was mechanically ventilated because of respiratory failure.

The FDA has also received 190 reports of serious nonfatal reactions following Definity administration and 9 such reports after Optison administration. In many of these cases, the patient had an “acute onset of symptoms suggestive of an anaphylactoid reaction.” Other cases described cardiopulmonary reactions with cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias, cardiac ischemia, hypotension, respiratory distress, and oxygen desaturation “without signs or symptoms of a typical allergic reaction.”

The boxed warning and warnings section also will recommend that vital signs, cardiac rhythm, and oxygen saturation be monitored in patients who receive these agents, and that resuscitation equipment and trained personnel be “readily available,” in patients who receive these agents, the FDA said.

The indications section will also point out that the safety and efficacy of Definity for use with exercise or pharmacologic stress testing has not been established. (One of the Definity-associated deaths was in a patient undergoing a cardiac stress test.)

The full summary is available at: www.fda.gov/medwatch/safety/2007/safety07.htm#bubblewww.fda.gov/medwatch/report.htm

Microbubble ultrasound contrast agents used in patients with suboptimal echocardiograms have been linked to serious cardiopulmonary reactions and several deaths, according to the Food and Drug Administration.

In October, the agency issued a notice on its MedWatch site alerting health care professionals that the agency had received reports of deaths and cardiopulmonary reactions after ultrasound microbubble contrast agents had been administered to patients undergoing echocardiography. Of the 11 deaths reported, 4 were due to cardiac arrest during the infusion or within 30 minutes of administration, and most of the serious, nonfatal reactions also occurred during this time period.

The manufacturers of Definity (perflutren lipid microsphere) injectable suspension and Optison (perflutren protein-type A microspheres for Injection), the only microbubble ultrasound contrast agents approved in the United States, have agreed to add a black box warning and other warnings to the product labels describing these risks. A contraindication against their use in patients at a particular risk for cardiopulmonary reactions will also be added to the label. These patients include with those with known cardiac shunts, clinically unstable or recent worsening of heart failure, symptomatic arrhythmias, or those at high risk for arrhythmias due to QT prolongation, respiratory failure, severe emphysema, pulmonary emboli “or other conditions that compromise pulmonary arterial vasculature.”

These agents are a sterile suspension of perflutren gas microspheres that are indicated for use in patients with suboptimal echocardiograms, and are used to “opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border,” according to the FDA.

Most of the reports have been associated with Definity, approved in 2001. There have been 10 postmarketing deaths reported with Definity and 1 following the administration of Optison, which was approved in 1997; marketing of Optison was temporarily suspended in 2005. In most of the deaths, the patient had a severe underlying condition: Some patients were on other medications the FDA statement said “could have contributed to their death.” Four of the deaths that followed cardiac arrest occurred during administration of Definity or within the 30 minutes that followed; two patients had severe heart failure and one was mechanically ventilated because of respiratory failure.

The FDA has also received 190 reports of serious nonfatal reactions following Definity administration and 9 such reports after Optison administration. In many of these cases, the patient had an “acute onset of symptoms suggestive of an anaphylactoid reaction.” Other cases described cardiopulmonary reactions with cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias, cardiac ischemia, hypotension, respiratory distress, and oxygen desaturation “without signs or symptoms of a typical allergic reaction.”

The boxed warning and warnings section also will recommend that vital signs, cardiac rhythm, and oxygen saturation be monitored in patients who receive these agents, and that resuscitation equipment and trained personnel be “readily available,” in patients who receive these agents, the FDA said.

The indications section will also point out that the safety and efficacy of Definity for use with exercise or pharmacologic stress testing has not been established. (One of the Definity-associated deaths was in a patient undergoing a cardiac stress test.)

The full summary is available at: www.fda.gov/medwatch/safety/2007/safety07.htm#bubblewww.fda.gov/medwatch/report.htm

Microbubble ultrasound contrast agents used in patients with suboptimal echocardiograms have been linked to serious cardiopulmonary reactions and several deaths, according to the Food and Drug Administration.

In October, the agency issued a notice on its MedWatch site alerting health care professionals that the agency had received reports of deaths and cardiopulmonary reactions after ultrasound microbubble contrast agents had been administered to patients undergoing echocardiography. Of the 11 deaths reported, 4 were due to cardiac arrest during the infusion or within 30 minutes of administration, and most of the serious, nonfatal reactions also occurred during this time period.

The manufacturers of Definity (perflutren lipid microsphere) injectable suspension and Optison (perflutren protein-type A microspheres for Injection), the only microbubble ultrasound contrast agents approved in the United States, have agreed to add a black box warning and other warnings to the product labels describing these risks. A contraindication against their use in patients at a particular risk for cardiopulmonary reactions will also be added to the label. These patients include with those with known cardiac shunts, clinically unstable or recent worsening of heart failure, symptomatic arrhythmias, or those at high risk for arrhythmias due to QT prolongation, respiratory failure, severe emphysema, pulmonary emboli “or other conditions that compromise pulmonary arterial vasculature.”

These agents are a sterile suspension of perflutren gas microspheres that are indicated for use in patients with suboptimal echocardiograms, and are used to “opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border,” according to the FDA.

Most of the reports have been associated with Definity, approved in 2001. There have been 10 postmarketing deaths reported with Definity and 1 following the administration of Optison, which was approved in 1997; marketing of Optison was temporarily suspended in 2005. In most of the deaths, the patient had a severe underlying condition: Some patients were on other medications the FDA statement said “could have contributed to their death.” Four of the deaths that followed cardiac arrest occurred during administration of Definity or within the 30 minutes that followed; two patients had severe heart failure and one was mechanically ventilated because of respiratory failure.

The FDA has also received 190 reports of serious nonfatal reactions following Definity administration and 9 such reports after Optison administration. In many of these cases, the patient had an “acute onset of symptoms suggestive of an anaphylactoid reaction.” Other cases described cardiopulmonary reactions with cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias, cardiac ischemia, hypotension, respiratory distress, and oxygen desaturation “without signs or symptoms of a typical allergic reaction.”

The boxed warning and warnings section also will recommend that vital signs, cardiac rhythm, and oxygen saturation be monitored in patients who receive these agents, and that resuscitation equipment and trained personnel be “readily available,” in patients who receive these agents, the FDA said.

The indications section will also point out that the safety and efficacy of Definity for use with exercise or pharmacologic stress testing has not been established. (One of the Definity-associated deaths was in a patient undergoing a cardiac stress test.)

The full summary is available at: www.fda.gov/medwatch/safety/2007/safety07.htm#bubblewww.fda.gov/medwatch/report.htm

A study of 1,047 children found no evidence of a causal association between exposure to ethylmercury from the preservative thimerosal in vaccines during the prenatal, neonatal, or first 7 months of life and neuropsychological outcomes at ages 7–10 years, said the authors.

“The associations that we detected were small, almost equally divided between positive and negative effects, and mostly sex-specific,” William W. Thompson, Ph.D., an epidemiologist in the National Center for Immunizations and Respiratory Diseases, at the Centers for Disease Control and Prevention (CDC), and his coauthors wrote in the New England Journal of Medicine.

“The study results were very reassuring,” Dr. Anne Schuchat, director of the CDC's National Center for Immunizations and Respiratory Diseases, said during a CDC-sponsored teleconference. “The bulk of the study found very, very similar performance in children who were exposed to high amounts of thimerosal and children exposed to low or no thimerosal and suggests the higher thimerosal content that vaccines had back in the 1990s did not lead to harmful effects in children in performance on standardized testing at ages 7–10.”

She noted that parental reports of tics were not associated with any higher exposure of thimerosal but based on evaluator observations during the testing; motor and phonic tics were increased by about twofold among boys with higher thimerosal exposure from birth to 7 months, an association that was not seen in girls. Because of similar findings in two previous studies, this issue is being evaluated further with CDC experts in developmental disability and consultations with outside pediatric neurologists, she said.

This was not an autism study. No measures of autism were included in the testing because the CDC is conducting a separate case-control study of autism and mercury exposure, the results of which are expected in the next year, Dr. Schuchat said.

In the cohort study, children enrolled in four HMOs, who were born between January 1993 and March 1997, were administered a wide range of standardized tests that measured 42 neuropsychological outcomes, including speech and language indexes, verbal memory, achievement, fine-motor coordination, visuospatial ability, attention, behavior regulation, tics, and general intellectual functioning, between the ages of 7 and 10 years. Estimates of their exposure to mercury from thimerosal in vaccines and immunoglobulins during the prenatal period, neonatal period (birth to 28 days) and the first 7 months (1–214 days) were based on computerized and personal immunization records, medical records, and parent interviews (N. Engl. J. Med. 2007;357:1281–92).

Between birth and 7 months, the median cumulative exposure to ethylmercury from thimerosal among the children was 112 mcg; 9% of the children were exposed to 62.5 mcg or less of mercury, and 25% had cumulative exposures of 150 mcg or more. (There was no exposure to a thimerosal-containing vaccine or immune globulin during the first 7 months of life in 1.5% of the children.) During the first 28 days, 30% of the children were not exposed to thimerosal and 1.6% had been exposed to more than 12.5 mcg of mercury in hepatitis B and immune globulins. Fewer than 11% of the children had been exposed to thimerosal prenatally when their mothers received vaccinations and immune globulins during pregnancy.

There were “few significant associations” among performance on neuropsychological test results and exposure to mercury in vaccines and immune globulins administered prenatally or up through 7 months of age, the authors reported.

These included a significant association between prenatal exposure to higher ethylmercury levels and a better performance on one measure of language and poorer performance on one measure of attention and executive functioning. Increasing levels of mercury exposure from birth to 7 months were associated with significantly better performance on one measure of fine-motor coordination and on one measure of attention and executive functioning.

Increased mercury exposure during the first 28 days was associated with worse performance on one measure of speech articulation and better performance on one measure of fine-motor coordination. Among the children overall, there was no association between neonatal exposure to mercury from thimerosal and total IQ, while among boys, there was a significant positive association with performance IQ, and among girls, there was a significant negative association with verbal IQ.

“Although the effect sizes were very small, the speech-articulation findings among all children and the lower verbal IQ findings among girls suggest a possible adverse association between neonatal exposure to mercury and language development,” the authors said. “Conversely, the finding of higher scores on the performance IQ tests in boys makes it difficult to draw general conclusions about possible effects of neonatal mercury exposure from vaccines and immune globulins on intellectual abilities.”

The weight of the evidence in this study does not support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins administered prenatally or during infancy and neuropsychological functioning at the age of 7 to 10 years,” they concluded. “The overall pattern of results suggests that the significant associations may have been chance findings stemming from the large number of statistical tests that we performed.”

Dr. Schuchat said that chance alone could explain these significant findings since a large number (378) of individual statistical comparisons were performed.

The authors disclosed some financial ties to vaccine manufacturers; Dr. Thompson is a former employee of Merck & Co.

Thimerosal has been removed from childhood vaccines, except for flu vaccines.

A study of 1,047 children found no evidence of a causal association between exposure to ethylmercury from the preservative thimerosal in vaccines during the prenatal, neonatal, or first 7 months of life and neuropsychological outcomes at ages 7–10 years, said the authors.

“The associations that we detected were small, almost equally divided between positive and negative effects, and mostly sex-specific,” William W. Thompson, Ph.D., an epidemiologist in the National Center for Immunizations and Respiratory Diseases, at the Centers for Disease Control and Prevention (CDC), and his coauthors wrote in the New England Journal of Medicine.

“The study results were very reassuring,” Dr. Anne Schuchat, director of the CDC's National Center for Immunizations and Respiratory Diseases, said during a CDC-sponsored teleconference. “The bulk of the study found very, very similar performance in children who were exposed to high amounts of thimerosal and children exposed to low or no thimerosal and suggests the higher thimerosal content that vaccines had back in the 1990s did not lead to harmful effects in children in performance on standardized testing at ages 7–10.”

She noted that parental reports of tics were not associated with any higher exposure of thimerosal but based on evaluator observations during the testing; motor and phonic tics were increased by about twofold among boys with higher thimerosal exposure from birth to 7 months, an association that was not seen in girls. Because of similar findings in two previous studies, this issue is being evaluated further with CDC experts in developmental disability and consultations with outside pediatric neurologists, she said.

This was not an autism study. No measures of autism were included in the testing because the CDC is conducting a separate case-control study of autism and mercury exposure, the results of which are expected in the next year, Dr. Schuchat said.

In the cohort study, children enrolled in four HMOs, who were born between January 1993 and March 1997, were administered a wide range of standardized tests that measured 42 neuropsychological outcomes, including speech and language indexes, verbal memory, achievement, fine-motor coordination, visuospatial ability, attention, behavior regulation, tics, and general intellectual functioning, between the ages of 7 and 10 years. Estimates of their exposure to mercury from thimerosal in vaccines and immunoglobulins during the prenatal period, neonatal period (birth to 28 days) and the first 7 months (1–214 days) were based on computerized and personal immunization records, medical records, and parent interviews (N. Engl. J. Med. 2007;357:1281–92).

Between birth and 7 months, the median cumulative exposure to ethylmercury from thimerosal among the children was 112 mcg; 9% of the children were exposed to 62.5 mcg or less of mercury, and 25% had cumulative exposures of 150 mcg or more. (There was no exposure to a thimerosal-containing vaccine or immune globulin during the first 7 months of life in 1.5% of the children.) During the first 28 days, 30% of the children were not exposed to thimerosal and 1.6% had been exposed to more than 12.5 mcg of mercury in hepatitis B and immune globulins. Fewer than 11% of the children had been exposed to thimerosal prenatally when their mothers received vaccinations and immune globulins during pregnancy.

There were “few significant associations” among performance on neuropsychological test results and exposure to mercury in vaccines and immune globulins administered prenatally or up through 7 months of age, the authors reported.

These included a significant association between prenatal exposure to higher ethylmercury levels and a better performance on one measure of language and poorer performance on one measure of attention and executive functioning. Increasing levels of mercury exposure from birth to 7 months were associated with significantly better performance on one measure of fine-motor coordination and on one measure of attention and executive functioning.

Increased mercury exposure during the first 28 days was associated with worse performance on one measure of speech articulation and better performance on one measure of fine-motor coordination. Among the children overall, there was no association between neonatal exposure to mercury from thimerosal and total IQ, while among boys, there was a significant positive association with performance IQ, and among girls, there was a significant negative association with verbal IQ.

“Although the effect sizes were very small, the speech-articulation findings among all children and the lower verbal IQ findings among girls suggest a possible adverse association between neonatal exposure to mercury and language development,” the authors said. “Conversely, the finding of higher scores on the performance IQ tests in boys makes it difficult to draw general conclusions about possible effects of neonatal mercury exposure from vaccines and immune globulins on intellectual abilities.”

The weight of the evidence in this study does not support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins administered prenatally or during infancy and neuropsychological functioning at the age of 7 to 10 years,” they concluded. “The overall pattern of results suggests that the significant associations may have been chance findings stemming from the large number of statistical tests that we performed.”

Dr. Schuchat said that chance alone could explain these significant findings since a large number (378) of individual statistical comparisons were performed.

The authors disclosed some financial ties to vaccine manufacturers; Dr. Thompson is a former employee of Merck & Co.

Thimerosal has been removed from childhood vaccines, except for flu vaccines.

A study of 1,047 children found no evidence of a causal association between exposure to ethylmercury from the preservative thimerosal in vaccines during the prenatal, neonatal, or first 7 months of life and neuropsychological outcomes at ages 7–10 years, said the authors.

“The associations that we detected were small, almost equally divided between positive and negative effects, and mostly sex-specific,” William W. Thompson, Ph.D., an epidemiologist in the National Center for Immunizations and Respiratory Diseases, at the Centers for Disease Control and Prevention (CDC), and his coauthors wrote in the New England Journal of Medicine.

“The study results were very reassuring,” Dr. Anne Schuchat, director of the CDC's National Center for Immunizations and Respiratory Diseases, said during a CDC-sponsored teleconference. “The bulk of the study found very, very similar performance in children who were exposed to high amounts of thimerosal and children exposed to low or no thimerosal and suggests the higher thimerosal content that vaccines had back in the 1990s did not lead to harmful effects in children in performance on standardized testing at ages 7–10.”

She noted that parental reports of tics were not associated with any higher exposure of thimerosal but based on evaluator observations during the testing; motor and phonic tics were increased by about twofold among boys with higher thimerosal exposure from birth to 7 months, an association that was not seen in girls. Because of similar findings in two previous studies, this issue is being evaluated further with CDC experts in developmental disability and consultations with outside pediatric neurologists, she said.

This was not an autism study. No measures of autism were included in the testing because the CDC is conducting a separate case-control study of autism and mercury exposure, the results of which are expected in the next year, Dr. Schuchat said.

In the cohort study, children enrolled in four HMOs, who were born between January 1993 and March 1997, were administered a wide range of standardized tests that measured 42 neuropsychological outcomes, including speech and language indexes, verbal memory, achievement, fine-motor coordination, visuospatial ability, attention, behavior regulation, tics, and general intellectual functioning, between the ages of 7 and 10 years. Estimates of their exposure to mercury from thimerosal in vaccines and immunoglobulins during the prenatal period, neonatal period (birth to 28 days) and the first 7 months (1–214 days) were based on computerized and personal immunization records, medical records, and parent interviews (N. Engl. J. Med. 2007;357:1281–92).

Between birth and 7 months, the median cumulative exposure to ethylmercury from thimerosal among the children was 112 mcg; 9% of the children were exposed to 62.5 mcg or less of mercury, and 25% had cumulative exposures of 150 mcg or more. (There was no exposure to a thimerosal-containing vaccine or immune globulin during the first 7 months of life in 1.5% of the children.) During the first 28 days, 30% of the children were not exposed to thimerosal and 1.6% had been exposed to more than 12.5 mcg of mercury in hepatitis B and immune globulins. Fewer than 11% of the children had been exposed to thimerosal prenatally when their mothers received vaccinations and immune globulins during pregnancy.

There were “few significant associations” among performance on neuropsychological test results and exposure to mercury in vaccines and immune globulins administered prenatally or up through 7 months of age, the authors reported.

These included a significant association between prenatal exposure to higher ethylmercury levels and a better performance on one measure of language and poorer performance on one measure of attention and executive functioning. Increasing levels of mercury exposure from birth to 7 months were associated with significantly better performance on one measure of fine-motor coordination and on one measure of attention and executive functioning.

Increased mercury exposure during the first 28 days was associated with worse performance on one measure of speech articulation and better performance on one measure of fine-motor coordination. Among the children overall, there was no association between neonatal exposure to mercury from thimerosal and total IQ, while among boys, there was a significant positive association with performance IQ, and among girls, there was a significant negative association with verbal IQ.

“Although the effect sizes were very small, the speech-articulation findings among all children and the lower verbal IQ findings among girls suggest a possible adverse association between neonatal exposure to mercury and language development,” the authors said. “Conversely, the finding of higher scores on the performance IQ tests in boys makes it difficult to draw general conclusions about possible effects of neonatal mercury exposure from vaccines and immune globulins on intellectual abilities.”

The weight of the evidence in this study does not support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins administered prenatally or during infancy and neuropsychological functioning at the age of 7 to 10 years,” they concluded. “The overall pattern of results suggests that the significant associations may have been chance findings stemming from the large number of statistical tests that we performed.”

Dr. Schuchat said that chance alone could explain these significant findings since a large number (378) of individual statistical comparisons were performed.

The authors disclosed some financial ties to vaccine manufacturers; Dr. Thompson is a former employee of Merck & Co.

Thimerosal has been removed from childhood vaccines, except for flu vaccines.