Elizabeth Mechcatie

Despite marked drops in all-cause and cardiovascular mortality in men with diabetes between 1971 and 2000, no such improvements were seen in women with diabetes in those periods, a study has shown.

“The improvements seen in men suggest that the improvements in diabetes care are working on longevity as well,” Edward W. Gregg, Ph.D., the study's lead author, said in a statement issued by the American College of Physicians. “But the finding in women is concerning and means we may need to explore whether different approaches are needed to improve health outcomes for women with diabetes.” Dr. Gregg is acting chief of the epidemiology and statistics branch of the division of diabetes translation at the Centers for Disease Control and Prevention in Atlanta.

The study analyzed data on about 20,000 people from three consecutive National Health and Nutrition Examination Surveys (NHANES), which examined the health of nationally representative cohorts of U.S. residents, between 1971–1975, 1976–1980, and 1988–1994. The authors also followed up mortality in participants in 1986, 1993, and 2000 for the three surveys. Participants were aged 35–74 years at baseline.

Data from three time periods, which included follow-up, were compared: 1971–1986, 1976–1992, and 1988–2000. The study was conducted to determine if all-cause and cardiovascular disease (CVD) mortality had dropped in diabetes patients, and to determine whether differences in mortality between diabetes patients and those without diabetes had narrowed. The study will appear in the August 7, 2007, print edition of the Annals of Internal Medicine, and was posted at www.annals.org

All-cause mortality in diabetic men went from 42.6 to 24.4 annual deaths per 1,000 persons between 1971–1986 and 1988–2000, a statistically significant 43% drop. During these periods, CVD mortality dropped from 26.4 to 12.8 annual deaths per 1,000 persons, which was not quite statistically significant.

But in women with diabetes, neither all-cause mortality nor CVD mortality improved between these periods. In addition, the difference in all-cause mortality between female diabetes patients and women without diabetes increased from 8.3 to 18.2 annual deaths per 1,000 persons. In men, however, the absolute difference in all-cause mortality in those with and without diabetes dropped from 23.6 annual deaths per 1,000 persons in 1971–1986 to 12.8 annual deaths per 1,000 persons in 1988–2000. The difference in CVD mortality between male diabetes patients and men without diabetes dropped from 16.8 to 8.1 annual deaths per 1,000 persons between these two periods.

The authors cited gender differences in coronary heart disease pathophysiology, less aggressive treatment of women, and more negative outcomes after revascularization and hospitalization for CVD in women as some reasons for the data.

Despite marked drops in all-cause and cardiovascular mortality in men with diabetes between 1971 and 2000, no such improvements were seen in women with diabetes in those periods, a study has shown.

“The improvements seen in men suggest that the improvements in diabetes care are working on longevity as well,” Edward W. Gregg, Ph.D., the study's lead author, said in a statement issued by the American College of Physicians. “But the finding in women is concerning and means we may need to explore whether different approaches are needed to improve health outcomes for women with diabetes.” Dr. Gregg is acting chief of the epidemiology and statistics branch of the division of diabetes translation at the Centers for Disease Control and Prevention in Atlanta.

The study analyzed data on about 20,000 people from three consecutive National Health and Nutrition Examination Surveys (NHANES), which examined the health of nationally representative cohorts of U.S. residents, between 1971–1975, 1976–1980, and 1988–1994. The authors also followed up mortality in participants in 1986, 1993, and 2000 for the three surveys. Participants were aged 35–74 years at baseline.

Data from three time periods, which included follow-up, were compared: 1971–1986, 1976–1992, and 1988–2000. The study was conducted to determine if all-cause and cardiovascular disease (CVD) mortality had dropped in diabetes patients, and to determine whether differences in mortality between diabetes patients and those without diabetes had narrowed. The study will appear in the August 7, 2007, print edition of the Annals of Internal Medicine, and was posted at www.annals.org

All-cause mortality in diabetic men went from 42.6 to 24.4 annual deaths per 1,000 persons between 1971–1986 and 1988–2000, a statistically significant 43% drop. During these periods, CVD mortality dropped from 26.4 to 12.8 annual deaths per 1,000 persons, which was not quite statistically significant.

But in women with diabetes, neither all-cause mortality nor CVD mortality improved between these periods. In addition, the difference in all-cause mortality between female diabetes patients and women without diabetes increased from 8.3 to 18.2 annual deaths per 1,000 persons. In men, however, the absolute difference in all-cause mortality in those with and without diabetes dropped from 23.6 annual deaths per 1,000 persons in 1971–1986 to 12.8 annual deaths per 1,000 persons in 1988–2000. The difference in CVD mortality between male diabetes patients and men without diabetes dropped from 16.8 to 8.1 annual deaths per 1,000 persons between these two periods.

The authors cited gender differences in coronary heart disease pathophysiology, less aggressive treatment of women, and more negative outcomes after revascularization and hospitalization for CVD in women as some reasons for the data.

Despite marked drops in all-cause and cardiovascular mortality in men with diabetes between 1971 and 2000, no such improvements were seen in women with diabetes in those periods, a study has shown.

“The improvements seen in men suggest that the improvements in diabetes care are working on longevity as well,” Edward W. Gregg, Ph.D., the study's lead author, said in a statement issued by the American College of Physicians. “But the finding in women is concerning and means we may need to explore whether different approaches are needed to improve health outcomes for women with diabetes.” Dr. Gregg is acting chief of the epidemiology and statistics branch of the division of diabetes translation at the Centers for Disease Control and Prevention in Atlanta.

The study analyzed data on about 20,000 people from three consecutive National Health and Nutrition Examination Surveys (NHANES), which examined the health of nationally representative cohorts of U.S. residents, between 1971–1975, 1976–1980, and 1988–1994. The authors also followed up mortality in participants in 1986, 1993, and 2000 for the three surveys. Participants were aged 35–74 years at baseline.

Data from three time periods, which included follow-up, were compared: 1971–1986, 1976–1992, and 1988–2000. The study was conducted to determine if all-cause and cardiovascular disease (CVD) mortality had dropped in diabetes patients, and to determine whether differences in mortality between diabetes patients and those without diabetes had narrowed. The study will appear in the August 7, 2007, print edition of the Annals of Internal Medicine, and was posted at www.annals.org

All-cause mortality in diabetic men went from 42.6 to 24.4 annual deaths per 1,000 persons between 1971–1986 and 1988–2000, a statistically significant 43% drop. During these periods, CVD mortality dropped from 26.4 to 12.8 annual deaths per 1,000 persons, which was not quite statistically significant.

But in women with diabetes, neither all-cause mortality nor CVD mortality improved between these periods. In addition, the difference in all-cause mortality between female diabetes patients and women without diabetes increased from 8.3 to 18.2 annual deaths per 1,000 persons. In men, however, the absolute difference in all-cause mortality in those with and without diabetes dropped from 23.6 annual deaths per 1,000 persons in 1971–1986 to 12.8 annual deaths per 1,000 persons in 1988–2000. The difference in CVD mortality between male diabetes patients and men without diabetes dropped from 16.8 to 8.1 annual deaths per 1,000 persons between these two periods.

The authors cited gender differences in coronary heart disease pathophysiology, less aggressive treatment of women, and more negative outcomes after revascularization and hospitalization for CVD in women as some reasons for the data.

For the first time, a transdermal drug delivery system is available for treating Parkinson's disease patients, a treatment option that provides both practical and theoretical benefits for this population, according to experts not involved in clinical trials of the product.

The Food and Drug Administration has approved a transdermal patch that contains rotigotine, a nonergotamine dopamine agonist that previously was not available in any form in the United States, for treating the signs and symptoms of early-stage idiopathic Parkinson's disease. Approval, which came in May, was based on three randomized, double-blind placebo-controlled studies in the United States and abroad of 1,154 patients with early Parkinson's, who were not taking other medications for Parkinson's. The patch will be marketed under the trade name Neupro by Schwarz Pharma LLC and was expected to be available in U.S. pharmacies by June 22–30, according to a spokesperson for the German company. At press time, the price was not available.

The option of a transdermal delivery system for patients who are tired of taking many pills is a clear advantage, said Dr. David Standaert, professor of neurology and director of the division of movement disorders at the University of Alabama at Birmingham. The pharmacology of rotigotine is a little different from that of the most widely used dopamine agonists, pramipexole and ropinirole, but the main difference is the transdermal system, he said in an interview.

Another advantage is that the continuous delivery of medication over 24 hours provides a stable blood level, which theoretically, could be an improvement over current treatments, he said. Recent research suggests that the peaks and troughs with conventional dopaminergic drugs may be responsible for some of the problems associated with oral therapy–end of the dose “wearing off” and dyskinesia–and possibly hallucinations and neuropsychiatric effects as well.

However, there is no evidence yet that the steady level provided by the patch will translate into long-term clinical benefits, he emphasized. “Many of us think it will, but I don't think we have the proof of that yet.” Dr. Standaert, who also is the director of the university's Center for Neurodegeneration and Experimental Therapeutics, was not involved in rotigotine studies, some of which were conducted there before he arrived. He has no financial ties to the manufacturer but has consulted on the pharmacologic properties of rotigotine to UCB, the U.S. pharmaceutical company that is in the process of acquiring Schwarz Pharma.

“This is an exciting step in that there are a lot of both theoretical and practical advantages to finally having patch therapy for Parkinson's,” agreed Dr. Michael Pourfar, a neurologist in the division of movement disorders, at North Shore University Hospital, Manhasset, N.Y. Because there are effective dopamine agonists available for Parkinson's, he said he would not want patients to feel like they need to change their medications. “But I do think this is something that will improve quality of life for many people,” he added in an interview, noting that for some patients, the patch could replace as many as six pills per day. He has not been involved in trials of rotigotine and has no financial ties to the manufacturer.

Rotigotine is delivered continuously though the silicone-based patch that is applied to clean, dry, intact skin and is replaced every 24 hours. It is available in three strengths: 2 mg, 4 mg, and 6 mg/24 hr. The recommended dosing is to start at 2 mg. When additional therapeutic effects are needed, the dose may be increased weekly by 2 mg/24 hours if tolerated, according to the package insert. In studies, the lowest effective dose was 4 mg/24 hours, and in dose-ranging studies, doses above 6 mg/24 hours were not more effective than the lower doses and were associated with a higher rate of adverse reactions. The patch should be applied to sites on the front of the abdomen, thigh, hip, flank, shoulder, or upper arm at about the same time every day, avoiding reapplication to the same site more than once every 14 days.

The change from baseline for the combined scores for the activities of daily living and motor components of the Unified Parkinson's Disease Rating Scale (UPDRS) was the primary outcome in the three studies, which enrolled early-stage Parkinson's disease patients who were not on dopamine agonist treatment, and whose mean age was 60–63 years. In one of the trials, a 28-week multicenter North American study, 277 patients received up to a 6 g/24 hours dose of rotigotine or placebo. The mean reduction in the combined UPDRS score from baseline was 4.0, compared with a mean 1.39 increase from baseline among those on placebo, a difference of 5.3 that was statistically significant.

The most common side effects in the three trials included dizziness, nausea, vomiting, drowsiness, and insomnia, “most of which are typical for this class of drugs,” according to the FDA statement announcing the approval. Nearly 40% of those on the patch had application site reactions-mostly mild or moderate-compared with 14% among those who received a placebo patch. The drug's label includes a warning about sulfite sensitivity, because the delivery system contains a sulfite that may cause allergic reactions.

The rotigotine patch is not approved for advanced disease, but it is being studied in this population. In a recently published placebo-controlled 24-week study of the rotigotine patch in 351 patients with advanced Parkinson's, those treated with two doses of the patch had significant reductions in the amount of daily “off” time than those on placebo (Neurology 2007;68:1262–7).

For the first time, a transdermal drug delivery system is available for treating Parkinson's disease patients, a treatment option that provides both practical and theoretical benefits for this population, according to experts not involved in clinical trials of the product.

The Food and Drug Administration has approved a transdermal patch that contains rotigotine, a nonergotamine dopamine agonist that previously was not available in any form in the United States, for treating the signs and symptoms of early-stage idiopathic Parkinson's disease. Approval, which came in May, was based on three randomized, double-blind placebo-controlled studies in the United States and abroad of 1,154 patients with early Parkinson's, who were not taking other medications for Parkinson's. The patch will be marketed under the trade name Neupro by Schwarz Pharma LLC and was expected to be available in U.S. pharmacies by June 22–30, according to a spokesperson for the German company. At press time, the price was not available.

The option of a transdermal delivery system for patients who are tired of taking many pills is a clear advantage, said Dr. David Standaert, professor of neurology and director of the division of movement disorders at the University of Alabama at Birmingham. The pharmacology of rotigotine is a little different from that of the most widely used dopamine agonists, pramipexole and ropinirole, but the main difference is the transdermal system, he said in an interview.

Another advantage is that the continuous delivery of medication over 24 hours provides a stable blood level, which theoretically, could be an improvement over current treatments, he said. Recent research suggests that the peaks and troughs with conventional dopaminergic drugs may be responsible for some of the problems associated with oral therapy–end of the dose “wearing off” and dyskinesia–and possibly hallucinations and neuropsychiatric effects as well.

However, there is no evidence yet that the steady level provided by the patch will translate into long-term clinical benefits, he emphasized. “Many of us think it will, but I don't think we have the proof of that yet.” Dr. Standaert, who also is the director of the university's Center for Neurodegeneration and Experimental Therapeutics, was not involved in rotigotine studies, some of which were conducted there before he arrived. He has no financial ties to the manufacturer but has consulted on the pharmacologic properties of rotigotine to UCB, the U.S. pharmaceutical company that is in the process of acquiring Schwarz Pharma.

“This is an exciting step in that there are a lot of both theoretical and practical advantages to finally having patch therapy for Parkinson's,” agreed Dr. Michael Pourfar, a neurologist in the division of movement disorders, at North Shore University Hospital, Manhasset, N.Y. Because there are effective dopamine agonists available for Parkinson's, he said he would not want patients to feel like they need to change their medications. “But I do think this is something that will improve quality of life for many people,” he added in an interview, noting that for some patients, the patch could replace as many as six pills per day. He has not been involved in trials of rotigotine and has no financial ties to the manufacturer.

Rotigotine is delivered continuously though the silicone-based patch that is applied to clean, dry, intact skin and is replaced every 24 hours. It is available in three strengths: 2 mg, 4 mg, and 6 mg/24 hr. The recommended dosing is to start at 2 mg. When additional therapeutic effects are needed, the dose may be increased weekly by 2 mg/24 hours if tolerated, according to the package insert. In studies, the lowest effective dose was 4 mg/24 hours, and in dose-ranging studies, doses above 6 mg/24 hours were not more effective than the lower doses and were associated with a higher rate of adverse reactions. The patch should be applied to sites on the front of the abdomen, thigh, hip, flank, shoulder, or upper arm at about the same time every day, avoiding reapplication to the same site more than once every 14 days.

The change from baseline for the combined scores for the activities of daily living and motor components of the Unified Parkinson's Disease Rating Scale (UPDRS) was the primary outcome in the three studies, which enrolled early-stage Parkinson's disease patients who were not on dopamine agonist treatment, and whose mean age was 60–63 years. In one of the trials, a 28-week multicenter North American study, 277 patients received up to a 6 g/24 hours dose of rotigotine or placebo. The mean reduction in the combined UPDRS score from baseline was 4.0, compared with a mean 1.39 increase from baseline among those on placebo, a difference of 5.3 that was statistically significant.

The most common side effects in the three trials included dizziness, nausea, vomiting, drowsiness, and insomnia, “most of which are typical for this class of drugs,” according to the FDA statement announcing the approval. Nearly 40% of those on the patch had application site reactions-mostly mild or moderate-compared with 14% among those who received a placebo patch. The drug's label includes a warning about sulfite sensitivity, because the delivery system contains a sulfite that may cause allergic reactions.

The rotigotine patch is not approved for advanced disease, but it is being studied in this population. In a recently published placebo-controlled 24-week study of the rotigotine patch in 351 patients with advanced Parkinson's, those treated with two doses of the patch had significant reductions in the amount of daily “off” time than those on placebo (Neurology 2007;68:1262–7).

For the first time, a transdermal drug delivery system is available for treating Parkinson's disease patients, a treatment option that provides both practical and theoretical benefits for this population, according to experts not involved in clinical trials of the product.

The Food and Drug Administration has approved a transdermal patch that contains rotigotine, a nonergotamine dopamine agonist that previously was not available in any form in the United States, for treating the signs and symptoms of early-stage idiopathic Parkinson's disease. Approval, which came in May, was based on three randomized, double-blind placebo-controlled studies in the United States and abroad of 1,154 patients with early Parkinson's, who were not taking other medications for Parkinson's. The patch will be marketed under the trade name Neupro by Schwarz Pharma LLC and was expected to be available in U.S. pharmacies by June 22–30, according to a spokesperson for the German company. At press time, the price was not available.

The option of a transdermal delivery system for patients who are tired of taking many pills is a clear advantage, said Dr. David Standaert, professor of neurology and director of the division of movement disorders at the University of Alabama at Birmingham. The pharmacology of rotigotine is a little different from that of the most widely used dopamine agonists, pramipexole and ropinirole, but the main difference is the transdermal system, he said in an interview.

Another advantage is that the continuous delivery of medication over 24 hours provides a stable blood level, which theoretically, could be an improvement over current treatments, he said. Recent research suggests that the peaks and troughs with conventional dopaminergic drugs may be responsible for some of the problems associated with oral therapy–end of the dose “wearing off” and dyskinesia–and possibly hallucinations and neuropsychiatric effects as well.

However, there is no evidence yet that the steady level provided by the patch will translate into long-term clinical benefits, he emphasized. “Many of us think it will, but I don't think we have the proof of that yet.” Dr. Standaert, who also is the director of the university's Center for Neurodegeneration and Experimental Therapeutics, was not involved in rotigotine studies, some of which were conducted there before he arrived. He has no financial ties to the manufacturer but has consulted on the pharmacologic properties of rotigotine to UCB, the U.S. pharmaceutical company that is in the process of acquiring Schwarz Pharma.

“This is an exciting step in that there are a lot of both theoretical and practical advantages to finally having patch therapy for Parkinson's,” agreed Dr. Michael Pourfar, a neurologist in the division of movement disorders, at North Shore University Hospital, Manhasset, N.Y. Because there are effective dopamine agonists available for Parkinson's, he said he would not want patients to feel like they need to change their medications. “But I do think this is something that will improve quality of life for many people,” he added in an interview, noting that for some patients, the patch could replace as many as six pills per day. He has not been involved in trials of rotigotine and has no financial ties to the manufacturer.

Rotigotine is delivered continuously though the silicone-based patch that is applied to clean, dry, intact skin and is replaced every 24 hours. It is available in three strengths: 2 mg, 4 mg, and 6 mg/24 hr. The recommended dosing is to start at 2 mg. When additional therapeutic effects are needed, the dose may be increased weekly by 2 mg/24 hours if tolerated, according to the package insert. In studies, the lowest effective dose was 4 mg/24 hours, and in dose-ranging studies, doses above 6 mg/24 hours were not more effective than the lower doses and were associated with a higher rate of adverse reactions. The patch should be applied to sites on the front of the abdomen, thigh, hip, flank, shoulder, or upper arm at about the same time every day, avoiding reapplication to the same site more than once every 14 days.

The change from baseline for the combined scores for the activities of daily living and motor components of the Unified Parkinson's Disease Rating Scale (UPDRS) was the primary outcome in the three studies, which enrolled early-stage Parkinson's disease patients who were not on dopamine agonist treatment, and whose mean age was 60–63 years. In one of the trials, a 28-week multicenter North American study, 277 patients received up to a 6 g/24 hours dose of rotigotine or placebo. The mean reduction in the combined UPDRS score from baseline was 4.0, compared with a mean 1.39 increase from baseline among those on placebo, a difference of 5.3 that was statistically significant.

The most common side effects in the three trials included dizziness, nausea, vomiting, drowsiness, and insomnia, “most of which are typical for this class of drugs,” according to the FDA statement announcing the approval. Nearly 40% of those on the patch had application site reactions-mostly mild or moderate-compared with 14% among those who received a placebo patch. The drug's label includes a warning about sulfite sensitivity, because the delivery system contains a sulfite that may cause allergic reactions.

The rotigotine patch is not approved for advanced disease, but it is being studied in this population. In a recently published placebo-controlled 24-week study of the rotigotine patch in 351 patients with advanced Parkinson's, those treated with two doses of the patch had significant reductions in the amount of daily “off” time than those on placebo (Neurology 2007;68:1262–7).

GAITHERSBURG, MD. — Clinical data would be needed to back manufacturers' claims that medical and surgical gowns, gloves, and masks containing antimicrobial agents prevent infections, when these types of products are reviewed for approval, according to a federal advisory panel.

The Food and Drug Administration's General Hospital and Personal Use Devices Advisory Panel met in May to address the scientific and clinical concerns, related to the safety and performance of these devices, that would be raised by the addition of antimicrobial agents. Other than two surgical gowns that became available almost 30 years ago, no such products have been cleared by the FDA, but there may be some interest in developing and marketing these types of products in the United States, according to the agency.

Devices incorporating antimicrobial agents that have been cleared by the FDA include intravascular, urinary, and ventricular catheters, which are associated with device-related infections, and wound care products.

The panel agreed that in vitro data would be adequate to allow a manufacturer to claim that personal protective equipment—surgical and isolation gowns, examination gloves, surgical gloves and masks, and N95 respirators—reduces or prevents contamination. But clinical data should also be required to justify any claim that such devices reduce or prevent colonization of bacteria in health care workers or patients, the panel said.

“The onus will be on industry” to provide data for claims regarding clinical benefits attributed to personal protective equipment, said Charles Edmiston Jr., Ph.D., professor of surgery and hospital epidemiologist, at the Medical College of Wisconsin, Milwaukee. For example, he said, a company could claim that the addition of antimicrobial agents to a new surgical gown eliminated contamination by vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, or other pathogens from the surface of the gown, if in vitro data were provided to support this indication. But the bar would be raised if, say, a company stated that adding antimicrobial agents to the gown would reduce the risks of nosocomial infections within an ICU patient population. Clinical data would be needed to validate such a statement, he added.

Panelist Dr. James Gordon, of a practice in West Bloomfield, Mich., that specializes in infection care, said that his hospital system would probably not use any of these devices unless they were associated with improved clinical outcomes.

The panel also agreed that the testing of such products would have to include both wet and dry states, which would cover a situation representing contact in body cavities or with blood and body fluids; and should include a variety of clinically relevant organisms. Products would also need to be tested for time periods ranging from a few minutes, which would represent a scenario of a health care worker entering an isolation room, to several hours, which could represent the amount of time such a device is used during a surgical procedure.

Safety concerns for such products could include whether the antimicrobial substance that was impregnated into a product leaches off, whether allergic reactions occur, and whether masks cause problems when worn by health care workers with lung diseases like COPD or emphysema. The safety of pediatric, neonatal, and immunocompromised patients, as well as women of child-bearing age, would also need to be evaluated, the panel said.

Another consideration would be whether inhaling subinhibitory levels of antibiotics through a mask could promote resistance, and whether “intimate contact with the nasopharynges with these masks could possibly create an environment where resistant organisms could develop,” Dr. Edmiston said.

The onus will be on industry to provide data for claims about the clinical benefits of personal protective equipment. DR. EDMISTON JR.

GAITHERSBURG, MD. — Clinical data would be needed to back manufacturers' claims that medical and surgical gowns, gloves, and masks containing antimicrobial agents prevent infections, when these types of products are reviewed for approval, according to a federal advisory panel.

The Food and Drug Administration's General Hospital and Personal Use Devices Advisory Panel met in May to address the scientific and clinical concerns, related to the safety and performance of these devices, that would be raised by the addition of antimicrobial agents. Other than two surgical gowns that became available almost 30 years ago, no such products have been cleared by the FDA, but there may be some interest in developing and marketing these types of products in the United States, according to the agency.

Devices incorporating antimicrobial agents that have been cleared by the FDA include intravascular, urinary, and ventricular catheters, which are associated with device-related infections, and wound care products.

The panel agreed that in vitro data would be adequate to allow a manufacturer to claim that personal protective equipment—surgical and isolation gowns, examination gloves, surgical gloves and masks, and N95 respirators—reduces or prevents contamination. But clinical data should also be required to justify any claim that such devices reduce or prevent colonization of bacteria in health care workers or patients, the panel said.

“The onus will be on industry” to provide data for claims regarding clinical benefits attributed to personal protective equipment, said Charles Edmiston Jr., Ph.D., professor of surgery and hospital epidemiologist, at the Medical College of Wisconsin, Milwaukee. For example, he said, a company could claim that the addition of antimicrobial agents to a new surgical gown eliminated contamination by vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, or other pathogens from the surface of the gown, if in vitro data were provided to support this indication. But the bar would be raised if, say, a company stated that adding antimicrobial agents to the gown would reduce the risks of nosocomial infections within an ICU patient population. Clinical data would be needed to validate such a statement, he added.

Panelist Dr. James Gordon, of a practice in West Bloomfield, Mich., that specializes in infection care, said that his hospital system would probably not use any of these devices unless they were associated with improved clinical outcomes.

The panel also agreed that the testing of such products would have to include both wet and dry states, which would cover a situation representing contact in body cavities or with blood and body fluids; and should include a variety of clinically relevant organisms. Products would also need to be tested for time periods ranging from a few minutes, which would represent a scenario of a health care worker entering an isolation room, to several hours, which could represent the amount of time such a device is used during a surgical procedure.

Safety concerns for such products could include whether the antimicrobial substance that was impregnated into a product leaches off, whether allergic reactions occur, and whether masks cause problems when worn by health care workers with lung diseases like COPD or emphysema. The safety of pediatric, neonatal, and immunocompromised patients, as well as women of child-bearing age, would also need to be evaluated, the panel said.

Another consideration would be whether inhaling subinhibitory levels of antibiotics through a mask could promote resistance, and whether “intimate contact with the nasopharynges with these masks could possibly create an environment where resistant organisms could develop,” Dr. Edmiston said.

The onus will be on industry to provide data for claims about the clinical benefits of personal protective equipment. DR. EDMISTON JR.

GAITHERSBURG, MD. — Clinical data would be needed to back manufacturers' claims that medical and surgical gowns, gloves, and masks containing antimicrobial agents prevent infections, when these types of products are reviewed for approval, according to a federal advisory panel.

The Food and Drug Administration's General Hospital and Personal Use Devices Advisory Panel met in May to address the scientific and clinical concerns, related to the safety and performance of these devices, that would be raised by the addition of antimicrobial agents. Other than two surgical gowns that became available almost 30 years ago, no such products have been cleared by the FDA, but there may be some interest in developing and marketing these types of products in the United States, according to the agency.

Devices incorporating antimicrobial agents that have been cleared by the FDA include intravascular, urinary, and ventricular catheters, which are associated with device-related infections, and wound care products.

The panel agreed that in vitro data would be adequate to allow a manufacturer to claim that personal protective equipment—surgical and isolation gowns, examination gloves, surgical gloves and masks, and N95 respirators—reduces or prevents contamination. But clinical data should also be required to justify any claim that such devices reduce or prevent colonization of bacteria in health care workers or patients, the panel said.

“The onus will be on industry” to provide data for claims regarding clinical benefits attributed to personal protective equipment, said Charles Edmiston Jr., Ph.D., professor of surgery and hospital epidemiologist, at the Medical College of Wisconsin, Milwaukee. For example, he said, a company could claim that the addition of antimicrobial agents to a new surgical gown eliminated contamination by vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, or other pathogens from the surface of the gown, if in vitro data were provided to support this indication. But the bar would be raised if, say, a company stated that adding antimicrobial agents to the gown would reduce the risks of nosocomial infections within an ICU patient population. Clinical data would be needed to validate such a statement, he added.

Panelist Dr. James Gordon, of a practice in West Bloomfield, Mich., that specializes in infection care, said that his hospital system would probably not use any of these devices unless they were associated with improved clinical outcomes.

The panel also agreed that the testing of such products would have to include both wet and dry states, which would cover a situation representing contact in body cavities or with blood and body fluids; and should include a variety of clinically relevant organisms. Products would also need to be tested for time periods ranging from a few minutes, which would represent a scenario of a health care worker entering an isolation room, to several hours, which could represent the amount of time such a device is used during a surgical procedure.

Safety concerns for such products could include whether the antimicrobial substance that was impregnated into a product leaches off, whether allergic reactions occur, and whether masks cause problems when worn by health care workers with lung diseases like COPD or emphysema. The safety of pediatric, neonatal, and immunocompromised patients, as well as women of child-bearing age, would also need to be evaluated, the panel said.

Another consideration would be whether inhaling subinhibitory levels of antibiotics through a mask could promote resistance, and whether “intimate contact with the nasopharynges with these masks could possibly create an environment where resistant organisms could develop,” Dr. Edmiston said.

The onus will be on industry to provide data for claims about the clinical benefits of personal protective equipment. DR. EDMISTON JR.

With one exception, timed-release drug products available in the United States that contain the expectorant guaifenesin have not been approved by the Food and Drug Administration and should be taken off the market, according to an agency announcement.

About 20 companies manufacture these products, most of which are by prescription only. They include Guaifenex (manufactured by Ethex Corp.), Crantex and Guaifen (Breckenridge Pharmaceutical Inc.), Amibid and Amitex (Actavis Group), Duraphen (Proethic Pharmaceuticals Inc.), Wellbid (Prasco), Ambi (Ambi Pharmaceuticals Inc.), and Maxifed (MCR American Pharmaceuticals Inc.). Many include other active ingredients, said the FDA.

The agency ordered manufacturers of these unapproved products to stop making them no later than Aug. 27 and to cease interstate shipment by Nov. 25, although some inventory will remain in pharmacies after that time. The action does not affect immediate-release formulations of guaifenesin, only timed-release formulations, which are also described as extended release, long acting, or sustained release.

The only timed-release products containing guaifenesin that have been formally approved by the FDA are those marketed over the counter as Mucinex or Humibid, by Adams Respiratory Therapeutics. Beside Mucinex and Humibid, which contain only guaifenesin, the company makes Mucinex-D, which also contains pseudoephedrine, and Mucinex-DM, which also contains dextromethorphan.

Timed-release products must be approved because the FDA needs to ensure that “the product releases its active ingredients safely and effectively, sustaining the intended effect over the entire time in which the product is intended to work,” said the FDA statement. Dose dumping is a major concern with these products, Deborah M. Autor, an attorney and director of the office of compliance in the FDA's Center for Drug Evaluation and Research (CDER), said in a telebriefing. The FDA did not look into whether there were any reports of adverse events linked to the unapproved guaifenesin products; adverse event reports did not spur this action, she said.

The guaifenesin products are the latest target of an FDA effort, announced in June 2006, to get unapproved, potentially dangerous drugs off the market. The first products targeted were unapproved prescription products containing the antihistamine carbinoxamine, which had been linked to 21 deaths in children under age 2. Others targeted since then include unapproved products containing quinine (December 2006), and unapproved products containing ergotamine (March 2007).

The FDA's Web site on unapproved drugs is available at www.fda.gov/cder/drug/unapproved_drugs/default.htm

With one exception, timed-release drug products available in the United States that contain the expectorant guaifenesin have not been approved by the Food and Drug Administration and should be taken off the market, according to an agency announcement.

About 20 companies manufacture these products, most of which are by prescription only. They include Guaifenex (manufactured by Ethex Corp.), Crantex and Guaifen (Breckenridge Pharmaceutical Inc.), Amibid and Amitex (Actavis Group), Duraphen (Proethic Pharmaceuticals Inc.), Wellbid (Prasco), Ambi (Ambi Pharmaceuticals Inc.), and Maxifed (MCR American Pharmaceuticals Inc.). Many include other active ingredients, said the FDA.

The agency ordered manufacturers of these unapproved products to stop making them no later than Aug. 27 and to cease interstate shipment by Nov. 25, although some inventory will remain in pharmacies after that time. The action does not affect immediate-release formulations of guaifenesin, only timed-release formulations, which are also described as extended release, long acting, or sustained release.

The only timed-release products containing guaifenesin that have been formally approved by the FDA are those marketed over the counter as Mucinex or Humibid, by Adams Respiratory Therapeutics. Beside Mucinex and Humibid, which contain only guaifenesin, the company makes Mucinex-D, which also contains pseudoephedrine, and Mucinex-DM, which also contains dextromethorphan.

Timed-release products must be approved because the FDA needs to ensure that “the product releases its active ingredients safely and effectively, sustaining the intended effect over the entire time in which the product is intended to work,” said the FDA statement. Dose dumping is a major concern with these products, Deborah M. Autor, an attorney and director of the office of compliance in the FDA's Center for Drug Evaluation and Research (CDER), said in a telebriefing. The FDA did not look into whether there were any reports of adverse events linked to the unapproved guaifenesin products; adverse event reports did not spur this action, she said.

The guaifenesin products are the latest target of an FDA effort, announced in June 2006, to get unapproved, potentially dangerous drugs off the market. The first products targeted were unapproved prescription products containing the antihistamine carbinoxamine, which had been linked to 21 deaths in children under age 2. Others targeted since then include unapproved products containing quinine (December 2006), and unapproved products containing ergotamine (March 2007).

The FDA's Web site on unapproved drugs is available at www.fda.gov/cder/drug/unapproved_drugs/default.htm

With one exception, timed-release drug products available in the United States that contain the expectorant guaifenesin have not been approved by the Food and Drug Administration and should be taken off the market, according to an agency announcement.

About 20 companies manufacture these products, most of which are by prescription only. They include Guaifenex (manufactured by Ethex Corp.), Crantex and Guaifen (Breckenridge Pharmaceutical Inc.), Amibid and Amitex (Actavis Group), Duraphen (Proethic Pharmaceuticals Inc.), Wellbid (Prasco), Ambi (Ambi Pharmaceuticals Inc.), and Maxifed (MCR American Pharmaceuticals Inc.). Many include other active ingredients, said the FDA.

The agency ordered manufacturers of these unapproved products to stop making them no later than Aug. 27 and to cease interstate shipment by Nov. 25, although some inventory will remain in pharmacies after that time. The action does not affect immediate-release formulations of guaifenesin, only timed-release formulations, which are also described as extended release, long acting, or sustained release.

The only timed-release products containing guaifenesin that have been formally approved by the FDA are those marketed over the counter as Mucinex or Humibid, by Adams Respiratory Therapeutics. Beside Mucinex and Humibid, which contain only guaifenesin, the company makes Mucinex-D, which also contains pseudoephedrine, and Mucinex-DM, which also contains dextromethorphan.

Timed-release products must be approved because the FDA needs to ensure that “the product releases its active ingredients safely and effectively, sustaining the intended effect over the entire time in which the product is intended to work,” said the FDA statement. Dose dumping is a major concern with these products, Deborah M. Autor, an attorney and director of the office of compliance in the FDA's Center for Drug Evaluation and Research (CDER), said in a telebriefing. The FDA did not look into whether there were any reports of adverse events linked to the unapproved guaifenesin products; adverse event reports did not spur this action, she said.

The guaifenesin products are the latest target of an FDA effort, announced in June 2006, to get unapproved, potentially dangerous drugs off the market. The first products targeted were unapproved prescription products containing the antihistamine carbinoxamine, which had been linked to 21 deaths in children under age 2. Others targeted since then include unapproved products containing quinine (December 2006), and unapproved products containing ergotamine (March 2007).

The FDA's Web site on unapproved drugs is available at www.fda.gov/cder/drug/unapproved_drugs/default.htm

GAITHERSBURG, MD. — A more modern version of the smallpox vaccine appears to be safe and effective enough to use “where it is determined that there is a high risk of exposure to smallpox virus,” according to a Food and Drug Administration advisory panel.

At a meeting, members of the FDA's Vaccines and Related Biological Products Advisory Committee agreed that the ACAM2000 vaccine should be submitted to postmarketing studies that follow people who developed vaccine-associated myocarditis and determine risk factors for myocarditis.

The vaccine, which is derived from Dryvax, the currently licensed smallpox vaccine, is not being considered for use in the general population. Panelists emphasized the nature of the situations in which the risk-benefit profile of ACAM2000 would be considered favorable.

“This and Dryvax are the least-safe vaccines that we will have licensed in this country, and we have to weigh that against the risk of smallpox,” said the panel chair, Dr. Ruth A. Karron, professor in the department of international health at Johns Hopkins University, Baltimore.

The rate of myocarditis—one in about every 150 vaccine recipients—was “far and above” any serious adverse event of that magnitude associated with other vaccines, emphasized Dr. Jack Stapleton, professor and director of infectious diseases at the University of Iowa, Iowa City.

If this were a vaccine being considered for routine use in the general population, the risk of myocarditis seen in clinical trials would be unacceptable, added Dr. Monica Farley, professor of medicine at Emory University, Atlanta.

Some other well-documented complications of smallpox vaccination that date back to the era of routine smallpox vaccination include generalized vaccinia, eczema vaccinatum, postvaccinial encephalitis, inadvertent inoculation, fetal vaccinia, and death.

The panel was not asked to vote specifically on whether to approve the vaccine. The FDA typically follows the advice of its advisory panels, although that advice is not binding.

If approved by the FDA, the vaccine would not be made available commercially. Instead, it would be used for the national vaccine stockpile and for military personnel deployed to areas of the world where the threat of exposure to smallpox as a biologic weapon is considered high.

Acambis Inc. manufactures the vaccine, which was developed under a contract with the Centers for Disease Control and Prevention for stockpiling purposes. In fact, Acambis has already supplied 192.5 million doses to the U.S. Strategic National Stockpile, according to the company. There is a limited supply of Dryvax remaining, which is itself reserved for the military and laboratory workers.

The derivation of ACAM2000 from Dryvax uses modern cell culture techniques without animal serum. The vaccine is grown in a continuous cell line, which provides a predictable, standardized manufacturing process, according to Acambis.

Dryvax was compared with ACAM2000 in two multicenter, double-blind randomized studies of about 2,800 previously healthy adults. Those studies were designed to show that ACAM2000 was not inferior to Dryvax.

In one study of people aged 18–30 years who had never been vaccinated against smallpox, the “take rate” of a cutaneous response—a generally accepted surrogate of protection—was 96% among those who received ACAM2000 and 99% among those who received Dryvax, a difference indicating noninferiority.

In a second study of people aged 31–84 years who had been vaccinated against smallpox, however, the take rate was 84% among those who received ACAM2000, compared with 98% of those who received Dryvax.

The majority of side effects were inoculation site reactions and systemic symptoms, including vaccine site pain, lymph node pain, headache, fatigue, and myalgia.

In both studies, participants were closely monitored for myocarditis, which was diagnosed in 10 naive recipients (7 of whom were in the ACAM2000 treatment group). The myocarditis cases occurred at a mean of 11 days after receiving the vaccine and resolved in all but one case, according to Acambis.

In the study of people without prior vaccination, the rate of myocarditis was about one case per 145 vaccinations, which is higher than anticipated, according to the FDA. That study's myocarditis rate was greater than the military's rate, which a Department of Defense official at the meeting said has been about one case per 6,000 primary vaccinations.

If the vaccine is approved, Acambis would launch a Risk Minimization Action Plan (RiskMAP). That would include education of vaccinees and health care providers, expedited reporting of serious adverse events, and phase IV studies to assess the vaccine's safety profile, long-term outcomes, and myocarditis risk factors.

GAITHERSBURG, MD. — A more modern version of the smallpox vaccine appears to be safe and effective enough to use “where it is determined that there is a high risk of exposure to smallpox virus,” according to a Food and Drug Administration advisory panel.

At a meeting, members of the FDA's Vaccines and Related Biological Products Advisory Committee agreed that the ACAM2000 vaccine should be submitted to postmarketing studies that follow people who developed vaccine-associated myocarditis and determine risk factors for myocarditis.

The vaccine, which is derived from Dryvax, the currently licensed smallpox vaccine, is not being considered for use in the general population. Panelists emphasized the nature of the situations in which the risk-benefit profile of ACAM2000 would be considered favorable.

“This and Dryvax are the least-safe vaccines that we will have licensed in this country, and we have to weigh that against the risk of smallpox,” said the panel chair, Dr. Ruth A. Karron, professor in the department of international health at Johns Hopkins University, Baltimore.

The rate of myocarditis—one in about every 150 vaccine recipients—was “far and above” any serious adverse event of that magnitude associated with other vaccines, emphasized Dr. Jack Stapleton, professor and director of infectious diseases at the University of Iowa, Iowa City.

If this were a vaccine being considered for routine use in the general population, the risk of myocarditis seen in clinical trials would be unacceptable, added Dr. Monica Farley, professor of medicine at Emory University, Atlanta.

Some other well-documented complications of smallpox vaccination that date back to the era of routine smallpox vaccination include generalized vaccinia, eczema vaccinatum, postvaccinial encephalitis, inadvertent inoculation, fetal vaccinia, and death.

The panel was not asked to vote specifically on whether to approve the vaccine. The FDA typically follows the advice of its advisory panels, although that advice is not binding.

If approved by the FDA, the vaccine would not be made available commercially. Instead, it would be used for the national vaccine stockpile and for military personnel deployed to areas of the world where the threat of exposure to smallpox as a biologic weapon is considered high.

Acambis Inc. manufactures the vaccine, which was developed under a contract with the Centers for Disease Control and Prevention for stockpiling purposes. In fact, Acambis has already supplied 192.5 million doses to the U.S. Strategic National Stockpile, according to the company. There is a limited supply of Dryvax remaining, which is itself reserved for the military and laboratory workers.

The derivation of ACAM2000 from Dryvax uses modern cell culture techniques without animal serum. The vaccine is grown in a continuous cell line, which provides a predictable, standardized manufacturing process, according to Acambis.

Dryvax was compared with ACAM2000 in two multicenter, double-blind randomized studies of about 2,800 previously healthy adults. Those studies were designed to show that ACAM2000 was not inferior to Dryvax.

In one study of people aged 18–30 years who had never been vaccinated against smallpox, the “take rate” of a cutaneous response—a generally accepted surrogate of protection—was 96% among those who received ACAM2000 and 99% among those who received Dryvax, a difference indicating noninferiority.

In a second study of people aged 31–84 years who had been vaccinated against smallpox, however, the take rate was 84% among those who received ACAM2000, compared with 98% of those who received Dryvax.

The majority of side effects were inoculation site reactions and systemic symptoms, including vaccine site pain, lymph node pain, headache, fatigue, and myalgia.

In both studies, participants were closely monitored for myocarditis, which was diagnosed in 10 naive recipients (7 of whom were in the ACAM2000 treatment group). The myocarditis cases occurred at a mean of 11 days after receiving the vaccine and resolved in all but one case, according to Acambis.

In the study of people without prior vaccination, the rate of myocarditis was about one case per 145 vaccinations, which is higher than anticipated, according to the FDA. That study's myocarditis rate was greater than the military's rate, which a Department of Defense official at the meeting said has been about one case per 6,000 primary vaccinations.

If the vaccine is approved, Acambis would launch a Risk Minimization Action Plan (RiskMAP). That would include education of vaccinees and health care providers, expedited reporting of serious adverse events, and phase IV studies to assess the vaccine's safety profile, long-term outcomes, and myocarditis risk factors.

GAITHERSBURG, MD. — A more modern version of the smallpox vaccine appears to be safe and effective enough to use “where it is determined that there is a high risk of exposure to smallpox virus,” according to a Food and Drug Administration advisory panel.

At a meeting, members of the FDA's Vaccines and Related Biological Products Advisory Committee agreed that the ACAM2000 vaccine should be submitted to postmarketing studies that follow people who developed vaccine-associated myocarditis and determine risk factors for myocarditis.

The vaccine, which is derived from Dryvax, the currently licensed smallpox vaccine, is not being considered for use in the general population. Panelists emphasized the nature of the situations in which the risk-benefit profile of ACAM2000 would be considered favorable.

“This and Dryvax are the least-safe vaccines that we will have licensed in this country, and we have to weigh that against the risk of smallpox,” said the panel chair, Dr. Ruth A. Karron, professor in the department of international health at Johns Hopkins University, Baltimore.

The rate of myocarditis—one in about every 150 vaccine recipients—was “far and above” any serious adverse event of that magnitude associated with other vaccines, emphasized Dr. Jack Stapleton, professor and director of infectious diseases at the University of Iowa, Iowa City.

If this were a vaccine being considered for routine use in the general population, the risk of myocarditis seen in clinical trials would be unacceptable, added Dr. Monica Farley, professor of medicine at Emory University, Atlanta.

Some other well-documented complications of smallpox vaccination that date back to the era of routine smallpox vaccination include generalized vaccinia, eczema vaccinatum, postvaccinial encephalitis, inadvertent inoculation, fetal vaccinia, and death.

The panel was not asked to vote specifically on whether to approve the vaccine. The FDA typically follows the advice of its advisory panels, although that advice is not binding.

If approved by the FDA, the vaccine would not be made available commercially. Instead, it would be used for the national vaccine stockpile and for military personnel deployed to areas of the world where the threat of exposure to smallpox as a biologic weapon is considered high.

Acambis Inc. manufactures the vaccine, which was developed under a contract with the Centers for Disease Control and Prevention for stockpiling purposes. In fact, Acambis has already supplied 192.5 million doses to the U.S. Strategic National Stockpile, according to the company. There is a limited supply of Dryvax remaining, which is itself reserved for the military and laboratory workers.

The derivation of ACAM2000 from Dryvax uses modern cell culture techniques without animal serum. The vaccine is grown in a continuous cell line, which provides a predictable, standardized manufacturing process, according to Acambis.

Dryvax was compared with ACAM2000 in two multicenter, double-blind randomized studies of about 2,800 previously healthy adults. Those studies were designed to show that ACAM2000 was not inferior to Dryvax.

In one study of people aged 18–30 years who had never been vaccinated against smallpox, the “take rate” of a cutaneous response—a generally accepted surrogate of protection—was 96% among those who received ACAM2000 and 99% among those who received Dryvax, a difference indicating noninferiority.

In a second study of people aged 31–84 years who had been vaccinated against smallpox, however, the take rate was 84% among those who received ACAM2000, compared with 98% of those who received Dryvax.

The majority of side effects were inoculation site reactions and systemic symptoms, including vaccine site pain, lymph node pain, headache, fatigue, and myalgia.

In both studies, participants were closely monitored for myocarditis, which was diagnosed in 10 naive recipients (7 of whom were in the ACAM2000 treatment group). The myocarditis cases occurred at a mean of 11 days after receiving the vaccine and resolved in all but one case, according to Acambis.

In the study of people without prior vaccination, the rate of myocarditis was about one case per 145 vaccinations, which is higher than anticipated, according to the FDA. That study's myocarditis rate was greater than the military's rate, which a Department of Defense official at the meeting said has been about one case per 6,000 primary vaccinations.

If the vaccine is approved, Acambis would launch a Risk Minimization Action Plan (RiskMAP). That would include education of vaccinees and health care providers, expedited reporting of serious adverse events, and phase IV studies to assess the vaccine's safety profile, long-term outcomes, and myocarditis risk factors.

For the first time, a transdermal drug delivery system is available for treating Parkinson's disease patients, a treatment option that provides both practical and theoretical benefits for this population, according to experts not involved in clinical trials of the product.

Last month, the Food and Drug Administration approved a transdermal patch containing rotigotine, a nonergotamine dopamine agonist previously not available in any form in the United States, for the signs and symptoms of early-stage idiopathic Parkinson's. Approval was based on three randomized, double-blind, placebo-controlled studies of 1,154 patients with early Parkinson's, who were not on other drugs for Parkinson's. The patch will be marketed as Neupro by the German company Schwarz Pharma LLC and should be available by June 22–30. At press time, price was not available.

A transdermal delivery system is one clear advantage for patients already taking many pills, said Dr. David Standaert, professor of neurology and director of the division of movement disorders at the University of Alabama at Birmingham. The pharmacology of rotigotine is a little different from that of the most widely used dopamine agonists, pramipexole and ropinirole, but the main difference is the transdermal system, he said in an interview.

Another advantage is that the continuous delivery of medication over 24 hours provides a stable blood level, he said. Research suggests the peaks and troughs with conventional dopaminergic drugs may cause some of the problems associated with oral therapy—end of the dose “wearing off” and dyskinesia—and possibly hallucinations and neuropsychiatric effects. However, there is no evidence that the steady level provided by the patch will translate into long-term clinical benefits. Dr. Standaert, who also is the director of the university's Center for Neurodegeneration and Experimental Therapeutics, was not involved in rotigotine studies. He has no financial ties to the manufacturer but has consulted on the pharmacologic properties of rotigotine to UCB, the U.S. pharmaceutical company that is in the process of acquiring Schwarz Pharma.

“There are a lot of both theoretical and practical advantages to finally having patch therapy for Parkinson's,” agreed Dr. Michael Pourfar, a neurologist in the division of movement disorders, at North Shore University Hospital, Manhasset, N.Y. Because there are effective dopamine agonists available for Parkinson's, he said he would not want patients to feel like they must switch medications. “But I do think this is something that will improve quality of life for many,” he added in an interview, noting that for some, the patch could replace as many as six pills per day. He has not been involved in trials of rotigotine and has no financial ties to the maker.

Rotigotine is delivered continuously though the silicone-based patch that is applied to clean, dry intact skin and is replaced every 24 hours. It is available in three strengths: 2 mg, 4 mg, and 6 mg/24 hr. The recommended dosing is to start at 2 mg. When additional therapeutic effects are needed, the dose may be increased weekly by 2 mg/24 hours if tolerated, according to the package insert. In studies, the lowest effective dose was 4 mg/24 hours, and in dose-ranging studies, doses above 6 mg/24 hours were not more effective and were tied to a higher rate of adverse reactions.

The patch should be applied to the front of the abdomen, thigh, hip, flank, shoulder, or upper arm at about the same time every day, avoiding same-site reapplication more than once every 14 days.

The change from baseline for the combined scores for the activities of daily living and motor components of the Unified Parkinson's Disease Rating Scale (UPDRS) was the primary outcome in the three studies, which enrolled early-stage Parkinson's disease patients not on dopamine agonist treatment, whose mean age was 60–63 years.

In one trial, a 28-week multicenter North American study, 277 patients received up to a 6 g/24 hours dose of rotigotine or placebo. The mean reduction in the combined UPDRS score from baseline was 4.0, versus a mean 1.39 increase from baseline among those on placebo, a statistically significant difference of 5.3. The most common side effects were dizziness, nausea, vomiting, drowsiness, and insomnia, “most of which are typical for this class of drugs,” said the FDA. Nearly 40% had application site reactions—mostly mild or moderate—versus 14% of those on a placebo patch. The delivery system contains a sulfite that may cause allergic reactions in sulfite-sensitive people.

The patch is not yet approved for advanced disease, but in a recently published, placebo-controlled, 24-week study of 351 patients with advanced Parkinson's, those treated with two doses of the patch had significant reductions in daily “off” time than those on placebo (Neurology 2007;68:1262–7).

For the first time, a transdermal drug delivery system is available for treating Parkinson's disease patients, a treatment option that provides both practical and theoretical benefits for this population, according to experts not involved in clinical trials of the product.

Last month, the Food and Drug Administration approved a transdermal patch containing rotigotine, a nonergotamine dopamine agonist previously not available in any form in the United States, for the signs and symptoms of early-stage idiopathic Parkinson's. Approval was based on three randomized, double-blind, placebo-controlled studies of 1,154 patients with early Parkinson's, who were not on other drugs for Parkinson's. The patch will be marketed as Neupro by the German company Schwarz Pharma LLC and should be available by June 22–30. At press time, price was not available.

A transdermal delivery system is one clear advantage for patients already taking many pills, said Dr. David Standaert, professor of neurology and director of the division of movement disorders at the University of Alabama at Birmingham. The pharmacology of rotigotine is a little different from that of the most widely used dopamine agonists, pramipexole and ropinirole, but the main difference is the transdermal system, he said in an interview.

Another advantage is that the continuous delivery of medication over 24 hours provides a stable blood level, he said. Research suggests the peaks and troughs with conventional dopaminergic drugs may cause some of the problems associated with oral therapy—end of the dose “wearing off” and dyskinesia—and possibly hallucinations and neuropsychiatric effects. However, there is no evidence that the steady level provided by the patch will translate into long-term clinical benefits. Dr. Standaert, who also is the director of the university's Center for Neurodegeneration and Experimental Therapeutics, was not involved in rotigotine studies. He has no financial ties to the manufacturer but has consulted on the pharmacologic properties of rotigotine to UCB, the U.S. pharmaceutical company that is in the process of acquiring Schwarz Pharma.

“There are a lot of both theoretical and practical advantages to finally having patch therapy for Parkinson's,” agreed Dr. Michael Pourfar, a neurologist in the division of movement disorders, at North Shore University Hospital, Manhasset, N.Y. Because there are effective dopamine agonists available for Parkinson's, he said he would not want patients to feel like they must switch medications. “But I do think this is something that will improve quality of life for many,” he added in an interview, noting that for some, the patch could replace as many as six pills per day. He has not been involved in trials of rotigotine and has no financial ties to the maker.

Rotigotine is delivered continuously though the silicone-based patch that is applied to clean, dry intact skin and is replaced every 24 hours. It is available in three strengths: 2 mg, 4 mg, and 6 mg/24 hr. The recommended dosing is to start at 2 mg. When additional therapeutic effects are needed, the dose may be increased weekly by 2 mg/24 hours if tolerated, according to the package insert. In studies, the lowest effective dose was 4 mg/24 hours, and in dose-ranging studies, doses above 6 mg/24 hours were not more effective and were tied to a higher rate of adverse reactions.

The patch should be applied to the front of the abdomen, thigh, hip, flank, shoulder, or upper arm at about the same time every day, avoiding same-site reapplication more than once every 14 days.

The change from baseline for the combined scores for the activities of daily living and motor components of the Unified Parkinson's Disease Rating Scale (UPDRS) was the primary outcome in the three studies, which enrolled early-stage Parkinson's disease patients not on dopamine agonist treatment, whose mean age was 60–63 years.

In one trial, a 28-week multicenter North American study, 277 patients received up to a 6 g/24 hours dose of rotigotine or placebo. The mean reduction in the combined UPDRS score from baseline was 4.0, versus a mean 1.39 increase from baseline among those on placebo, a statistically significant difference of 5.3. The most common side effects were dizziness, nausea, vomiting, drowsiness, and insomnia, “most of which are typical for this class of drugs,” said the FDA. Nearly 40% had application site reactions—mostly mild or moderate—versus 14% of those on a placebo patch. The delivery system contains a sulfite that may cause allergic reactions in sulfite-sensitive people.

The patch is not yet approved for advanced disease, but in a recently published, placebo-controlled, 24-week study of 351 patients with advanced Parkinson's, those treated with two doses of the patch had significant reductions in daily “off” time than those on placebo (Neurology 2007;68:1262–7).

For the first time, a transdermal drug delivery system is available for treating Parkinson's disease patients, a treatment option that provides both practical and theoretical benefits for this population, according to experts not involved in clinical trials of the product.

Last month, the Food and Drug Administration approved a transdermal patch containing rotigotine, a nonergotamine dopamine agonist previously not available in any form in the United States, for the signs and symptoms of early-stage idiopathic Parkinson's. Approval was based on three randomized, double-blind, placebo-controlled studies of 1,154 patients with early Parkinson's, who were not on other drugs for Parkinson's. The patch will be marketed as Neupro by the German company Schwarz Pharma LLC and should be available by June 22–30. At press time, price was not available.

A transdermal delivery system is one clear advantage for patients already taking many pills, said Dr. David Standaert, professor of neurology and director of the division of movement disorders at the University of Alabama at Birmingham. The pharmacology of rotigotine is a little different from that of the most widely used dopamine agonists, pramipexole and ropinirole, but the main difference is the transdermal system, he said in an interview.

Another advantage is that the continuous delivery of medication over 24 hours provides a stable blood level, he said. Research suggests the peaks and troughs with conventional dopaminergic drugs may cause some of the problems associated with oral therapy—end of the dose “wearing off” and dyskinesia—and possibly hallucinations and neuropsychiatric effects. However, there is no evidence that the steady level provided by the patch will translate into long-term clinical benefits. Dr. Standaert, who also is the director of the university's Center for Neurodegeneration and Experimental Therapeutics, was not involved in rotigotine studies. He has no financial ties to the manufacturer but has consulted on the pharmacologic properties of rotigotine to UCB, the U.S. pharmaceutical company that is in the process of acquiring Schwarz Pharma.

“There are a lot of both theoretical and practical advantages to finally having patch therapy for Parkinson's,” agreed Dr. Michael Pourfar, a neurologist in the division of movement disorders, at North Shore University Hospital, Manhasset, N.Y. Because there are effective dopamine agonists available for Parkinson's, he said he would not want patients to feel like they must switch medications. “But I do think this is something that will improve quality of life for many,” he added in an interview, noting that for some, the patch could replace as many as six pills per day. He has not been involved in trials of rotigotine and has no financial ties to the maker.

Rotigotine is delivered continuously though the silicone-based patch that is applied to clean, dry intact skin and is replaced every 24 hours. It is available in three strengths: 2 mg, 4 mg, and 6 mg/24 hr. The recommended dosing is to start at 2 mg. When additional therapeutic effects are needed, the dose may be increased weekly by 2 mg/24 hours if tolerated, according to the package insert. In studies, the lowest effective dose was 4 mg/24 hours, and in dose-ranging studies, doses above 6 mg/24 hours were not more effective and were tied to a higher rate of adverse reactions.

The patch should be applied to the front of the abdomen, thigh, hip, flank, shoulder, or upper arm at about the same time every day, avoiding same-site reapplication more than once every 14 days.

The change from baseline for the combined scores for the activities of daily living and motor components of the Unified Parkinson's Disease Rating Scale (UPDRS) was the primary outcome in the three studies, which enrolled early-stage Parkinson's disease patients not on dopamine agonist treatment, whose mean age was 60–63 years.

In one trial, a 28-week multicenter North American study, 277 patients received up to a 6 g/24 hours dose of rotigotine or placebo. The mean reduction in the combined UPDRS score from baseline was 4.0, versus a mean 1.39 increase from baseline among those on placebo, a statistically significant difference of 5.3. The most common side effects were dizziness, nausea, vomiting, drowsiness, and insomnia, “most of which are typical for this class of drugs,” said the FDA. Nearly 40% had application site reactions—mostly mild or moderate—versus 14% of those on a placebo patch. The delivery system contains a sulfite that may cause allergic reactions in sulfite-sensitive people.

The patch is not yet approved for advanced disease, but in a recently published, placebo-controlled, 24-week study of 351 patients with advanced Parkinson's, those treated with two doses of the patch had significant reductions in daily “off” time than those on placebo (Neurology 2007;68:1262–7).

The Food and Drug Administration has requested that a boxed warning explaining the increased risk of nephrogenic systemic fibrosis in patients with renal insufficiency be added to the labels of gadolinium-based contrast agents, according to an alert posted on the agency's MedWatch Web site.

Joint pain is a common finding in patients who develop nephrogenic systemic fibrosis.

The FDA has requested that the manufacturers add this information to the warnings section of the prescribing information of the five marketed gadolinium-based contrast agents (GBCA), which are used to enhance the quality of magnetic resonance imaging.

The risk of nephrogenic systemic fibrosis (NSF) has been associated with exposure to these agents in patients with acute or chronic severe renal insufficiency (glomerular filtration rate less than 30 mL/min per 1.73 square meters) and in patients with acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period, according to the FDA.

“Healthcare professionals should avoid the use of a GBCA in these patients unless the diagnostic information is essential and not available with noncontrast enhanced magnetic resonance imaging,” according to the alert. No cases of NSF have been reported in patients with normal kidney function, or mild to moderate kidney insufficiency.

The agency is advising patients be screened for kidney problems before they receive one of the imaging agents, and the recommended dose should not be exceeded.

Physicians should consider having hemodialysis patients undergo the procedure promptly after a GBCA is administered, according to the FDA. Clearance rates of GBCA have been reported to be as high as 99% after three hemodialysis sessions, although it is not known whether hemodialysis prevents NSF.

NSF—a debilitating and potentially fatal disease identified in 1997, which affects the skin, muscle, and internal organs—has been reported only in patients with acute or chronic severe renal insufficiency. Signs and symptoms include joint stiffness and pain deep in the hip as well as limited range of motion in the arms, legs, hands, or feet.

Whether the risk of NSF is similar for all the agents is not known. Postmarketing reports show that Omniscan (manufactured by GE HealthCare) is the most commonly reported agent, followed by Magnevist (Bayer Schering Pharma) and OptiMark (Mallinckrodt).

GBCAs are used off label for magnetic resonance angiography (MRA), but “some radiologists believe that these agents help provide detailed images of blood vessels,” according to the FDA.

The FDA first notified health care professionals about this risk in June 2006, after learning about 25 such reports in Denmark, and updated the information on the risk in December 2006.

More information is available at www.fda.gov/medwatch/safety/2007/safety07.htm#Gadoliniumwww.fda.gov/medwatch

The Food and Drug Administration has requested that a boxed warning explaining the increased risk of nephrogenic systemic fibrosis in patients with renal insufficiency be added to the labels of gadolinium-based contrast agents, according to an alert posted on the agency's MedWatch Web site.

Joint pain is a common finding in patients who develop nephrogenic systemic fibrosis.

The FDA has requested that the manufacturers add this information to the warnings section of the prescribing information of the five marketed gadolinium-based contrast agents (GBCA), which are used to enhance the quality of magnetic resonance imaging.

The risk of nephrogenic systemic fibrosis (NSF) has been associated with exposure to these agents in patients with acute or chronic severe renal insufficiency (glomerular filtration rate less than 30 mL/min per 1.73 square meters) and in patients with acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period, according to the FDA.

“Healthcare professionals should avoid the use of a GBCA in these patients unless the diagnostic information is essential and not available with noncontrast enhanced magnetic resonance imaging,” according to the alert. No cases of NSF have been reported in patients with normal kidney function, or mild to moderate kidney insufficiency.

The agency is advising patients be screened for kidney problems before they receive one of the imaging agents, and the recommended dose should not be exceeded.

Physicians should consider having hemodialysis patients undergo the procedure promptly after a GBCA is administered, according to the FDA. Clearance rates of GBCA have been reported to be as high as 99% after three hemodialysis sessions, although it is not known whether hemodialysis prevents NSF.

NSF—a debilitating and potentially fatal disease identified in 1997, which affects the skin, muscle, and internal organs—has been reported only in patients with acute or chronic severe renal insufficiency. Signs and symptoms include joint stiffness and pain deep in the hip as well as limited range of motion in the arms, legs, hands, or feet.

Whether the risk of NSF is similar for all the agents is not known. Postmarketing reports show that Omniscan (manufactured by GE HealthCare) is the most commonly reported agent, followed by Magnevist (Bayer Schering Pharma) and OptiMark (Mallinckrodt).

GBCAs are used off label for magnetic resonance angiography (MRA), but “some radiologists believe that these agents help provide detailed images of blood vessels,” according to the FDA.

The FDA first notified health care professionals about this risk in June 2006, after learning about 25 such reports in Denmark, and updated the information on the risk in December 2006.

More information is available at www.fda.gov/medwatch/safety/2007/safety07.htm#Gadoliniumwww.fda.gov/medwatch

The Food and Drug Administration has requested that a boxed warning explaining the increased risk of nephrogenic systemic fibrosis in patients with renal insufficiency be added to the labels of gadolinium-based contrast agents, according to an alert posted on the agency's MedWatch Web site.

Joint pain is a common finding in patients who develop nephrogenic systemic fibrosis.

The FDA has requested that the manufacturers add this information to the warnings section of the prescribing information of the five marketed gadolinium-based contrast agents (GBCA), which are used to enhance the quality of magnetic resonance imaging.

The risk of nephrogenic systemic fibrosis (NSF) has been associated with exposure to these agents in patients with acute or chronic severe renal insufficiency (glomerular filtration rate less than 30 mL/min per 1.73 square meters) and in patients with acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period, according to the FDA.

“Healthcare professionals should avoid the use of a GBCA in these patients unless the diagnostic information is essential and not available with noncontrast enhanced magnetic resonance imaging,” according to the alert. No cases of NSF have been reported in patients with normal kidney function, or mild to moderate kidney insufficiency.

The agency is advising patients be screened for kidney problems before they receive one of the imaging agents, and the recommended dose should not be exceeded.

Physicians should consider having hemodialysis patients undergo the procedure promptly after a GBCA is administered, according to the FDA. Clearance rates of GBCA have been reported to be as high as 99% after three hemodialysis sessions, although it is not known whether hemodialysis prevents NSF.

NSF—a debilitating and potentially fatal disease identified in 1997, which affects the skin, muscle, and internal organs—has been reported only in patients with acute or chronic severe renal insufficiency. Signs and symptoms include joint stiffness and pain deep in the hip as well as limited range of motion in the arms, legs, hands, or feet.

Whether the risk of NSF is similar for all the agents is not known. Postmarketing reports show that Omniscan (manufactured by GE HealthCare) is the most commonly reported agent, followed by Magnevist (Bayer Schering Pharma) and OptiMark (Mallinckrodt).

GBCAs are used off label for magnetic resonance angiography (MRA), but “some radiologists believe that these agents help provide detailed images of blood vessels,” according to the FDA.

The FDA first notified health care professionals about this risk in June 2006, after learning about 25 such reports in Denmark, and updated the information on the risk in December 2006.

More information is available at www.fda.gov/medwatch/safety/2007/safety07.htm#Gadoliniumwww.fda.gov/medwatch

ROCKVILLE, MD. — A Food and Drug Administration advisory panel unanimously recommended that the combination antihypertensive product irbesartan and hydrochlorothiazide (HCTZ) be approved as a first-line treatment for hypertension.

At a meeting on April 18, the Cardiovascular and Renal Drugs Advisory Committee voted 7–0 in favor of approving the fixed-dose angiotensin receptor blocker-diuretic combination product as initial therapy.

The company has proposed that Avalide be indicated as initial treatment of severe hypertension. The panel was asked to comment on the wording of the indication statement that would be included in the label. Several were supportive of wording that Avalide can be considered as initial treatment when control of blood pressure is not likely to be achieved with one drug, or for moderate to severe hypertension.

The product, marketed as Avalide by Bristol-Myers Squibb (BMS), was approved in 1997 for treating hypertension, with a statement in its label that says the combination therapy should not be used until a patient has failed to achieve the desired effect with monotherapy.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

The combination antihypertensives that have previously been approved as first-line treatments are Capozide (captopril and HCTZ), Ziac (bisoprolol/HCTZ), and Hyzaar (losartan/HCTZ).

At the meeting on Avalide, BMS provided the results of two studies. The first, a pivotal trial of 695 patients (mean age was 52) with severe hypertension (an untreated diastolic blood pressure of at least 110 mm Hg or on monotherapy with a diastolic blood pressure of at least 100 mm Hg), compared Avalide with irbesartan monotherapy as initial therapy. The second, a supportive trial, compared Avalide with irbesartan and HCTZ monotherapies in patients with moderate hypertension. The studies used forced titration to 300 mg/25 mg of Avalide, 300 mg of irbesartan, or 25 mg of HCTZ.

In the pivotal trial, 47% of those on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, the primary end point, compared with 33% of those on irbesartan monotherapy, a highly significant difference.

Among black subjects (about 14% of the subjects), 40% of those on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, compared with nearly 15% of those on irbesartan. In diabetic subjects, 33% had achieved blood pressure goal below 140/90 mm Hg, compared with 23% of those on irbesartan at 5 weeks.

Overall, Avalide was safe and well tolerated, and was comparable to irbesartan monotherapy, with no increase in dizziness or syncope and no serious adverse events related to treatment. No deaths were reported, according to BMS.

About 4% of patients in each group experienced dizziness, and headache was reported in 4% of those on Avalide, and 6% of those on irbesartan. Hypotension was reported in 0.6% of those on Avalide, and none of those on monotherapy.

About 2% in each group discontinued treatment for an adverse event. Among the 92 patients 65 and older, Avalide was well tolerated, there were no cases of hypotension or syncope, and dizziness was no more common than in younger patients.

In the supportive study of about 500 patients with moderate hypertension, Avalide was more effective in reducing blood pressure than either irbesartan or HCTZ alone, had a comparable safety profile, and was well tolerated in the elderly, according to BMS.

Several members of the advisory panel said that the company should get more data on the combination as first line treatment in elderly patients and in patients with renal dysfunction.

Approval as a first-line treatment would not affect the patent for Avalide, which expires in 2012, a BMS spokesperson said.

ROCKVILLE, MD. — A Food and Drug Administration advisory panel unanimously recommended that the combination antihypertensive product irbesartan and hydrochlorothiazide (HCTZ) be approved as a first-line treatment for hypertension.

At a meeting on April 18, the Cardiovascular and Renal Drugs Advisory Committee voted 7–0 in favor of approving the fixed-dose angiotensin receptor blocker-diuretic combination product as initial therapy.

The company has proposed that Avalide be indicated as initial treatment of severe hypertension. The panel was asked to comment on the wording of the indication statement that would be included in the label. Several were supportive of wording that Avalide can be considered as initial treatment when control of blood pressure is not likely to be achieved with one drug, or for moderate to severe hypertension.

The product, marketed as Avalide by Bristol-Myers Squibb (BMS), was approved in 1997 for treating hypertension, with a statement in its label that says the combination therapy should not be used until a patient has failed to achieve the desired effect with monotherapy.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

The combination antihypertensives that have previously been approved as first-line treatments are Capozide (captopril and HCTZ), Ziac (bisoprolol/HCTZ), and Hyzaar (losartan/HCTZ).

At the meeting on Avalide, BMS provided the results of two studies. The first, a pivotal trial of 695 patients (mean age was 52) with severe hypertension (an untreated diastolic blood pressure of at least 110 mm Hg or on monotherapy with a diastolic blood pressure of at least 100 mm Hg), compared Avalide with irbesartan monotherapy as initial therapy. The second, a supportive trial, compared Avalide with irbesartan and HCTZ monotherapies in patients with moderate hypertension. The studies used forced titration to 300 mg/25 mg of Avalide, 300 mg of irbesartan, or 25 mg of HCTZ.

In the pivotal trial, 47% of those on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, the primary end point, compared with 33% of those on irbesartan monotherapy, a highly significant difference.

Among black subjects (about 14% of the subjects), 40% of those on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, compared with nearly 15% of those on irbesartan. In diabetic subjects, 33% had achieved blood pressure goal below 140/90 mm Hg, compared with 23% of those on irbesartan at 5 weeks.

Overall, Avalide was safe and well tolerated, and was comparable to irbesartan monotherapy, with no increase in dizziness or syncope and no serious adverse events related to treatment. No deaths were reported, according to BMS.

About 4% of patients in each group experienced dizziness, and headache was reported in 4% of those on Avalide, and 6% of those on irbesartan. Hypotension was reported in 0.6% of those on Avalide, and none of those on monotherapy.

About 2% in each group discontinued treatment for an adverse event. Among the 92 patients 65 and older, Avalide was well tolerated, there were no cases of hypotension or syncope, and dizziness was no more common than in younger patients.

In the supportive study of about 500 patients with moderate hypertension, Avalide was more effective in reducing blood pressure than either irbesartan or HCTZ alone, had a comparable safety profile, and was well tolerated in the elderly, according to BMS.

Several members of the advisory panel said that the company should get more data on the combination as first line treatment in elderly patients and in patients with renal dysfunction.

Approval as a first-line treatment would not affect the patent for Avalide, which expires in 2012, a BMS spokesperson said.

ROCKVILLE, MD. — A Food and Drug Administration advisory panel unanimously recommended that the combination antihypertensive product irbesartan and hydrochlorothiazide (HCTZ) be approved as a first-line treatment for hypertension.

At a meeting on April 18, the Cardiovascular and Renal Drugs Advisory Committee voted 7–0 in favor of approving the fixed-dose angiotensin receptor blocker-diuretic combination product as initial therapy.

The company has proposed that Avalide be indicated as initial treatment of severe hypertension. The panel was asked to comment on the wording of the indication statement that would be included in the label. Several were supportive of wording that Avalide can be considered as initial treatment when control of blood pressure is not likely to be achieved with one drug, or for moderate to severe hypertension.

The product, marketed as Avalide by Bristol-Myers Squibb (BMS), was approved in 1997 for treating hypertension, with a statement in its label that says the combination therapy should not be used until a patient has failed to achieve the desired effect with monotherapy.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

The combination antihypertensives that have previously been approved as first-line treatments are Capozide (captopril and HCTZ), Ziac (bisoprolol/HCTZ), and Hyzaar (losartan/HCTZ).

At the meeting on Avalide, BMS provided the results of two studies. The first, a pivotal trial of 695 patients (mean age was 52) with severe hypertension (an untreated diastolic blood pressure of at least 110 mm Hg or on monotherapy with a diastolic blood pressure of at least 100 mm Hg), compared Avalide with irbesartan monotherapy as initial therapy. The second, a supportive trial, compared Avalide with irbesartan and HCTZ monotherapies in patients with moderate hypertension. The studies used forced titration to 300 mg/25 mg of Avalide, 300 mg of irbesartan, or 25 mg of HCTZ.

In the pivotal trial, 47% of those on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, the primary end point, compared with 33% of those on irbesartan monotherapy, a highly significant difference.

Among black subjects (about 14% of the subjects), 40% of those on Avalide had achieved a diastolic blood pressure below 90 mm Hg at 5 weeks, compared with nearly 15% of those on irbesartan. In diabetic subjects, 33% had achieved blood pressure goal below 140/90 mm Hg, compared with 23% of those on irbesartan at 5 weeks.

Overall, Avalide was safe and well tolerated, and was comparable to irbesartan monotherapy, with no increase in dizziness or syncope and no serious adverse events related to treatment. No deaths were reported, according to BMS.

About 4% of patients in each group experienced dizziness, and headache was reported in 4% of those on Avalide, and 6% of those on irbesartan. Hypotension was reported in 0.6% of those on Avalide, and none of those on monotherapy.

About 2% in each group discontinued treatment for an adverse event. Among the 92 patients 65 and older, Avalide was well tolerated, there were no cases of hypotension or syncope, and dizziness was no more common than in younger patients.

In the supportive study of about 500 patients with moderate hypertension, Avalide was more effective in reducing blood pressure than either irbesartan or HCTZ alone, had a comparable safety profile, and was well tolerated in the elderly, according to BMS.

Several members of the advisory panel said that the company should get more data on the combination as first line treatment in elderly patients and in patients with renal dysfunction.

Approval as a first-line treatment would not affect the patent for Avalide, which expires in 2012, a BMS spokesperson said.

The results of two large British trials that followed epilepsy patients for several years indicate that lamotrigine should be the drug of first choice for people with partial epilepsy and that valproate should be the drug of first choice for people with generalized and unclassifiable epilepsy, investigators reported.

The two Standard and New Antiepileptic Drugs (SANAD) studies were unblinded, randomized, controlled studies conducted in hospital-based outpatient clinics in the United Kingdom.

One study compared the established epilepsy drug carbamazepine with gabapentin, lamotrigine, oxcarbazepine, and topiramate in 1,721 patients with at least two clinically definite, unprovoked epileptic seizures in the previous year. The study included newly diagnosed patients, those who had failed monotherapy and those who had gone into remission but relapsed after treatment was stopped. Their mean age was 38–40 years, and they were followed for up to 6 years, wrote Dr. Anthony G. Marson of the University of Liverpool (England) and his associates.

Patients taking lamotrigine had significantly longer time to treatment failure for any reason (inadequate seizure control or unacceptable adverse events) than did those taking the standard treatment carbamazepine and the newer drugs gabapentin and topiramate, the authors reported. Lamotrigine had an advantage over oxcarbazepine, but it was not significant.

For time elapsed before achieving 12 months of remission, carbamazepine was significantly better than gabapentin. Their analyses suggested there was a nonsignificant advantage for carbamazepine over lamotrigine, topiramate, and oxcarbazepine for this end point. Lamotrigine, they noted, was considered “noninferior” to carbamazepine for 12-month remission from seizures, they added.

“Although there might be circumstances where other drugs are preferred (consideration of teratogenicity, bone health, drug interactions), the better tolerability seen in lamotrigine than carbamazepine, with noninferiority of longer-term efficacy outcomes, lends support to lamotrigine as first-choice treatment for most patients with partial epilepsy,” the authors concluded (Lancet 2007;369:1000–15).

The second SANAD study enrolled 716 patients (mean age 22 years) with generalized onset seizures and seizures that were difficult to classify. Valproate, which the authors said is considered the standard treatment for these patients, was compared with lamotrigine or topiramate for up to 7 years.

Valproate was significantly more effective than topiramate for time to treatment failure, and significantly more effective than lamotrigine for 12-months remission. Based on these results, they concluded that valproate “should remain the first-line treatment for most patients with an idiopathic generalised epilepsy or seizures that are difficult to classify.” But, they added, “there will always be some individual circumstances that would favour the choice of an alternative drug,” such as family planning or drug interactions (Lancet 2007;369:1016–26).

In an accompanying editorial, Dr. Jacqueline French of the department of neurology, University of Pennsylvania, Philadelphia, said that the SANAD studies overcame many of the methodologic problems that have affected studies directly comparing newer antiepileptic drugs such as lamotrigine, topiramate, or levetiracetam with older drugs like carbamazepine or phenytoin. These studies “almost always” conclude that the newer drug is as effective but better tolerated than the older drug, she said (Lancet 2007;369:970–1).

The SANAD studies also are timely because many new drugs have been introduced over the past few decades, she added.

But she said that the question of whether it is possible to identify a drug as the treatment of first choice for patients with epilepsy remained.

Another concern she expressed was that designating a drug as first choice “may reduce the likelihood that a physician will make an effort to match the drug to the patient.” An individualized approach would consider features of a drug that may not be addressed in trials like the SANAD studies, she said, citing as an example lamotrigine's side effect of insomnia, which may not make it the ideal choice for a patient with a sleep disorder.

“Simple is good, but overly simplistic may not provide the optimum benefit to our patients,” Dr. French said.

“It might be wiser to conclude from SANAD that lamotrigine is the drug of first choice in patients with partial seizures, and valproate for patients with generalised or unclassified seizures in the absence of factors that would lead to an alternative choice.”

The results of two large British trials that followed epilepsy patients for several years indicate that lamotrigine should be the drug of first choice for people with partial epilepsy and that valproate should be the drug of first choice for people with generalized and unclassifiable epilepsy, investigators reported.

The two Standard and New Antiepileptic Drugs (SANAD) studies were unblinded, randomized, controlled studies conducted in hospital-based outpatient clinics in the United Kingdom.

One study compared the established epilepsy drug carbamazepine with gabapentin, lamotrigine, oxcarbazepine, and topiramate in 1,721 patients with at least two clinically definite, unprovoked epileptic seizures in the previous year. The study included newly diagnosed patients, those who had failed monotherapy and those who had gone into remission but relapsed after treatment was stopped. Their mean age was 38–40 years, and they were followed for up to 6 years, wrote Dr. Anthony G. Marson of the University of Liverpool (England) and his associates.

Patients taking lamotrigine had significantly longer time to treatment failure for any reason (inadequate seizure control or unacceptable adverse events) than did those taking the standard treatment carbamazepine and the newer drugs gabapentin and topiramate, the authors reported. Lamotrigine had an advantage over oxcarbazepine, but it was not significant.

For time elapsed before achieving 12 months of remission, carbamazepine was significantly better than gabapentin. Their analyses suggested there was a nonsignificant advantage for carbamazepine over lamotrigine, topiramate, and oxcarbazepine for this end point. Lamotrigine, they noted, was considered “noninferior” to carbamazepine for 12-month remission from seizures, they added.

“Although there might be circumstances where other drugs are preferred (consideration of teratogenicity, bone health, drug interactions), the better tolerability seen in lamotrigine than carbamazepine, with noninferiority of longer-term efficacy outcomes, lends support to lamotrigine as first-choice treatment for most patients with partial epilepsy,” the authors concluded (Lancet 2007;369:1000–15).

The second SANAD study enrolled 716 patients (mean age 22 years) with generalized onset seizures and seizures that were difficult to classify. Valproate, which the authors said is considered the standard treatment for these patients, was compared with lamotrigine or topiramate for up to 7 years.

Valproate was significantly more effective than topiramate for time to treatment failure, and significantly more effective than lamotrigine for 12-months remission. Based on these results, they concluded that valproate “should remain the first-line treatment for most patients with an idiopathic generalised epilepsy or seizures that are difficult to classify.” But, they added, “there will always be some individual circumstances that would favour the choice of an alternative drug,” such as family planning or drug interactions (Lancet 2007;369:1016–26).

In an accompanying editorial, Dr. Jacqueline French of the department of neurology, University of Pennsylvania, Philadelphia, said that the SANAD studies overcame many of the methodologic problems that have affected studies directly comparing newer antiepileptic drugs such as lamotrigine, topiramate, or levetiracetam with older drugs like carbamazepine or phenytoin. These studies “almost always” conclude that the newer drug is as effective but better tolerated than the older drug, she said (Lancet 2007;369:970–1).

The SANAD studies also are timely because many new drugs have been introduced over the past few decades, she added.

But she said that the question of whether it is possible to identify a drug as the treatment of first choice for patients with epilepsy remained.

Another concern she expressed was that designating a drug as first choice “may reduce the likelihood that a physician will make an effort to match the drug to the patient.” An individualized approach would consider features of a drug that may not be addressed in trials like the SANAD studies, she said, citing as an example lamotrigine's side effect of insomnia, which may not make it the ideal choice for a patient with a sleep disorder.

“Simple is good, but overly simplistic may not provide the optimum benefit to our patients,” Dr. French said.

“It might be wiser to conclude from SANAD that lamotrigine is the drug of first choice in patients with partial seizures, and valproate for patients with generalised or unclassified seizures in the absence of factors that would lead to an alternative choice.”

The results of two large British trials that followed epilepsy patients for several years indicate that lamotrigine should be the drug of first choice for people with partial epilepsy and that valproate should be the drug of first choice for people with generalized and unclassifiable epilepsy, investigators reported.

The two Standard and New Antiepileptic Drugs (SANAD) studies were unblinded, randomized, controlled studies conducted in hospital-based outpatient clinics in the United Kingdom.

One study compared the established epilepsy drug carbamazepine with gabapentin, lamotrigine, oxcarbazepine, and topiramate in 1,721 patients with at least two clinically definite, unprovoked epileptic seizures in the previous year. The study included newly diagnosed patients, those who had failed monotherapy and those who had gone into remission but relapsed after treatment was stopped. Their mean age was 38–40 years, and they were followed for up to 6 years, wrote Dr. Anthony G. Marson of the University of Liverpool (England) and his associates.

Patients taking lamotrigine had significantly longer time to treatment failure for any reason (inadequate seizure control or unacceptable adverse events) than did those taking the standard treatment carbamazepine and the newer drugs gabapentin and topiramate, the authors reported. Lamotrigine had an advantage over oxcarbazepine, but it was not significant.

For time elapsed before achieving 12 months of remission, carbamazepine was significantly better than gabapentin. Their analyses suggested there was a nonsignificant advantage for carbamazepine over lamotrigine, topiramate, and oxcarbazepine for this end point. Lamotrigine, they noted, was considered “noninferior” to carbamazepine for 12-month remission from seizures, they added.

“Although there might be circumstances where other drugs are preferred (consideration of teratogenicity, bone health, drug interactions), the better tolerability seen in lamotrigine than carbamazepine, with noninferiority of longer-term efficacy outcomes, lends support to lamotrigine as first-choice treatment for most patients with partial epilepsy,” the authors concluded (Lancet 2007;369:1000–15).

The second SANAD study enrolled 716 patients (mean age 22 years) with generalized onset seizures and seizures that were difficult to classify. Valproate, which the authors said is considered the standard treatment for these patients, was compared with lamotrigine or topiramate for up to 7 years.

Valproate was significantly more effective than topiramate for time to treatment failure, and significantly more effective than lamotrigine for 12-months remission. Based on these results, they concluded that valproate “should remain the first-line treatment for most patients with an idiopathic generalised epilepsy or seizures that are difficult to classify.” But, they added, “there will always be some individual circumstances that would favour the choice of an alternative drug,” such as family planning or drug interactions (Lancet 2007;369:1016–26).

In an accompanying editorial, Dr. Jacqueline French of the department of neurology, University of Pennsylvania, Philadelphia, said that the SANAD studies overcame many of the methodologic problems that have affected studies directly comparing newer antiepileptic drugs such as lamotrigine, topiramate, or levetiracetam with older drugs like carbamazepine or phenytoin. These studies “almost always” conclude that the newer drug is as effective but better tolerated than the older drug, she said (Lancet 2007;369:970–1).

The SANAD studies also are timely because many new drugs have been introduced over the past few decades, she added.

But she said that the question of whether it is possible to identify a drug as the treatment of first choice for patients with epilepsy remained.

Another concern she expressed was that designating a drug as first choice “may reduce the likelihood that a physician will make an effort to match the drug to the patient.” An individualized approach would consider features of a drug that may not be addressed in trials like the SANAD studies, she said, citing as an example lamotrigine's side effect of insomnia, which may not make it the ideal choice for a patient with a sleep disorder.

“Simple is good, but overly simplistic may not provide the optimum benefit to our patients,” Dr. French said.

“It might be wiser to conclude from SANAD that lamotrigine is the drug of first choice in patients with partial seizures, and valproate for patients with generalised or unclassified seizures in the absence of factors that would lead to an alternative choice.”

The Food and Drug Administration has issued an alert about a higher rate of deaths associated with the antibiotic linezolid in a recent study of patients with catheter-related bloodstream infections.

For patients infected with gram-positive organisms, there was no difference in death rates between patients on linezolid (Zyvox) and patients on a comparator antibiotic. “In contrast, mortality was higher in patients treated with linezolid who were infected with gram-negative organisms alone, with both gram-positive and gram-negative organisms, or who had no infection when they entered the study,” according to the FDA advisory.

Linezolid is not approved for treating catheter-related bloodstream infections, catheter-site infections, or for treating infections caused by gram-negative bacteria, the FDA cautioned.

The open-label trial enrolled 726 seriously ill patients aged 13 years and older with intravascular catheter-related bloodstream infections, including those with catheter-site infections. Almost half the patients were in an intensive care unit, and 26% were intubated. Patients were randomized to either linezolid 600 mg intravenously or orally every 12 hours, or to 1 g of vancomycin administered every 12 hours for 7–28 days. Those on vancomycin could be switched to oxacillin or dicloxacillin if the pathogen was methicillin susceptible, and could also receive concomitant therapy for gram-negative infections.

Up to 84 days after receiving the first dose of the drug, mortality was 21.5% in patients on linezolid and 16% in patients on a comparator antibiotic. In patients with gram-positive infections only, mortality was similar for patients on linezolid and those on a comparator (16.7% vs. 17.2%, respectively).

But among those with gram-negative organisms only, 27% of patients taking linezolid died, vs. 9% of those on a comparator. Among patients with gram-positive and gram-negative pathogens, 35% of those on linezolid died, vs. 18% of those on a comparator. Among patients with no infection at baseline, 26% of those on linezolid died, vs. 13% of those on a comparator.

The FDA cautioned that the advisory is based on a preliminary analysis of the data, and that the agency has not come to any final conclusions about the implications of this new study.

Information for health care professionals is available at www.fda.gov/medwatch/safety/2007/safety07.htm#Zyvoxwww.fda.gov/medwatch

The Food and Drug Administration has issued an alert about a higher rate of deaths associated with the antibiotic linezolid in a recent study of patients with catheter-related bloodstream infections.

For patients infected with gram-positive organisms, there was no difference in death rates between patients on linezolid (Zyvox) and patients on a comparator antibiotic. “In contrast, mortality was higher in patients treated with linezolid who were infected with gram-negative organisms alone, with both gram-positive and gram-negative organisms, or who had no infection when they entered the study,” according to the FDA advisory.

Linezolid is not approved for treating catheter-related bloodstream infections, catheter-site infections, or for treating infections caused by gram-negative bacteria, the FDA cautioned.

The open-label trial enrolled 726 seriously ill patients aged 13 years and older with intravascular catheter-related bloodstream infections, including those with catheter-site infections. Almost half the patients were in an intensive care unit, and 26% were intubated. Patients were randomized to either linezolid 600 mg intravenously or orally every 12 hours, or to 1 g of vancomycin administered every 12 hours for 7–28 days. Those on vancomycin could be switched to oxacillin or dicloxacillin if the pathogen was methicillin susceptible, and could also receive concomitant therapy for gram-negative infections.

Up to 84 days after receiving the first dose of the drug, mortality was 21.5% in patients on linezolid and 16% in patients on a comparator antibiotic. In patients with gram-positive infections only, mortality was similar for patients on linezolid and those on a comparator (16.7% vs. 17.2%, respectively).

But among those with gram-negative organisms only, 27% of patients taking linezolid died, vs. 9% of those on a comparator. Among patients with gram-positive and gram-negative pathogens, 35% of those on linezolid died, vs. 18% of those on a comparator. Among patients with no infection at baseline, 26% of those on linezolid died, vs. 13% of those on a comparator.

The FDA cautioned that the advisory is based on a preliminary analysis of the data, and that the agency has not come to any final conclusions about the implications of this new study.

Information for health care professionals is available at www.fda.gov/medwatch/safety/2007/safety07.htm#Zyvoxwww.fda.gov/medwatch

The Food and Drug Administration has issued an alert about a higher rate of deaths associated with the antibiotic linezolid in a recent study of patients with catheter-related bloodstream infections.

For patients infected with gram-positive organisms, there was no difference in death rates between patients on linezolid (Zyvox) and patients on a comparator antibiotic. “In contrast, mortality was higher in patients treated with linezolid who were infected with gram-negative organisms alone, with both gram-positive and gram-negative organisms, or who had no infection when they entered the study,” according to the FDA advisory.

Linezolid is not approved for treating catheter-related bloodstream infections, catheter-site infections, or for treating infections caused by gram-negative bacteria, the FDA cautioned.

The open-label trial enrolled 726 seriously ill patients aged 13 years and older with intravascular catheter-related bloodstream infections, including those with catheter-site infections. Almost half the patients were in an intensive care unit, and 26% were intubated. Patients were randomized to either linezolid 600 mg intravenously or orally every 12 hours, or to 1 g of vancomycin administered every 12 hours for 7–28 days. Those on vancomycin could be switched to oxacillin or dicloxacillin if the pathogen was methicillin susceptible, and could also receive concomitant therapy for gram-negative infections.

Up to 84 days after receiving the first dose of the drug, mortality was 21.5% in patients on linezolid and 16% in patients on a comparator antibiotic. In patients with gram-positive infections only, mortality was similar for patients on linezolid and those on a comparator (16.7% vs. 17.2%, respectively).

But among those with gram-negative organisms only, 27% of patients taking linezolid died, vs. 9% of those on a comparator. Among patients with gram-positive and gram-negative pathogens, 35% of those on linezolid died, vs. 18% of those on a comparator. Among patients with no infection at baseline, 26% of those on linezolid died, vs. 13% of those on a comparator.

The FDA cautioned that the advisory is based on a preliminary analysis of the data, and that the agency has not come to any final conclusions about the implications of this new study.

Information for health care professionals is available at www.fda.gov/medwatch/safety/2007/safety07.htm#Zyvoxwww.fda.gov/medwatch