Elizabeth Mechcatie

SILVER SPRING, MD. — More information on the risks and severity of hypersensitivity reactions associated with the monoclonal antibody motavizumab is needed before it is approved for preventing serious lower respiratory tract infections with respiratory syncytial virus in high-risk infants, according to the majority of a Food and Drug Administration advisory panel.

The FDA's Antiviral Drug Products Advisory Committee voted 14 to 3 against recommending approval of motavizumab for the indication proposed by its manufacturer, MedImmune LLC: the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease (premature infants, children with chronic lung disease of prematurity, and children with hemodynamically significant congenital heart disease).

Like palivizumab (Synagis), approved in 1998 for RSV prophylaxis, motavizumab is a monoclonal antibody that binds to the F protein of RSV, but has a higher binding affinity to the protein and exerts a greater degree of neutralizing activity against RSV isolates in vitro, according to MedImmune, which also manufactures palivizumab. The proposed dosing for motavizumab is the same as for palivizumab: 15 mg/kg, administered by intramuscular injection once a month during the RSV season. Several panelists voiced concerns that Medimmune would phase out palivizumab once motavizumab was approved; a MedImmune spokesperson said that the company has never made a statement about such plans.

Panelists agreed that motavizumab had been shown to be effective in preventing RSV, but although the data suggested that it might be more effective than palivizumab, they agreed that it had not been shown to be superior. Moreover, the potential for hypersensitivity reactions among those on motavizumab in clinical trials was a major safety concern that needed to be studied further before approval, including in children who were more severely ill than those in the clinical trials. Although these reactions were rare, they were significant when they occurred and appeared to have an immunologic basis, according to the panel.

“Hypersensitivity and skin issues aside, I'm not really seeing a difference,” said panelist Patrick Clay, Pharm.D., director of the Dybedal Center for Clinical Research, Kansas City (Mo.) University. While it would be helpful to have more than one option for RSV prophylaxis, he pointed out that with the data available, it was unclear how a clinician would choose one or the other.

Panelist Dr. Yvonne Maldonado, chief of infectious diseases, Packard Children's Hospital, Stanford (Calif.) University, said that there was a “strong suggestion” that motavizumab was more effective than palivizumab, but there were not enough differences between the two drugs at this point to help practicing clinicians decide when the newer drug should be used. A “better definition of the safety profile would be really helpful for the clinician,” she noted.

In a phase III randomized, double-blind noninferiority study, motavizumab was compared with palivizumab in 6,635 premature infants (under 35 weeks' gestation) who were younger than 6 months, and in children younger than 24 months who had been premature and had chronic lung disease, in a 1:1 ratio. (Both drugs were administered at a dosage of 15 mg/kg once a month for five doses.) The proportion of patients who were hospitalized for RSV, the primary end point, was 1.4% among those on motavizumab, compared with 1.9% of those on palivizumab, which met the noninferiority criteria for the study. (Most of the patients in each group completed the study and about 96% in each group received all five scheduled doses.)

The overall safety profiles were similar between the two groups, with the exception of hypersensitivity reactions: More patients who received motavizumab developed urticaria (0.4%) and allergic rash (0. 8%), compared with those on palivizumab (0.1% and 0.3%). In addition, eight of those on motavizumab had a grade 3-4 hypersensitivity reaction, compared with none of those on palivizumab.

In the five studies that comprised the entire safety database for motavizumab, there were 19 grade 3-4 hypersensitivity events among those on motavizumab, compared with none among those on palivizumab. Of the 5,360 patients who received motavizumab, there were three cases “suggestive of anaphylaxis,” according to the FDA reviewer.

In a study that was considered a supportive study, motavizumab was compared with placebo in 1,410 Native American term infants, who were at a greater risk of RSV infections. The incidence of RSV hospitalizations was 8.3% among those on motavizumab compared with 1.4% among those on placebo, a significant difference.

The allergist on the panel, Dr. Prescott Atkinson, professor and director of the division of pediatric allergy and immunology, Children's Hospital, Birmingham, Ala., said he voted against approval because he was convinced that the risks were higher with this drug, but “it's not clear to me that it's more efficacious than the drug we already have.”

If studies showed it was 10% more effective than palivizumab in reducing hospitalizations, then the risks of non–life-threatening skin reactions and rare cases of more severe anaphylaxis “might be acceptable risks in this high-risk population who comes in and not infrequently expires from RSV,” he added.

Since approval, an estimated 1.2 million people have received palivizumab and 10 cases of anaphylaxis have been reported to the FDA's voluntary adverse event reporting program, according to the FDA.

A warning about the potential for anaphylaxis is on the palivizumab label.

If motavizumab is approved, MedImmune plans to market the drug as Rezield, with a risk management plan that would include educating prescribers about how to manage skin reactions.

The plan also would involve enhanced vigilance of adverse events. Postmarketing studies would address issues that include evaluating the rates and severity of hypersensitivity reactions associated with motavizumab, the emergence of motavizumab-resistant RSV, and adverse event rates in the real-world setting.

SILVER SPRING, MD. — More information on the risks and severity of hypersensitivity reactions associated with the monoclonal antibody motavizumab is needed before it is approved for preventing serious lower respiratory tract infections with respiratory syncytial virus in high-risk infants, according to the majority of a Food and Drug Administration advisory panel.

The FDA's Antiviral Drug Products Advisory Committee voted 14 to 3 against recommending approval of motavizumab for the indication proposed by its manufacturer, MedImmune LLC: the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease (premature infants, children with chronic lung disease of prematurity, and children with hemodynamically significant congenital heart disease).

Like palivizumab (Synagis), approved in 1998 for RSV prophylaxis, motavizumab is a monoclonal antibody that binds to the F protein of RSV, but has a higher binding affinity to the protein and exerts a greater degree of neutralizing activity against RSV isolates in vitro, according to MedImmune, which also manufactures palivizumab. The proposed dosing for motavizumab is the same as for palivizumab: 15 mg/kg, administered by intramuscular injection once a month during the RSV season. Several panelists voiced concerns that Medimmune would phase out palivizumab once motavizumab was approved; a MedImmune spokesperson said that the company has never made a statement about such plans.

Panelists agreed that motavizumab had been shown to be effective in preventing RSV, but although the data suggested that it might be more effective than palivizumab, they agreed that it had not been shown to be superior. Moreover, the potential for hypersensitivity reactions among those on motavizumab in clinical trials was a major safety concern that needed to be studied further before approval, including in children who were more severely ill than those in the clinical trials. Although these reactions were rare, they were significant when they occurred and appeared to have an immunologic basis, according to the panel.

“Hypersensitivity and skin issues aside, I'm not really seeing a difference,” said panelist Patrick Clay, Pharm.D., director of the Dybedal Center for Clinical Research, Kansas City (Mo.) University. While it would be helpful to have more than one option for RSV prophylaxis, he pointed out that with the data available, it was unclear how a clinician would choose one or the other.

Panelist Dr. Yvonne Maldonado, chief of infectious diseases, Packard Children's Hospital, Stanford (Calif.) University, said that there was a “strong suggestion” that motavizumab was more effective than palivizumab, but there were not enough differences between the two drugs at this point to help practicing clinicians decide when the newer drug should be used. A “better definition of the safety profile would be really helpful for the clinician,” she noted.

In a phase III randomized, double-blind noninferiority study, motavizumab was compared with palivizumab in 6,635 premature infants (under 35 weeks' gestation) who were younger than 6 months, and in children younger than 24 months who had been premature and had chronic lung disease, in a 1:1 ratio. (Both drugs were administered at a dosage of 15 mg/kg once a month for five doses.) The proportion of patients who were hospitalized for RSV, the primary end point, was 1.4% among those on motavizumab, compared with 1.9% of those on palivizumab, which met the noninferiority criteria for the study. (Most of the patients in each group completed the study and about 96% in each group received all five scheduled doses.)

The overall safety profiles were similar between the two groups, with the exception of hypersensitivity reactions: More patients who received motavizumab developed urticaria (0.4%) and allergic rash (0. 8%), compared with those on palivizumab (0.1% and 0.3%). In addition, eight of those on motavizumab had a grade 3-4 hypersensitivity reaction, compared with none of those on palivizumab.

In the five studies that comprised the entire safety database for motavizumab, there were 19 grade 3-4 hypersensitivity events among those on motavizumab, compared with none among those on palivizumab. Of the 5,360 patients who received motavizumab, there were three cases “suggestive of anaphylaxis,” according to the FDA reviewer.

In a study that was considered a supportive study, motavizumab was compared with placebo in 1,410 Native American term infants, who were at a greater risk of RSV infections. The incidence of RSV hospitalizations was 8.3% among those on motavizumab compared with 1.4% among those on placebo, a significant difference.

The allergist on the panel, Dr. Prescott Atkinson, professor and director of the division of pediatric allergy and immunology, Children's Hospital, Birmingham, Ala., said he voted against approval because he was convinced that the risks were higher with this drug, but “it's not clear to me that it's more efficacious than the drug we already have.”

If studies showed it was 10% more effective than palivizumab in reducing hospitalizations, then the risks of non–life-threatening skin reactions and rare cases of more severe anaphylaxis “might be acceptable risks in this high-risk population who comes in and not infrequently expires from RSV,” he added.

Since approval, an estimated 1.2 million people have received palivizumab and 10 cases of anaphylaxis have been reported to the FDA's voluntary adverse event reporting program, according to the FDA.

A warning about the potential for anaphylaxis is on the palivizumab label.

If motavizumab is approved, MedImmune plans to market the drug as Rezield, with a risk management plan that would include educating prescribers about how to manage skin reactions.

The plan also would involve enhanced vigilance of adverse events. Postmarketing studies would address issues that include evaluating the rates and severity of hypersensitivity reactions associated with motavizumab, the emergence of motavizumab-resistant RSV, and adverse event rates in the real-world setting.

SILVER SPRING, MD. — More information on the risks and severity of hypersensitivity reactions associated with the monoclonal antibody motavizumab is needed before it is approved for preventing serious lower respiratory tract infections with respiratory syncytial virus in high-risk infants, according to the majority of a Food and Drug Administration advisory panel.

The FDA's Antiviral Drug Products Advisory Committee voted 14 to 3 against recommending approval of motavizumab for the indication proposed by its manufacturer, MedImmune LLC: the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease (premature infants, children with chronic lung disease of prematurity, and children with hemodynamically significant congenital heart disease).

Like palivizumab (Synagis), approved in 1998 for RSV prophylaxis, motavizumab is a monoclonal antibody that binds to the F protein of RSV, but has a higher binding affinity to the protein and exerts a greater degree of neutralizing activity against RSV isolates in vitro, according to MedImmune, which also manufactures palivizumab. The proposed dosing for motavizumab is the same as for palivizumab: 15 mg/kg, administered by intramuscular injection once a month during the RSV season. Several panelists voiced concerns that Medimmune would phase out palivizumab once motavizumab was approved; a MedImmune spokesperson said that the company has never made a statement about such plans.

Panelists agreed that motavizumab had been shown to be effective in preventing RSV, but although the data suggested that it might be more effective than palivizumab, they agreed that it had not been shown to be superior. Moreover, the potential for hypersensitivity reactions among those on motavizumab in clinical trials was a major safety concern that needed to be studied further before approval, including in children who were more severely ill than those in the clinical trials. Although these reactions were rare, they were significant when they occurred and appeared to have an immunologic basis, according to the panel.

“Hypersensitivity and skin issues aside, I'm not really seeing a difference,” said panelist Patrick Clay, Pharm.D., director of the Dybedal Center for Clinical Research, Kansas City (Mo.) University. While it would be helpful to have more than one option for RSV prophylaxis, he pointed out that with the data available, it was unclear how a clinician would choose one or the other.

Panelist Dr. Yvonne Maldonado, chief of infectious diseases, Packard Children's Hospital, Stanford (Calif.) University, said that there was a “strong suggestion” that motavizumab was more effective than palivizumab, but there were not enough differences between the two drugs at this point to help practicing clinicians decide when the newer drug should be used. A “better definition of the safety profile would be really helpful for the clinician,” she noted.

In a phase III randomized, double-blind noninferiority study, motavizumab was compared with palivizumab in 6,635 premature infants (under 35 weeks' gestation) who were younger than 6 months, and in children younger than 24 months who had been premature and had chronic lung disease, in a 1:1 ratio. (Both drugs were administered at a dosage of 15 mg/kg once a month for five doses.) The proportion of patients who were hospitalized for RSV, the primary end point, was 1.4% among those on motavizumab, compared with 1.9% of those on palivizumab, which met the noninferiority criteria for the study. (Most of the patients in each group completed the study and about 96% in each group received all five scheduled doses.)

The overall safety profiles were similar between the two groups, with the exception of hypersensitivity reactions: More patients who received motavizumab developed urticaria (0.4%) and allergic rash (0. 8%), compared with those on palivizumab (0.1% and 0.3%). In addition, eight of those on motavizumab had a grade 3-4 hypersensitivity reaction, compared with none of those on palivizumab.

In the five studies that comprised the entire safety database for motavizumab, there were 19 grade 3-4 hypersensitivity events among those on motavizumab, compared with none among those on palivizumab. Of the 5,360 patients who received motavizumab, there were three cases “suggestive of anaphylaxis,” according to the FDA reviewer.

In a study that was considered a supportive study, motavizumab was compared with placebo in 1,410 Native American term infants, who were at a greater risk of RSV infections. The incidence of RSV hospitalizations was 8.3% among those on motavizumab compared with 1.4% among those on placebo, a significant difference.

The allergist on the panel, Dr. Prescott Atkinson, professor and director of the division of pediatric allergy and immunology, Children's Hospital, Birmingham, Ala., said he voted against approval because he was convinced that the risks were higher with this drug, but “it's not clear to me that it's more efficacious than the drug we already have.”

If studies showed it was 10% more effective than palivizumab in reducing hospitalizations, then the risks of non–life-threatening skin reactions and rare cases of more severe anaphylaxis “might be acceptable risks in this high-risk population who comes in and not infrequently expires from RSV,” he added.

Since approval, an estimated 1.2 million people have received palivizumab and 10 cases of anaphylaxis have been reported to the FDA's voluntary adverse event reporting program, according to the FDA.

A warning about the potential for anaphylaxis is on the palivizumab label.

If motavizumab is approved, MedImmune plans to market the drug as Rezield, with a risk management plan that would include educating prescribers about how to manage skin reactions.

The plan also would involve enhanced vigilance of adverse events. Postmarketing studies would address issues that include evaluating the rates and severity of hypersensitivity reactions associated with motavizumab, the emergence of motavizumab-resistant RSV, and adverse event rates in the real-world setting.

An increased rate of cardiovascular deaths in patients with type 2 diabetes treated with olmesartan, compared with placebo, in two studies is the focus of a safety review by the Food and Drug Administration, the agency announced last month.

The FDA plans to evaluate the data from the two clinical trials, which are examining whether treatment with olmesartan slows the progression of kidney disease in patients with type 2 diabetes. In both studies, there were more cardiovascular deaths—myocardial infarction, sudden death, or stroke—in those treated with olmesartan than in those on placebo. Olmesartan is an angiotensin II receptor blocker (ARB), marketed as Benicar by Daiichi Sankyo Inc. for hypertension.

“The review is ongoing and the agency has not concluded that Benicar increases the risk of death,” the statement said. “FDA currently believes that the benefits of Benicar in patients with high blood pressure continue to outweigh its potential risks.” The FDA is advising health care professionals to continue to follow the recommendations in the olmesartan label when prescribing the drug and to report adverse events in patients treated with the drug to the agency's MedWatch adverse event reporting program.

Both studies were completed in 2009. One, the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, conducted in Germany, compared the time to first occurrence of microalbuminuria in 4,447 patients with type 2 diabetes and at least one additional cardiovascular risk factor and normoalbuminuria before being randomized to placebo or olmesartan.

The second study—Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial (ORIENT)—was conducted in China and Japan, and compared the first occurrence of the doubling of serum creatinine level, death, or end-stage renal disease over 5 years in 566 patients with type 2 diabetes and a clinical diagnosis of diabetic nephropathy.

Cardiovascular deaths were secondary end points in both trials. In ROADMAP, 15 cardiovascular deaths occurred in the olmesartan-treated patients, compared with 3 in the placebo patients; 7 of those 15 were sudden cardiac deaths. In ORIENT, 10 cardiovascular deaths occurred in the treated patients, while 3 occurred in the placebo group.

An increased rate of cardiovascular deaths in patients with type 2 diabetes treated with olmesartan, compared with placebo, in two studies is the focus of a safety review by the Food and Drug Administration, the agency announced last month.

The FDA plans to evaluate the data from the two clinical trials, which are examining whether treatment with olmesartan slows the progression of kidney disease in patients with type 2 diabetes. In both studies, there were more cardiovascular deaths—myocardial infarction, sudden death, or stroke—in those treated with olmesartan than in those on placebo. Olmesartan is an angiotensin II receptor blocker (ARB), marketed as Benicar by Daiichi Sankyo Inc. for hypertension.

“The review is ongoing and the agency has not concluded that Benicar increases the risk of death,” the statement said. “FDA currently believes that the benefits of Benicar in patients with high blood pressure continue to outweigh its potential risks.” The FDA is advising health care professionals to continue to follow the recommendations in the olmesartan label when prescribing the drug and to report adverse events in patients treated with the drug to the agency's MedWatch adverse event reporting program.

Both studies were completed in 2009. One, the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, conducted in Germany, compared the time to first occurrence of microalbuminuria in 4,447 patients with type 2 diabetes and at least one additional cardiovascular risk factor and normoalbuminuria before being randomized to placebo or olmesartan.

The second study—Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial (ORIENT)—was conducted in China and Japan, and compared the first occurrence of the doubling of serum creatinine level, death, or end-stage renal disease over 5 years in 566 patients with type 2 diabetes and a clinical diagnosis of diabetic nephropathy.

Cardiovascular deaths were secondary end points in both trials. In ROADMAP, 15 cardiovascular deaths occurred in the olmesartan-treated patients, compared with 3 in the placebo patients; 7 of those 15 were sudden cardiac deaths. In ORIENT, 10 cardiovascular deaths occurred in the treated patients, while 3 occurred in the placebo group.

An increased rate of cardiovascular deaths in patients with type 2 diabetes treated with olmesartan, compared with placebo, in two studies is the focus of a safety review by the Food and Drug Administration, the agency announced last month.

The FDA plans to evaluate the data from the two clinical trials, which are examining whether treatment with olmesartan slows the progression of kidney disease in patients with type 2 diabetes. In both studies, there were more cardiovascular deaths—myocardial infarction, sudden death, or stroke—in those treated with olmesartan than in those on placebo. Olmesartan is an angiotensin II receptor blocker (ARB), marketed as Benicar by Daiichi Sankyo Inc. for hypertension.

“The review is ongoing and the agency has not concluded that Benicar increases the risk of death,” the statement said. “FDA currently believes that the benefits of Benicar in patients with high blood pressure continue to outweigh its potential risks.” The FDA is advising health care professionals to continue to follow the recommendations in the olmesartan label when prescribing the drug and to report adverse events in patients treated with the drug to the agency's MedWatch adverse event reporting program.

Both studies were completed in 2009. One, the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, conducted in Germany, compared the time to first occurrence of microalbuminuria in 4,447 patients with type 2 diabetes and at least one additional cardiovascular risk factor and normoalbuminuria before being randomized to placebo or olmesartan.

The second study—Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial (ORIENT)—was conducted in China and Japan, and compared the first occurrence of the doubling of serum creatinine level, death, or end-stage renal disease over 5 years in 566 patients with type 2 diabetes and a clinical diagnosis of diabetic nephropathy.

Cardiovascular deaths were secondary end points in both trials. In ROADMAP, 15 cardiovascular deaths occurred in the olmesartan-treated patients, compared with 3 in the placebo patients; 7 of those 15 were sudden cardiac deaths. In ORIENT, 10 cardiovascular deaths occurred in the treated patients, while 3 occurred in the placebo group.

A program that would educate health care professionals about prescribing long-acting and extended-release opioid drugs is among the elements of the proposed risk management plan for this class of drugs, the Food and Drug Administration has announced.

At this time, however, mandatory registration of patients and prescribers in the risk management program is not included in the FDA’s proposed Risk Evaluation and Mitigation Strategy (REMS) for long-acting (LA) and extended-release (ER) opioid drugs, an idea that had been considered a possibility and one that is included in the risk management programs for some other drugs. But the agency plans to monitor the program’s effects “and may consider further steps if the REMS does not prove effective in curbing serious adverse outcomes resulting from inappropriate prescribing, abuse, and misuse,” according to the proposal, which was posted on the FDA Web site June 28.

The proposed REMS – developed with input from manufacturers and groups representing health care providers, pharmacies, and patients – is “intended to reduce serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of LA and ER opioids, while maintaining patient access to these medications,” according to the statement. These drugs include morphine ER, oxymorphone ER, oxycodone ER, hydromorphone ER, fentanyl transdermal patches, and methadone.

Some of the input for the proposed plan was provided at meetings held by the FDA, including one in December 2009, where an industry working group presented its ideas. The FDA has scheduled a joint meeting of two of its advisory panels, the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee for July 22-23, where the proposal will be reviewed by outside experts on the panels. The public has the opportunity to provide comments during an open public hearing portion of these meetings.

The agency will consider the comments made at this meeting in finalizing the proposal, and once finalized, will request that the manufacturers of the affected products develop a REMS based on the finalized proposal and submit it for approval by the agency, according to the statement.

Under the proposed REMS, the FDA would require manufacturers of these products to develop a prescriber education program that would be “designed to further train healthcare professionals on appropriate patient selection, dosing and patient monitoring when using LA and ER opioids,” according to the statement. The full proposal says that the agency would encourage sponsors to partner with “an appropriate, independent third party” to develop the prescriber training program and to consider incentives such as continuing medical education credit to encourage prescribers to undergo this training.

The proposal states that requiring patient enrollment would be “overly burdensome” and could create a stigma for patients, ultimately affecting access to those drugs. An idea proposed at the December meeting – requiring clinicians to provide proof that they had undergone training in prescribing LA opioids in order to obtain Drug Enforcement Agency registration to prescribe these products – would necessitate legislation and is not included in the proposal at this time, according to background information in the proposal.

A program that would educate health care professionals about prescribing long-acting and extended-release opioid drugs is among the elements of the proposed risk management plan for this class of drugs, the Food and Drug Administration has announced.

At this time, however, mandatory registration of patients and prescribers in the risk management program is not included in the FDA’s proposed Risk Evaluation and Mitigation Strategy (REMS) for long-acting (LA) and extended-release (ER) opioid drugs, an idea that had been considered a possibility and one that is included in the risk management programs for some other drugs. But the agency plans to monitor the program’s effects “and may consider further steps if the REMS does not prove effective in curbing serious adverse outcomes resulting from inappropriate prescribing, abuse, and misuse,” according to the proposal, which was posted on the FDA Web site June 28.

The proposed REMS – developed with input from manufacturers and groups representing health care providers, pharmacies, and patients – is “intended to reduce serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of LA and ER opioids, while maintaining patient access to these medications,” according to the statement. These drugs include morphine ER, oxymorphone ER, oxycodone ER, hydromorphone ER, fentanyl transdermal patches, and methadone.

Some of the input for the proposed plan was provided at meetings held by the FDA, including one in December 2009, where an industry working group presented its ideas. The FDA has scheduled a joint meeting of two of its advisory panels, the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee for July 22-23, where the proposal will be reviewed by outside experts on the panels. The public has the opportunity to provide comments during an open public hearing portion of these meetings.

The agency will consider the comments made at this meeting in finalizing the proposal, and once finalized, will request that the manufacturers of the affected products develop a REMS based on the finalized proposal and submit it for approval by the agency, according to the statement.

Under the proposed REMS, the FDA would require manufacturers of these products to develop a prescriber education program that would be “designed to further train healthcare professionals on appropriate patient selection, dosing and patient monitoring when using LA and ER opioids,” according to the statement. The full proposal says that the agency would encourage sponsors to partner with “an appropriate, independent third party” to develop the prescriber training program and to consider incentives such as continuing medical education credit to encourage prescribers to undergo this training.

The proposal states that requiring patient enrollment would be “overly burdensome” and could create a stigma for patients, ultimately affecting access to those drugs. An idea proposed at the December meeting – requiring clinicians to provide proof that they had undergone training in prescribing LA opioids in order to obtain Drug Enforcement Agency registration to prescribe these products – would necessitate legislation and is not included in the proposal at this time, according to background information in the proposal.

A program that would educate health care professionals about prescribing long-acting and extended-release opioid drugs is among the elements of the proposed risk management plan for this class of drugs, the Food and Drug Administration has announced.

At this time, however, mandatory registration of patients and prescribers in the risk management program is not included in the FDA’s proposed Risk Evaluation and Mitigation Strategy (REMS) for long-acting (LA) and extended-release (ER) opioid drugs, an idea that had been considered a possibility and one that is included in the risk management programs for some other drugs. But the agency plans to monitor the program’s effects “and may consider further steps if the REMS does not prove effective in curbing serious adverse outcomes resulting from inappropriate prescribing, abuse, and misuse,” according to the proposal, which was posted on the FDA Web site June 28.

The proposed REMS – developed with input from manufacturers and groups representing health care providers, pharmacies, and patients – is “intended to reduce serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of LA and ER opioids, while maintaining patient access to these medications,” according to the statement. These drugs include morphine ER, oxymorphone ER, oxycodone ER, hydromorphone ER, fentanyl transdermal patches, and methadone.

Some of the input for the proposed plan was provided at meetings held by the FDA, including one in December 2009, where an industry working group presented its ideas. The FDA has scheduled a joint meeting of two of its advisory panels, the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee for July 22-23, where the proposal will be reviewed by outside experts on the panels. The public has the opportunity to provide comments during an open public hearing portion of these meetings.

The agency will consider the comments made at this meeting in finalizing the proposal, and once finalized, will request that the manufacturers of the affected products develop a REMS based on the finalized proposal and submit it for approval by the agency, according to the statement.

Under the proposed REMS, the FDA would require manufacturers of these products to develop a prescriber education program that would be “designed to further train healthcare professionals on appropriate patient selection, dosing and patient monitoring when using LA and ER opioids,” according to the statement. The full proposal says that the agency would encourage sponsors to partner with “an appropriate, independent third party” to develop the prescriber training program and to consider incentives such as continuing medical education credit to encourage prescribers to undergo this training.

The proposal states that requiring patient enrollment would be “overly burdensome” and could create a stigma for patients, ultimately affecting access to those drugs. An idea proposed at the December meeting – requiring clinicians to provide proof that they had undergone training in prescribing LA opioids in order to obtain Drug Enforcement Agency registration to prescribe these products – would necessitate legislation and is not included in the proposal at this time, according to background information in the proposal.

The complete set of data from the BLISS-76 study of belimumab in seropositive patients with systemic lupus erythematosus supports the efficacy of the B-lymphocyte stimulator inhibitor as a treatment for SLE, and provides encouraging safety data, according to Dr. Ronald van Vollenhoven, speaking to a standing-room-only session at the European Congress of Rheumatology on June 16.

In what was the first full presentation of the BLISS-76 (Belimumab in Subjects With Systemic Lupus Erythematosus–76) data at a scientific meeting, Dr. van Vollenhoven, a rheumatologist at the Karolinska Institute in Stockholm, discussed how belimumab plus standard therapy was effective in reducing disease activity and severe flares, as well as achieving a higher response rate, compared with standard care alone. The treatment and placebo groups had similar adverse events.

Two doses were studied: 1 mg/kg and 10 mg/kg administered intravenously once every 4 weeks. Efficacy according to the trial’s primary outcome was seen with the higher dose. Most of the trial’s secondary end points either achieved significance for at least one of the dosages vs. placebo, or showed trends in the right direction, he added.

Based on these data as well as those from the previously reported BLISS-52 trial with the same drug, “the clear conclusion is that belimumab is efficacious,” Dr. van Vollenhoven said in an interview. Although the magnitude of the differences in response rates between active drug and placebo could have been larger, BLISS-76 was a successful study, he noted.

Among the unanswered questions that may need to be explored further is whether doses between 1 mg/kg and 10 mg/kg might also be efficacious, he added. Additional analyses are ongoing to determine if any group of patients is more likely to benefit from the drug.

Human Genome Sciences Inc. (HGS) and GlaxoSmithKline (GSK) are developing belimumab, which inhibits the biological activity of B-lymphocyte stimulator (BLyS), as a treatment for SLE. HGS has filed for approval for the 10-mg/kg dose in the United States.

BLISS-76, a 76-week, double-blind, international study that compared the two belimumab doses vs. placebo in 819 seropositive patients with SLE, is one of the two pivotal studies to evaluate the safety and efficacy of belimumab in this population. Patients in the study had to have an antinuclear antibody ratio of at least 1:80 and/or anti–double-stranded DNA of at least 30 IU/mL, with a SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus–National Assessment SLE Disease Activity Index) score of at least 6 on stable therapy.

Patients had had the disease for a mean of 7.5 years, 63% used antimalarials, 76% used steroids, and 56% used immunosuppressants. Patients received standard-of-care treatment and were randomized to receive either IV belimumab at days 0, 14, 28, and then every 28 days for 72 weeks, or placebo.

Some of the top-line BLISS-76 results were reported in November 2009 by HGS and GSK. At that time, the developers announced that the study had met its primary end point, which was the patient response rate as measured by the SLE Responder Index (SRI) at 52 weeks. In all, 43% of those on the higher dose and 41% of those on the lower dose met this end point, compared with 34% of those on placebo. The difference between the higher dose and placebo was statistically significant.

According to the SRI, which was developed in collaboration with the Food and Drug Administration, a patient response is defined as an improvement in the SELENA-SLEDAI score of 4 points or greater, with no clinically significant worsening on the either the BILAG (British Isles Lupus Assessment Group) index or the Physician’s Global Assessment (PGA).

Secondary end points included components of the primary end point. In all, 47% of those on the higher dose and 43% of those on the lower dose had at least a 4-point reduction in the SELENA-SLEDAI score at 52 weeks, compared with 36% among placebo. The difference between the higher dose and placebo was significant.

The proportion of patients who did not have a worsening in the PGA score greater than 0.3 points was 69% and 73% in the 10-mg/kg and 1-mg/kg groups, respectively, compared with 63% in the placebo group. The difference between the 1-mg/kg dose and placebo was significant. There were no statistically significant improvements in PGA or in steroid dose reductions among the two belimumab-treated groups, compared with placebo, according to Dr. van Vollenhoven.

In addition, 69% of those on the 10-mg/kg dose, 75% of those on the 1-mg/kg dose, and 65% of those on placebo had no new BILAG grade A or B scores. The difference between the 1-mg/kg dose and placebo was significant.

There were no significant differences between the three groups in the risk of having a flare, or in the median time to the first flare, based on the SELENA Flare Index (SFI). But the proportion of patients who had a severe SFI flare was lower in the two treatment groups (18% of those on the higher dose and 16% of those on the lower dose, compared with 24% of those on placebo), he said, noting that the difference was significant between the 1-mg/kg and placebo groups.

Other secondary end points included the mean in SF-36 Physical Component Summary (PCS) scores from baseline to week 52, which increased by a mean of 3.4, 4.4 and 2.9, in the 10-mg/kg, 1-mg/kg and placebo groups, respectively. The difference was significant only between placebo and the 1-mg/kg dose. The change in the FACIT-F (Functional Assessment of Chronic Illness Therapy–Fatigue) score from baseline at 52 weeks increased by a mean of 4.6, 5.7, and 2.9 respectively, with the difference being significant between the 1-mg/kg dose and placebo, Dr. van Vollenhoven said. “These data are important in that they reflect patient-reported aspects of the disease, namely physical function and fatigue, which are of major importance in terms of quality of life,” Dr. van Vollenhoven said in the interview. “In fact, fatigue has been identified by lupus patients in our unit as their most important symptom.”

He added, “All these instruments are blunt, however. It’s like having an old radio with a lot of background noise.”

In the study, treatment was well tolerated, with similar rates of deaths, adverse events, serious adverse events, infections, and laboratory abnormalities in the three groups. There was a modest increase in serious or severe infusion reactions among those on belimumab, compared with those on placebo, he noted. The overall infusion reaction rate was 13%-15% in the two belimumab groups, compared with 10% in the placebo group; the rate of severe infusion reactions was 1.1% in the 10-mg/kg group and 0.4% in the 1-mg/kg and placebo groups. Thus, the clinical response to the 10-mg dose appeared to be more robust. However, we need to learn more in the future about refining doses.”

There were six malignancies in the study, one in a patient on placebo, and five in the belimumab-treated patients. The infection rate was 72% in the two belimumab groups, compared with 67% in the placebo group; the serious infection rate was 7% in the 10-mg group, 6% in the 1-mg/kg group, and 5% in the placebo group, Dr. van Vollenhoven said.

Dr. van Vollenhoven was an investigator in the BLISS-76 study and is a consultant to HGS and GSK; he also served on the BLISS-52 and BLISS-76 steering committees. Some of the investigators on this trial are HGS employees.

The complete set of data from the BLISS-76 study of belimumab in seropositive patients with systemic lupus erythematosus supports the efficacy of the B-lymphocyte stimulator inhibitor as a treatment for SLE, and provides encouraging safety data, according to Dr. Ronald van Vollenhoven, speaking to a standing-room-only session at the European Congress of Rheumatology on June 16.

In what was the first full presentation of the BLISS-76 (Belimumab in Subjects With Systemic Lupus Erythematosus–76) data at a scientific meeting, Dr. van Vollenhoven, a rheumatologist at the Karolinska Institute in Stockholm, discussed how belimumab plus standard therapy was effective in reducing disease activity and severe flares, as well as achieving a higher response rate, compared with standard care alone. The treatment and placebo groups had similar adverse events.

Two doses were studied: 1 mg/kg and 10 mg/kg administered intravenously once every 4 weeks. Efficacy according to the trial’s primary outcome was seen with the higher dose. Most of the trial’s secondary end points either achieved significance for at least one of the dosages vs. placebo, or showed trends in the right direction, he added.

Based on these data as well as those from the previously reported BLISS-52 trial with the same drug, “the clear conclusion is that belimumab is efficacious,” Dr. van Vollenhoven said in an interview. Although the magnitude of the differences in response rates between active drug and placebo could have been larger, BLISS-76 was a successful study, he noted.

Among the unanswered questions that may need to be explored further is whether doses between 1 mg/kg and 10 mg/kg might also be efficacious, he added. Additional analyses are ongoing to determine if any group of patients is more likely to benefit from the drug.

Human Genome Sciences Inc. (HGS) and GlaxoSmithKline (GSK) are developing belimumab, which inhibits the biological activity of B-lymphocyte stimulator (BLyS), as a treatment for SLE. HGS has filed for approval for the 10-mg/kg dose in the United States.

BLISS-76, a 76-week, double-blind, international study that compared the two belimumab doses vs. placebo in 819 seropositive patients with SLE, is one of the two pivotal studies to evaluate the safety and efficacy of belimumab in this population. Patients in the study had to have an antinuclear antibody ratio of at least 1:80 and/or anti–double-stranded DNA of at least 30 IU/mL, with a SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus–National Assessment SLE Disease Activity Index) score of at least 6 on stable therapy.

Patients had had the disease for a mean of 7.5 years, 63% used antimalarials, 76% used steroids, and 56% used immunosuppressants. Patients received standard-of-care treatment and were randomized to receive either IV belimumab at days 0, 14, 28, and then every 28 days for 72 weeks, or placebo.

Some of the top-line BLISS-76 results were reported in November 2009 by HGS and GSK. At that time, the developers announced that the study had met its primary end point, which was the patient response rate as measured by the SLE Responder Index (SRI) at 52 weeks. In all, 43% of those on the higher dose and 41% of those on the lower dose met this end point, compared with 34% of those on placebo. The difference between the higher dose and placebo was statistically significant.

According to the SRI, which was developed in collaboration with the Food and Drug Administration, a patient response is defined as an improvement in the SELENA-SLEDAI score of 4 points or greater, with no clinically significant worsening on the either the BILAG (British Isles Lupus Assessment Group) index or the Physician’s Global Assessment (PGA).

Secondary end points included components of the primary end point. In all, 47% of those on the higher dose and 43% of those on the lower dose had at least a 4-point reduction in the SELENA-SLEDAI score at 52 weeks, compared with 36% among placebo. The difference between the higher dose and placebo was significant.

The proportion of patients who did not have a worsening in the PGA score greater than 0.3 points was 69% and 73% in the 10-mg/kg and 1-mg/kg groups, respectively, compared with 63% in the placebo group. The difference between the 1-mg/kg dose and placebo was significant. There were no statistically significant improvements in PGA or in steroid dose reductions among the two belimumab-treated groups, compared with placebo, according to Dr. van Vollenhoven.

In addition, 69% of those on the 10-mg/kg dose, 75% of those on the 1-mg/kg dose, and 65% of those on placebo had no new BILAG grade A or B scores. The difference between the 1-mg/kg dose and placebo was significant.

There were no significant differences between the three groups in the risk of having a flare, or in the median time to the first flare, based on the SELENA Flare Index (SFI). But the proportion of patients who had a severe SFI flare was lower in the two treatment groups (18% of those on the higher dose and 16% of those on the lower dose, compared with 24% of those on placebo), he said, noting that the difference was significant between the 1-mg/kg and placebo groups.

Other secondary end points included the mean in SF-36 Physical Component Summary (PCS) scores from baseline to week 52, which increased by a mean of 3.4, 4.4 and 2.9, in the 10-mg/kg, 1-mg/kg and placebo groups, respectively. The difference was significant only between placebo and the 1-mg/kg dose. The change in the FACIT-F (Functional Assessment of Chronic Illness Therapy–Fatigue) score from baseline at 52 weeks increased by a mean of 4.6, 5.7, and 2.9 respectively, with the difference being significant between the 1-mg/kg dose and placebo, Dr. van Vollenhoven said. “These data are important in that they reflect patient-reported aspects of the disease, namely physical function and fatigue, which are of major importance in terms of quality of life,” Dr. van Vollenhoven said in the interview. “In fact, fatigue has been identified by lupus patients in our unit as their most important symptom.”

He added, “All these instruments are blunt, however. It’s like having an old radio with a lot of background noise.”

In the study, treatment was well tolerated, with similar rates of deaths, adverse events, serious adverse events, infections, and laboratory abnormalities in the three groups. There was a modest increase in serious or severe infusion reactions among those on belimumab, compared with those on placebo, he noted. The overall infusion reaction rate was 13%-15% in the two belimumab groups, compared with 10% in the placebo group; the rate of severe infusion reactions was 1.1% in the 10-mg/kg group and 0.4% in the 1-mg/kg and placebo groups. Thus, the clinical response to the 10-mg dose appeared to be more robust. However, we need to learn more in the future about refining doses.”

There were six malignancies in the study, one in a patient on placebo, and five in the belimumab-treated patients. The infection rate was 72% in the two belimumab groups, compared with 67% in the placebo group; the serious infection rate was 7% in the 10-mg group, 6% in the 1-mg/kg group, and 5% in the placebo group, Dr. van Vollenhoven said.

Dr. van Vollenhoven was an investigator in the BLISS-76 study and is a consultant to HGS and GSK; he also served on the BLISS-52 and BLISS-76 steering committees. Some of the investigators on this trial are HGS employees.

The complete set of data from the BLISS-76 study of belimumab in seropositive patients with systemic lupus erythematosus supports the efficacy of the B-lymphocyte stimulator inhibitor as a treatment for SLE, and provides encouraging safety data, according to Dr. Ronald van Vollenhoven, speaking to a standing-room-only session at the European Congress of Rheumatology on June 16.

In what was the first full presentation of the BLISS-76 (Belimumab in Subjects With Systemic Lupus Erythematosus–76) data at a scientific meeting, Dr. van Vollenhoven, a rheumatologist at the Karolinska Institute in Stockholm, discussed how belimumab plus standard therapy was effective in reducing disease activity and severe flares, as well as achieving a higher response rate, compared with standard care alone. The treatment and placebo groups had similar adverse events.

Two doses were studied: 1 mg/kg and 10 mg/kg administered intravenously once every 4 weeks. Efficacy according to the trial’s primary outcome was seen with the higher dose. Most of the trial’s secondary end points either achieved significance for at least one of the dosages vs. placebo, or showed trends in the right direction, he added.

Based on these data as well as those from the previously reported BLISS-52 trial with the same drug, “the clear conclusion is that belimumab is efficacious,” Dr. van Vollenhoven said in an interview. Although the magnitude of the differences in response rates between active drug and placebo could have been larger, BLISS-76 was a successful study, he noted.

Among the unanswered questions that may need to be explored further is whether doses between 1 mg/kg and 10 mg/kg might also be efficacious, he added. Additional analyses are ongoing to determine if any group of patients is more likely to benefit from the drug.

Human Genome Sciences Inc. (HGS) and GlaxoSmithKline (GSK) are developing belimumab, which inhibits the biological activity of B-lymphocyte stimulator (BLyS), as a treatment for SLE. HGS has filed for approval for the 10-mg/kg dose in the United States.

BLISS-76, a 76-week, double-blind, international study that compared the two belimumab doses vs. placebo in 819 seropositive patients with SLE, is one of the two pivotal studies to evaluate the safety and efficacy of belimumab in this population. Patients in the study had to have an antinuclear antibody ratio of at least 1:80 and/or anti–double-stranded DNA of at least 30 IU/mL, with a SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus–National Assessment SLE Disease Activity Index) score of at least 6 on stable therapy.

Patients had had the disease for a mean of 7.5 years, 63% used antimalarials, 76% used steroids, and 56% used immunosuppressants. Patients received standard-of-care treatment and were randomized to receive either IV belimumab at days 0, 14, 28, and then every 28 days for 72 weeks, or placebo.

Some of the top-line BLISS-76 results were reported in November 2009 by HGS and GSK. At that time, the developers announced that the study had met its primary end point, which was the patient response rate as measured by the SLE Responder Index (SRI) at 52 weeks. In all, 43% of those on the higher dose and 41% of those on the lower dose met this end point, compared with 34% of those on placebo. The difference between the higher dose and placebo was statistically significant.

According to the SRI, which was developed in collaboration with the Food and Drug Administration, a patient response is defined as an improvement in the SELENA-SLEDAI score of 4 points or greater, with no clinically significant worsening on the either the BILAG (British Isles Lupus Assessment Group) index or the Physician’s Global Assessment (PGA).

Secondary end points included components of the primary end point. In all, 47% of those on the higher dose and 43% of those on the lower dose had at least a 4-point reduction in the SELENA-SLEDAI score at 52 weeks, compared with 36% among placebo. The difference between the higher dose and placebo was significant.

The proportion of patients who did not have a worsening in the PGA score greater than 0.3 points was 69% and 73% in the 10-mg/kg and 1-mg/kg groups, respectively, compared with 63% in the placebo group. The difference between the 1-mg/kg dose and placebo was significant. There were no statistically significant improvements in PGA or in steroid dose reductions among the two belimumab-treated groups, compared with placebo, according to Dr. van Vollenhoven.

In addition, 69% of those on the 10-mg/kg dose, 75% of those on the 1-mg/kg dose, and 65% of those on placebo had no new BILAG grade A or B scores. The difference between the 1-mg/kg dose and placebo was significant.

There were no significant differences between the three groups in the risk of having a flare, or in the median time to the first flare, based on the SELENA Flare Index (SFI). But the proportion of patients who had a severe SFI flare was lower in the two treatment groups (18% of those on the higher dose and 16% of those on the lower dose, compared with 24% of those on placebo), he said, noting that the difference was significant between the 1-mg/kg and placebo groups.

Other secondary end points included the mean in SF-36 Physical Component Summary (PCS) scores from baseline to week 52, which increased by a mean of 3.4, 4.4 and 2.9, in the 10-mg/kg, 1-mg/kg and placebo groups, respectively. The difference was significant only between placebo and the 1-mg/kg dose. The change in the FACIT-F (Functional Assessment of Chronic Illness Therapy–Fatigue) score from baseline at 52 weeks increased by a mean of 4.6, 5.7, and 2.9 respectively, with the difference being significant between the 1-mg/kg dose and placebo, Dr. van Vollenhoven said. “These data are important in that they reflect patient-reported aspects of the disease, namely physical function and fatigue, which are of major importance in terms of quality of life,” Dr. van Vollenhoven said in the interview. “In fact, fatigue has been identified by lupus patients in our unit as their most important symptom.”

He added, “All these instruments are blunt, however. It’s like having an old radio with a lot of background noise.”

In the study, treatment was well tolerated, with similar rates of deaths, adverse events, serious adverse events, infections, and laboratory abnormalities in the three groups. There was a modest increase in serious or severe infusion reactions among those on belimumab, compared with those on placebo, he noted. The overall infusion reaction rate was 13%-15% in the two belimumab groups, compared with 10% in the placebo group; the rate of severe infusion reactions was 1.1% in the 10-mg/kg group and 0.4% in the 1-mg/kg and placebo groups. Thus, the clinical response to the 10-mg dose appeared to be more robust. However, we need to learn more in the future about refining doses.”

There were six malignancies in the study, one in a patient on placebo, and five in the belimumab-treated patients. The infection rate was 72% in the two belimumab groups, compared with 67% in the placebo group; the serious infection rate was 7% in the 10-mg group, 6% in the 1-mg/kg group, and 5% in the placebo group, Dr. van Vollenhoven said.

Dr. van Vollenhoven was an investigator in the BLISS-76 study and is a consultant to HGS and GSK; he also served on the BLISS-52 and BLISS-76 steering committees. Some of the investigators on this trial are HGS employees.

A test for the 2009 H1N1 influenza A virus that has been available under an emergency use provision since last summer has been cleared for use by the Food and Drug Administration, the agency announced.

This test was made available in July 2009 through an Emergency Use Authorization (EUA), which allows the FDA to authorize the use of unapproved medical products when a public health emergency has been declared. The first wave of the 2009 influenza virus A outbreaks in the spring of 2009 was the basis of the public health emergency declared in April 2009, and tests for the virus were subsequently made available under the EUA.

The test cleared by the FDA is the Simplexa Influenza A H1N1 (2009), which is manufactured by Focus Diagnostics Inc. This was the first test to be made available commercially through the EUA, according to a statement from the company.

“With this clearance, the availability of Simplexa H1N1 test will not be affected when the public health emergency expires,” Dr. Jeffrey Shuren, director of the FDA's Center for Devices and Radiological Health, said in the FDA statement announcing clearance of the test.

The test uses specimens from nasal swabs or aspirates; a positive test indicates infection with the 2009 H1N1 influenza virus, but a negative test result “does not preclude influenza virus infection,” according to the FDA statement.

The FDA's information on 2009 H1N1 influenza is available at www.fda.gov/NewsEvents/PublicHealthFocus/ucm150305.htm#tests

A test for the 2009 H1N1 influenza A virus that has been available under an emergency use provision since last summer has been cleared for use by the Food and Drug Administration, the agency announced.

This test was made available in July 2009 through an Emergency Use Authorization (EUA), which allows the FDA to authorize the use of unapproved medical products when a public health emergency has been declared. The first wave of the 2009 influenza virus A outbreaks in the spring of 2009 was the basis of the public health emergency declared in April 2009, and tests for the virus were subsequently made available under the EUA.

The test cleared by the FDA is the Simplexa Influenza A H1N1 (2009), which is manufactured by Focus Diagnostics Inc. This was the first test to be made available commercially through the EUA, according to a statement from the company.

“With this clearance, the availability of Simplexa H1N1 test will not be affected when the public health emergency expires,” Dr. Jeffrey Shuren, director of the FDA's Center for Devices and Radiological Health, said in the FDA statement announcing clearance of the test.

The test uses specimens from nasal swabs or aspirates; a positive test indicates infection with the 2009 H1N1 influenza virus, but a negative test result “does not preclude influenza virus infection,” according to the FDA statement.

The FDA's information on 2009 H1N1 influenza is available at www.fda.gov/NewsEvents/PublicHealthFocus/ucm150305.htm#tests

A test for the 2009 H1N1 influenza A virus that has been available under an emergency use provision since last summer has been cleared for use by the Food and Drug Administration, the agency announced.

This test was made available in July 2009 through an Emergency Use Authorization (EUA), which allows the FDA to authorize the use of unapproved medical products when a public health emergency has been declared. The first wave of the 2009 influenza virus A outbreaks in the spring of 2009 was the basis of the public health emergency declared in April 2009, and tests for the virus were subsequently made available under the EUA.

The test cleared by the FDA is the Simplexa Influenza A H1N1 (2009), which is manufactured by Focus Diagnostics Inc. This was the first test to be made available commercially through the EUA, according to a statement from the company.

“With this clearance, the availability of Simplexa H1N1 test will not be affected when the public health emergency expires,” Dr. Jeffrey Shuren, director of the FDA's Center for Devices and Radiological Health, said in the FDA statement announcing clearance of the test.

The test uses specimens from nasal swabs or aspirates; a positive test indicates infection with the 2009 H1N1 influenza virus, but a negative test result “does not preclude influenza virus infection,” according to the FDA statement.

The FDA's information on 2009 H1N1 influenza is available at www.fda.gov/NewsEvents/PublicHealthFocus/ucm150305.htm#tests

A report by the Institute of Medicine recommends changing federal standards to require a marked reduction in the amount of sodium that can be added to food by manufacturers, restaurants, and food service companies.

The report on strategies to reduce sodium intake recommends an incremental stepwise approach that would gradually reduce sodium content to allow people to become accustomed to lower sodium levels in food.

Excessive dietary sodium intake in the United States is an “urgent public health problem,” Dr. Jane E. Henney, chair of the committee that wrote the report, said during a briefing held by the IOM.

The report's main recommendation calls for the Food and Drug Administration to set mandatory standards for the safe levels of sodium that is added to food, utilizing the agency's authority to modify the current “Generally Recognized as Safe (GRAS)” status of salt and other sodium-containing compounds.

The report also suggested that maximum levels be established for salt and other sodium-containing compounds “that will allow people to consume a normal diet with a reasonable likelihood of keeping their sodium intake to recommended levels,” Dr. Henney added.

Reducing sodium intake has the potential to prevent 100,000 deaths per year and save billions in health care costs, she said. While a certain level of sodium intake is safe, the amount consumed by the average person in the United States is “far beyond” the essential levels needed, noted Dr. Henney, professor of medicine at the University of Cincinnati.

People in the United States consume an average of more than 3,400 mg of sodium a day (the amount in about 1.5 teaspoons of salt), which is about 50% higher than the recommended maximum recommended intakef 2,300 mg for adults (the amount in about 1 teaspoon of salt).

Because the use of a maximum level of intake can be mistakenly perceived as a desirable amount, the report recommends that the daily value for sodium be changed to 1,500 mg per day, which is the adequate intake for adults.

Dr. Henney said that the FDA should “expeditiously” start the process of rule making that will be needed to change the amount allowed in food, which is a long process.

A statement issued by the FDA in response to the release of the IOM report said that the agency plans to review the report's recommendations and will “build plans for how the FDA can continue to work with other federal agencies, public health and consumer groups, and the food industry to support the reduction of sodium levels in the food supply.”

In addition, an interagency working group on sodium will be established by of the Department of Health and Human Services.

The IOM report, done at the request of Congress in 2008, was sponsored by the FDA; the Centers for Disease Control and Prevention; the National Heart, Lung, and Blood Institute; and the Office of Disease Prevention and Health Promotion at HHS.

The report is available at www.iom.edu/Reports/2010/Strategies-to-Reduce-Sodium-Intake-in-the-United-States.aspx

The IOM, citing an “urgent public health problem,” says the daily value for sodium should be 1,500 mg/day.

Source Louise A. Koenig/Elsevier Global Medical News

Source Elsevier Global Medical News

A report by the Institute of Medicine recommends changing federal standards to require a marked reduction in the amount of sodium that can be added to food by manufacturers, restaurants, and food service companies.

The report on strategies to reduce sodium intake recommends an incremental stepwise approach that would gradually reduce sodium content to allow people to become accustomed to lower sodium levels in food.

Excessive dietary sodium intake in the United States is an “urgent public health problem,” Dr. Jane E. Henney, chair of the committee that wrote the report, said during a briefing held by the IOM.

The report's main recommendation calls for the Food and Drug Administration to set mandatory standards for the safe levels of sodium that is added to food, utilizing the agency's authority to modify the current “Generally Recognized as Safe (GRAS)” status of salt and other sodium-containing compounds.

The report also suggested that maximum levels be established for salt and other sodium-containing compounds “that will allow people to consume a normal diet with a reasonable likelihood of keeping their sodium intake to recommended levels,” Dr. Henney added.

Reducing sodium intake has the potential to prevent 100,000 deaths per year and save billions in health care costs, she said. While a certain level of sodium intake is safe, the amount consumed by the average person in the United States is “far beyond” the essential levels needed, noted Dr. Henney, professor of medicine at the University of Cincinnati.

People in the United States consume an average of more than 3,400 mg of sodium a day (the amount in about 1.5 teaspoons of salt), which is about 50% higher than the recommended maximum recommended intakef 2,300 mg for adults (the amount in about 1 teaspoon of salt).

Because the use of a maximum level of intake can be mistakenly perceived as a desirable amount, the report recommends that the daily value for sodium be changed to 1,500 mg per day, which is the adequate intake for adults.

Dr. Henney said that the FDA should “expeditiously” start the process of rule making that will be needed to change the amount allowed in food, which is a long process.

A statement issued by the FDA in response to the release of the IOM report said that the agency plans to review the report's recommendations and will “build plans for how the FDA can continue to work with other federal agencies, public health and consumer groups, and the food industry to support the reduction of sodium levels in the food supply.”

In addition, an interagency working group on sodium will be established by of the Department of Health and Human Services.

The IOM report, done at the request of Congress in 2008, was sponsored by the FDA; the Centers for Disease Control and Prevention; the National Heart, Lung, and Blood Institute; and the Office of Disease Prevention and Health Promotion at HHS.

The report is available at www.iom.edu/Reports/2010/Strategies-to-Reduce-Sodium-Intake-in-the-United-States.aspx

The IOM, citing an “urgent public health problem,” says the daily value for sodium should be 1,500 mg/day.

Source Louise A. Koenig/Elsevier Global Medical News

Source Elsevier Global Medical News

A report by the Institute of Medicine recommends changing federal standards to require a marked reduction in the amount of sodium that can be added to food by manufacturers, restaurants, and food service companies.

The report on strategies to reduce sodium intake recommends an incremental stepwise approach that would gradually reduce sodium content to allow people to become accustomed to lower sodium levels in food.

Excessive dietary sodium intake in the United States is an “urgent public health problem,” Dr. Jane E. Henney, chair of the committee that wrote the report, said during a briefing held by the IOM.

The report's main recommendation calls for the Food and Drug Administration to set mandatory standards for the safe levels of sodium that is added to food, utilizing the agency's authority to modify the current “Generally Recognized as Safe (GRAS)” status of salt and other sodium-containing compounds.

The report also suggested that maximum levels be established for salt and other sodium-containing compounds “that will allow people to consume a normal diet with a reasonable likelihood of keeping their sodium intake to recommended levels,” Dr. Henney added.

Reducing sodium intake has the potential to prevent 100,000 deaths per year and save billions in health care costs, she said. While a certain level of sodium intake is safe, the amount consumed by the average person in the United States is “far beyond” the essential levels needed, noted Dr. Henney, professor of medicine at the University of Cincinnati.

People in the United States consume an average of more than 3,400 mg of sodium a day (the amount in about 1.5 teaspoons of salt), which is about 50% higher than the recommended maximum recommended intakef 2,300 mg for adults (the amount in about 1 teaspoon of salt).

Because the use of a maximum level of intake can be mistakenly perceived as a desirable amount, the report recommends that the daily value for sodium be changed to 1,500 mg per day, which is the adequate intake for adults.

Dr. Henney said that the FDA should “expeditiously” start the process of rule making that will be needed to change the amount allowed in food, which is a long process.

A statement issued by the FDA in response to the release of the IOM report said that the agency plans to review the report's recommendations and will “build plans for how the FDA can continue to work with other federal agencies, public health and consumer groups, and the food industry to support the reduction of sodium levels in the food supply.”

In addition, an interagency working group on sodium will be established by of the Department of Health and Human Services.

The IOM report, done at the request of Congress in 2008, was sponsored by the FDA; the Centers for Disease Control and Prevention; the National Heart, Lung, and Blood Institute; and the Office of Disease Prevention and Health Promotion at HHS.

The report is available at www.iom.edu/Reports/2010/Strategies-to-Reduce-Sodium-Intake-in-the-United-States.aspx

The IOM, citing an “urgent public health problem,” says the daily value for sodium should be 1,500 mg/day.

Source Louise A. Koenig/Elsevier Global Medical News

Source Elsevier Global Medical News

SILVER SPRING, MD. — More information on the risks and severity of hypersensitivity reactions associated with the monoclonal antibody motavizumab is needed before it is approved for preventing serious lower respiratory tract infections with respiratory syncytial virus in high-risk infants, according to the majority of a Food and Drug Administration advisory panel.

The FDA's Antiviral Drug Products Advisory Committee voted 14-3 against recommending approval of motavizumab for the indication proposed by its manufacturer, MedImmune LLC., which is the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease (premature infants, children with chronic lung disease of prematurity, and children with hemodynamically significant congenital heart disease).

Like palivizumab (Synagis), approved in 1998 for RSV prophylaxis, motavizumab is a monoclonal antibody that binds to the F protein of RSV, but has a higher binding affinity to the protein and exerts a greater degree of neutralizing activity against RSV isolates in vitro, according to MedImmune, which also manufactures palivizumab. The proposed dosing for motavizumab is the same as for palivizumab: 15 mg/kg, administered by intramuscular injection once a month during the RSV season. Several panelists voiced concerns that Medimmune would phase out palivizumab once motavizumab was approved; a MedImmune spokesperson said that the company has never made a statement about such plans.

Panelists agreed that motavizumab had been shown to be effective in preventing RSV, but although the data suggested that it might be more effective than palivizumab, they agreed that it had not been shown to be superior. Moreover, the potential for hypersensitivity reactions among those on motavizumab in clinical trials was a major safety concern that needed to be studied further before approval, including in children who were more severely ill than those in the clinical trials. Although these reactions were rare, they were significant when they occurred and appeared to have an immunologic basis, according to the panel.

“Hypersensitivity and skin issues aside, I'm not really seeing a difference,” said panelist Patrick Clay, Pharm.D., director of the Dybedal Center for Clinical Research, Kansas City (Mo.) University. While it would be helpful to have more than one option for RSV prophylaxis, he pointed out that with the data available, it was unclear how a clinician would choose one or the other.

Panelist Dr. Yvonne Maldonado, chief of infectious diseases, Packard Children's Hospital, Stanford (Calif.) University, said that there was a “strong suggestion” that motavizumab was more effective than palivizumab, but there were not enough differences between the two drugs at this point to help practicing clinicians decide when the newer drug should be used. A “better definition of the safety profile would be really helpful for the clinician,” she noted.

In a phase III randomized, double-blind noninferiority study, motavizumab was compared with palivizumab in 6,635 premature infants (under 35 weeks' gestation) who were younger than 6 months, and in children younger than 24 months who had been premature and had chronic lung disease, in a 1:1 ratio. (Both drugs were administered at a dosage of 15 mg/kg once a month for five doses.) The proportion of patients who were hospitalized for RSV, the primary end point, was 1.4% among those on motavizumab, compared with 1.9% of those on palivizumab, which met the noninferiority criteria for the study. (Most of the patients in each group completed the study and about 96% in each group received all five scheduled doses.)

The overall safety profiles were similar between the two groups, with the exception of hypersensitivity reactions: More patients who received motavizumab developed urticaria (0.4%) and allergic rash (0. 8%), compared with those on palivizumab (0.1% and 0.3%). In addition, eight of those on motavizumab had a grade 3-4 hypersensitivity reaction, compared with none of those on palivizumab.

In the five studies that comprised the entire safety database for motavizumab, there were 19 grade 3-4 hypersensitivity events among those on motavizumab, compared with none among those on palivizumab. Of the 5,360 patients who received motavizumab, there were three cases “suggestive of anaphylaxis,” according to the FDA reviewer.

In a study that was considered a supportive study, motavizumab was compared with placebo in 1,410 Native American term infants, who were at a greater risk of RSV infections. The incidence of RSV hospitalizations was 8.3% among those on motavizumab compared with 1.4% among those on placebo, a significant difference.

The allergist on the panel, Dr. Prescott Atkinson, professor and director of the division of pediatric allergy and immunology, Children's Hospital, Birmingham, Ala., said he voted against approval because he was convinced that the risks were higher with this drug, but “it's not clear to me that it's more efficacious than the drug we already have.”

If studies showed it was 10% more effective than palivizumab in reducing hospitalizations, then the risks of non–life-threatening skin reactions and rare cases of more severe anaphylaxis “might be acceptable risks in this high-risk population who comes in and not infrequently expires from RSV,” he added.

Since approval, an estimated 1.2 million people have received palivizumab and 10 cases of anaphylaxis have been reported to the FDA's voluntary adverse event reporting program, according to the FDA. A warning about the potential for anaphylaxis is on the palivizumab label.

If motavizumab is approved, MedImmune plans to market the drug as Rezield, with a risk management plan that would include educating prescribers about how to manage skin reactions, enhanced vigilance of adverse events, and postmarketing studies that would address issues that include evaluating the rates and severity of hypersensitivity reactions associated with motavizumab, the emergence of motavizumab-resistant RSV, and adverse event rates in the real-world setting.

The FDA is expected to make a decision on motavizumab by June 24. MedImmune has not filed for approval elsewhere, but plans to file for approval in the European Union, according to a company spokesperson. Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting, but the FDA occasionally grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, MD. — More information on the risks and severity of hypersensitivity reactions associated with the monoclonal antibody motavizumab is needed before it is approved for preventing serious lower respiratory tract infections with respiratory syncytial virus in high-risk infants, according to the majority of a Food and Drug Administration advisory panel.

The FDA's Antiviral Drug Products Advisory Committee voted 14-3 against recommending approval of motavizumab for the indication proposed by its manufacturer, MedImmune LLC., which is the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease (premature infants, children with chronic lung disease of prematurity, and children with hemodynamically significant congenital heart disease).

Like palivizumab (Synagis), approved in 1998 for RSV prophylaxis, motavizumab is a monoclonal antibody that binds to the F protein of RSV, but has a higher binding affinity to the protein and exerts a greater degree of neutralizing activity against RSV isolates in vitro, according to MedImmune, which also manufactures palivizumab. The proposed dosing for motavizumab is the same as for palivizumab: 15 mg/kg, administered by intramuscular injection once a month during the RSV season. Several panelists voiced concerns that Medimmune would phase out palivizumab once motavizumab was approved; a MedImmune spokesperson said that the company has never made a statement about such plans.

Panelists agreed that motavizumab had been shown to be effective in preventing RSV, but although the data suggested that it might be more effective than palivizumab, they agreed that it had not been shown to be superior. Moreover, the potential for hypersensitivity reactions among those on motavizumab in clinical trials was a major safety concern that needed to be studied further before approval, including in children who were more severely ill than those in the clinical trials. Although these reactions were rare, they were significant when they occurred and appeared to have an immunologic basis, according to the panel.

“Hypersensitivity and skin issues aside, I'm not really seeing a difference,” said panelist Patrick Clay, Pharm.D., director of the Dybedal Center for Clinical Research, Kansas City (Mo.) University. While it would be helpful to have more than one option for RSV prophylaxis, he pointed out that with the data available, it was unclear how a clinician would choose one or the other.

Panelist Dr. Yvonne Maldonado, chief of infectious diseases, Packard Children's Hospital, Stanford (Calif.) University, said that there was a “strong suggestion” that motavizumab was more effective than palivizumab, but there were not enough differences between the two drugs at this point to help practicing clinicians decide when the newer drug should be used. A “better definition of the safety profile would be really helpful for the clinician,” she noted.

In a phase III randomized, double-blind noninferiority study, motavizumab was compared with palivizumab in 6,635 premature infants (under 35 weeks' gestation) who were younger than 6 months, and in children younger than 24 months who had been premature and had chronic lung disease, in a 1:1 ratio. (Both drugs were administered at a dosage of 15 mg/kg once a month for five doses.) The proportion of patients who were hospitalized for RSV, the primary end point, was 1.4% among those on motavizumab, compared with 1.9% of those on palivizumab, which met the noninferiority criteria for the study. (Most of the patients in each group completed the study and about 96% in each group received all five scheduled doses.)

The overall safety profiles were similar between the two groups, with the exception of hypersensitivity reactions: More patients who received motavizumab developed urticaria (0.4%) and allergic rash (0. 8%), compared with those on palivizumab (0.1% and 0.3%). In addition, eight of those on motavizumab had a grade 3-4 hypersensitivity reaction, compared with none of those on palivizumab.

In the five studies that comprised the entire safety database for motavizumab, there were 19 grade 3-4 hypersensitivity events among those on motavizumab, compared with none among those on palivizumab. Of the 5,360 patients who received motavizumab, there were three cases “suggestive of anaphylaxis,” according to the FDA reviewer.

In a study that was considered a supportive study, motavizumab was compared with placebo in 1,410 Native American term infants, who were at a greater risk of RSV infections. The incidence of RSV hospitalizations was 8.3% among those on motavizumab compared with 1.4% among those on placebo, a significant difference.

The allergist on the panel, Dr. Prescott Atkinson, professor and director of the division of pediatric allergy and immunology, Children's Hospital, Birmingham, Ala., said he voted against approval because he was convinced that the risks were higher with this drug, but “it's not clear to me that it's more efficacious than the drug we already have.”

If studies showed it was 10% more effective than palivizumab in reducing hospitalizations, then the risks of non–life-threatening skin reactions and rare cases of more severe anaphylaxis “might be acceptable risks in this high-risk population who comes in and not infrequently expires from RSV,” he added.

Since approval, an estimated 1.2 million people have received palivizumab and 10 cases of anaphylaxis have been reported to the FDA's voluntary adverse event reporting program, according to the FDA. A warning about the potential for anaphylaxis is on the palivizumab label.

If motavizumab is approved, MedImmune plans to market the drug as Rezield, with a risk management plan that would include educating prescribers about how to manage skin reactions, enhanced vigilance of adverse events, and postmarketing studies that would address issues that include evaluating the rates and severity of hypersensitivity reactions associated with motavizumab, the emergence of motavizumab-resistant RSV, and adverse event rates in the real-world setting.

The FDA is expected to make a decision on motavizumab by June 24. MedImmune has not filed for approval elsewhere, but plans to file for approval in the European Union, according to a company spokesperson. Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting, but the FDA occasionally grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, MD. — More information on the risks and severity of hypersensitivity reactions associated with the monoclonal antibody motavizumab is needed before it is approved for preventing serious lower respiratory tract infections with respiratory syncytial virus in high-risk infants, according to the majority of a Food and Drug Administration advisory panel.

The FDA's Antiviral Drug Products Advisory Committee voted 14-3 against recommending approval of motavizumab for the indication proposed by its manufacturer, MedImmune LLC., which is the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease (premature infants, children with chronic lung disease of prematurity, and children with hemodynamically significant congenital heart disease).

Like palivizumab (Synagis), approved in 1998 for RSV prophylaxis, motavizumab is a monoclonal antibody that binds to the F protein of RSV, but has a higher binding affinity to the protein and exerts a greater degree of neutralizing activity against RSV isolates in vitro, according to MedImmune, which also manufactures palivizumab. The proposed dosing for motavizumab is the same as for palivizumab: 15 mg/kg, administered by intramuscular injection once a month during the RSV season. Several panelists voiced concerns that Medimmune would phase out palivizumab once motavizumab was approved; a MedImmune spokesperson said that the company has never made a statement about such plans.

Panelists agreed that motavizumab had been shown to be effective in preventing RSV, but although the data suggested that it might be more effective than palivizumab, they agreed that it had not been shown to be superior. Moreover, the potential for hypersensitivity reactions among those on motavizumab in clinical trials was a major safety concern that needed to be studied further before approval, including in children who were more severely ill than those in the clinical trials. Although these reactions were rare, they were significant when they occurred and appeared to have an immunologic basis, according to the panel.

“Hypersensitivity and skin issues aside, I'm not really seeing a difference,” said panelist Patrick Clay, Pharm.D., director of the Dybedal Center for Clinical Research, Kansas City (Mo.) University. While it would be helpful to have more than one option for RSV prophylaxis, he pointed out that with the data available, it was unclear how a clinician would choose one or the other.

Panelist Dr. Yvonne Maldonado, chief of infectious diseases, Packard Children's Hospital, Stanford (Calif.) University, said that there was a “strong suggestion” that motavizumab was more effective than palivizumab, but there were not enough differences between the two drugs at this point to help practicing clinicians decide when the newer drug should be used. A “better definition of the safety profile would be really helpful for the clinician,” she noted.

In a phase III randomized, double-blind noninferiority study, motavizumab was compared with palivizumab in 6,635 premature infants (under 35 weeks' gestation) who were younger than 6 months, and in children younger than 24 months who had been premature and had chronic lung disease, in a 1:1 ratio. (Both drugs were administered at a dosage of 15 mg/kg once a month for five doses.) The proportion of patients who were hospitalized for RSV, the primary end point, was 1.4% among those on motavizumab, compared with 1.9% of those on palivizumab, which met the noninferiority criteria for the study. (Most of the patients in each group completed the study and about 96% in each group received all five scheduled doses.)

The overall safety profiles were similar between the two groups, with the exception of hypersensitivity reactions: More patients who received motavizumab developed urticaria (0.4%) and allergic rash (0. 8%), compared with those on palivizumab (0.1% and 0.3%). In addition, eight of those on motavizumab had a grade 3-4 hypersensitivity reaction, compared with none of those on palivizumab.

In the five studies that comprised the entire safety database for motavizumab, there were 19 grade 3-4 hypersensitivity events among those on motavizumab, compared with none among those on palivizumab. Of the 5,360 patients who received motavizumab, there were three cases “suggestive of anaphylaxis,” according to the FDA reviewer.

In a study that was considered a supportive study, motavizumab was compared with placebo in 1,410 Native American term infants, who were at a greater risk of RSV infections. The incidence of RSV hospitalizations was 8.3% among those on motavizumab compared with 1.4% among those on placebo, a significant difference.

The allergist on the panel, Dr. Prescott Atkinson, professor and director of the division of pediatric allergy and immunology, Children's Hospital, Birmingham, Ala., said he voted against approval because he was convinced that the risks were higher with this drug, but “it's not clear to me that it's more efficacious than the drug we already have.”

If studies showed it was 10% more effective than palivizumab in reducing hospitalizations, then the risks of non–life-threatening skin reactions and rare cases of more severe anaphylaxis “might be acceptable risks in this high-risk population who comes in and not infrequently expires from RSV,” he added.

Since approval, an estimated 1.2 million people have received palivizumab and 10 cases of anaphylaxis have been reported to the FDA's voluntary adverse event reporting program, according to the FDA. A warning about the potential for anaphylaxis is on the palivizumab label.

If motavizumab is approved, MedImmune plans to market the drug as Rezield, with a risk management plan that would include educating prescribers about how to manage skin reactions, enhanced vigilance of adverse events, and postmarketing studies that would address issues that include evaluating the rates and severity of hypersensitivity reactions associated with motavizumab, the emergence of motavizumab-resistant RSV, and adverse event rates in the real-world setting.

The FDA is expected to make a decision on motavizumab by June 24. MedImmune has not filed for approval elsewhere, but plans to file for approval in the European Union, according to a company spokesperson. Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting, but the FDA occasionally grants a waiver to a panelist with a conflict of interest.

Major Finding: A significant positive association was identified between maternal consumption of alcohol during pregnancy and childhood AML, but not with childhood ALL, when compared with nonexposed controls.

Data Source: 21 case-control studies.

Disclosures: The authors had no disclosures to report. The study was funded with a grant from the World Cancer Research Fund.

Alcohol intake during pregnancy was associated with a significant increase in the risk of acute myeloid leukemia in children who were exposed during pregnancy, but not with an increased risk of acute lymphoblastic leukemia, in a review and meta-analysis of case-control studies from numerous countries.

The results “indicate that the risk of childhood AML increases with maternal alcohol consumption during pregnancy,” reported Dr. Paule Latino-Martel of the University of Paris XIII and associates (Cancer Epidemiol. Biomarkers Prev. 2010;19:OF1-23).

This was the first meta-analysis the authors were aware of that investigated the role of in utero exposure to alcohol in relation to childhood leukemia. The studies had limitations, they said, and more studies with detailed information on alcohol exposure are needed.

The 21 studies included in the review comprised 20 different study populations, for a total of 8,128 cases and 10,207 controls. Because data collection varied among the studies, only relevant studies were included in categorical and dose-response meta-analyses.

A meta-analysis of nine studies found the significant positive association between maternal alcohol consumption during pregnancy and the risk of childhood acute myeloid leukemia (AML), with an odds ratio of 1.56. Maternal consumption of alcohol during pregnancy was not significantly associated with an increased risk of acute lymphoblastic leukemia (ALL), compared with no exposure.

A few studies included data that made it possible to do a dose-response analysis, which was “consistent with a stronger association with AML compared with ALL.” An increase of one drink per week was associated with odds ratios of 1.04 for ALL and 1.24 for AML, but the authors said that the results were heterogenous, and no conclusions could be made about the amount of alcohol intake that was associated with an increased risk. More studies with more details on alcohol exposure are needed, they added.

Examining the data on childhood age, the authors found no association between maternal alcohol intake during pregnancy and ALL that was diagnosed at age 0–4 years. But the association between in utero exposure to alcohol and AML that was diagnosed in children aged 0–4 years was significant in five studies (OR, 2.68), which the authors said was “consistent with the potential role of prenatal exposure to alcohol in the etiology of AML.”

“The biological plausibility of this association is supported by the fact that alcoholic beverages are recognized as carcinogenic for humans and are involved in several fetal alcohol-related diseases,” they said. But the reason why in utero exposure to alcohol “may specifically modify the risk of AML in young children is unknown,” the authors said. They pointed out that the peak of AML cases in children is earlier than that of ALL, which suggests “a stronger association or shorter latency of AML with prenatal exposures.”

With little information in the studies on alcohol type, the authors were not able to determine whether maternal consumption of one type of alcohol over another (beer vs. wine vs. spirits) was associated with a greater risk of leukemia.

Based on a meta-analysis of studies that provided information on alcohol intake by trimester, the authors found no association between childhood ALL and alcohol consumption in any trimester. Data were limited for AML, but in the two studies that included this information, the odds ratio “tended to be slightly higher when alcohol was consumed in the second and third trimesters compared with the first trimester,” they said.

Major Finding: A significant positive association was identified between maternal consumption of alcohol during pregnancy and childhood AML, but not with childhood ALL, when compared with nonexposed controls.

Data Source: 21 case-control studies.

Disclosures: The authors had no disclosures to report. The study was funded with a grant from the World Cancer Research Fund.

Alcohol intake during pregnancy was associated with a significant increase in the risk of acute myeloid leukemia in children who were exposed during pregnancy, but not with an increased risk of acute lymphoblastic leukemia, in a review and meta-analysis of case-control studies from numerous countries.

The results “indicate that the risk of childhood AML increases with maternal alcohol consumption during pregnancy,” reported Dr. Paule Latino-Martel of the University of Paris XIII and associates (Cancer Epidemiol. Biomarkers Prev. 2010;19:OF1-23).

This was the first meta-analysis the authors were aware of that investigated the role of in utero exposure to alcohol in relation to childhood leukemia. The studies had limitations, they said, and more studies with detailed information on alcohol exposure are needed.

The 21 studies included in the review comprised 20 different study populations, for a total of 8,128 cases and 10,207 controls. Because data collection varied among the studies, only relevant studies were included in categorical and dose-response meta-analyses.

A meta-analysis of nine studies found the significant positive association between maternal alcohol consumption during pregnancy and the risk of childhood acute myeloid leukemia (AML), with an odds ratio of 1.56. Maternal consumption of alcohol during pregnancy was not significantly associated with an increased risk of acute lymphoblastic leukemia (ALL), compared with no exposure.

A few studies included data that made it possible to do a dose-response analysis, which was “consistent with a stronger association with AML compared with ALL.” An increase of one drink per week was associated with odds ratios of 1.04 for ALL and 1.24 for AML, but the authors said that the results were heterogenous, and no conclusions could be made about the amount of alcohol intake that was associated with an increased risk. More studies with more details on alcohol exposure are needed, they added.

Examining the data on childhood age, the authors found no association between maternal alcohol intake during pregnancy and ALL that was diagnosed at age 0–4 years. But the association between in utero exposure to alcohol and AML that was diagnosed in children aged 0–4 years was significant in five studies (OR, 2.68), which the authors said was “consistent with the potential role of prenatal exposure to alcohol in the etiology of AML.”

“The biological plausibility of this association is supported by the fact that alcoholic beverages are recognized as carcinogenic for humans and are involved in several fetal alcohol-related diseases,” they said. But the reason why in utero exposure to alcohol “may specifically modify the risk of AML in young children is unknown,” the authors said. They pointed out that the peak of AML cases in children is earlier than that of ALL, which suggests “a stronger association or shorter latency of AML with prenatal exposures.”

With little information in the studies on alcohol type, the authors were not able to determine whether maternal consumption of one type of alcohol over another (beer vs. wine vs. spirits) was associated with a greater risk of leukemia.

Based on a meta-analysis of studies that provided information on alcohol intake by trimester, the authors found no association between childhood ALL and alcohol consumption in any trimester. Data were limited for AML, but in the two studies that included this information, the odds ratio “tended to be slightly higher when alcohol was consumed in the second and third trimesters compared with the first trimester,” they said.

Major Finding: A significant positive association was identified between maternal consumption of alcohol during pregnancy and childhood AML, but not with childhood ALL, when compared with nonexposed controls.

Data Source: 21 case-control studies.

Disclosures: The authors had no disclosures to report. The study was funded with a grant from the World Cancer Research Fund.

Alcohol intake during pregnancy was associated with a significant increase in the risk of acute myeloid leukemia in children who were exposed during pregnancy, but not with an increased risk of acute lymphoblastic leukemia, in a review and meta-analysis of case-control studies from numerous countries.

The results “indicate that the risk of childhood AML increases with maternal alcohol consumption during pregnancy,” reported Dr. Paule Latino-Martel of the University of Paris XIII and associates (Cancer Epidemiol. Biomarkers Prev. 2010;19:OF1-23).

This was the first meta-analysis the authors were aware of that investigated the role of in utero exposure to alcohol in relation to childhood leukemia. The studies had limitations, they said, and more studies with detailed information on alcohol exposure are needed.

The 21 studies included in the review comprised 20 different study populations, for a total of 8,128 cases and 10,207 controls. Because data collection varied among the studies, only relevant studies were included in categorical and dose-response meta-analyses.

A meta-analysis of nine studies found the significant positive association between maternal alcohol consumption during pregnancy and the risk of childhood acute myeloid leukemia (AML), with an odds ratio of 1.56. Maternal consumption of alcohol during pregnancy was not significantly associated with an increased risk of acute lymphoblastic leukemia (ALL), compared with no exposure.

A few studies included data that made it possible to do a dose-response analysis, which was “consistent with a stronger association with AML compared with ALL.” An increase of one drink per week was associated with odds ratios of 1.04 for ALL and 1.24 for AML, but the authors said that the results were heterogenous, and no conclusions could be made about the amount of alcohol intake that was associated with an increased risk. More studies with more details on alcohol exposure are needed, they added.

Examining the data on childhood age, the authors found no association between maternal alcohol intake during pregnancy and ALL that was diagnosed at age 0–4 years. But the association between in utero exposure to alcohol and AML that was diagnosed in children aged 0–4 years was significant in five studies (OR, 2.68), which the authors said was “consistent with the potential role of prenatal exposure to alcohol in the etiology of AML.”

“The biological plausibility of this association is supported by the fact that alcoholic beverages are recognized as carcinogenic for humans and are involved in several fetal alcohol-related diseases,” they said. But the reason why in utero exposure to alcohol “may specifically modify the risk of AML in young children is unknown,” the authors said. They pointed out that the peak of AML cases in children is earlier than that of ALL, which suggests “a stronger association or shorter latency of AML with prenatal exposures.”

With little information in the studies on alcohol type, the authors were not able to determine whether maternal consumption of one type of alcohol over another (beer vs. wine vs. spirits) was associated with a greater risk of leukemia.

Based on a meta-analysis of studies that provided information on alcohol intake by trimester, the authors found no association between childhood ALL and alcohol consumption in any trimester. Data were limited for AML, but in the two studies that included this information, the odds ratio “tended to be slightly higher when alcohol was consumed in the second and third trimesters compared with the first trimester,” they said.

Major Finding: A significant association between in utero exposure to alcohol and childhood acute myeloid leukemia was noted in five studies of children diagnosed at age 0-4 years (OR 2.68) when compared with nonexposed controls.

Data Source: Meta-analysis of 21 case-control studies.

Disclosures: The authors had no disclosures to report. The study was funded with a grant from the World Cancer Research Fund.

Alcohol intake during pregnancy was associated with a significant increase in the risk of acute myeloid leukemia in children who were exposed during pregnancy, but not with an increased risk of acute lymphoblastic leukemia, in a review and meta-analysis of case-control studies from numerous countries.

The results “indicate that the risk of childhood AML increases with maternal alcohol consumption during pregnancy,” reported Dr. Paule Latino-Martel of the University of Paris XIII and associates (Cancer Epidemiol. Biomarkers Prev. 2010;19:OF1-23).

This was the first meta-analysis the authors were aware of that investigated the role of in utero exposure to alcohol in relation to childhood leukemia. The studies had limitations, they said, and more studies with detailed information on alcohol exposure are needed.

The 21 studies included in the review comprised 20 different study populations, for a total of 8,128 cases and 10,207 controls. Because data collection varied among the studies, only relevant studies were included in categorical and dose-response meta-analyses.

A meta-analysis of nine studies found the significant positive association between maternal alcohol consumption during pregnancy and the risk of childhood acute myeloid leukemia (AML), with an odds ratio of 1.56. Maternal consumption of alcohol during pregnancy was not significantly associated with an increased risk of acute lymphoblastic leukemia (ALL), compared with no exposure.

A few studies included data that made it possible to do a dose-response analysis, which was “consistent with a stronger association with AML compared with ALL.”

For each increase of one drink per week, the increase in odds ratios was 1.04 for ALL and 1.24 for AML, but the authors said that the results were heterogeneous, and no conclusions could be made about the amount of alcohol intake that was associated with an increased risk. More studies with more details on alcohol exposure are needed, they added.

Examining the data on childhood age, the authors found no association between maternal alcohol intake during pregnancy and ALL that was diagnosed at age 0-4 years.

But the association between in utero exposure to alcohol and AML that was diagnosed in children aged 0-4 years was significant in five studies (OR 2.68), which the authors said was “consistent with the potential role of prenatal exposure to alcohol in the etiology of AML.”

“The biological plausibility of this association is supported by the fact that alcoholic beverages are recognized as carcinogenic for humans and are involved in several fetal alcohol-related diseases,” they said.

But the reason why in utero exposure to alcohol “may specifically modify the risk of AML in young children is unknown,” the authors said. They pointed out that the peak of AML cases in children is earlier than that of ALL, which suggests “a stronger association or shorter latency of AML with prenatal exposures.”

With little information in the studies on the type of alcohol consumed, the authors were not able to determine whether maternal consumption of one type of alcohol over another (beer vs. wine vs. spirits) was associated with a greater risk of leukemia.

The data available did not suggest, however, that one type of alcohol posed a greater risk than did another type, they wrote.

Based on a meta-analysis of those studies that provided information on alcohol intake by trimester, the authors found no association between childhood ALL and alcohol consumption during any trimester.

For AML, the data were limited, but in the two studies that included this information, the odds ratio “tended to be slightly higher when alcohol was consumed in the second and third trimesters compared with the first trimester,” they said.

The association between maternal alcohol intake and the risk of childhood leukemia—particularly AML—should be studied further and in large birth cohort studies, they recommended.

Noting that an estimated 12% of pregnant women in the United States drink alcohol during pregnancy (and 30% in Sweden, 52% in France, 59% in Australia, and 60% in Russia), they urged that efforts to reduce alcohol use be directed toward women during pregnancy as well as before they become pregnant, which might help “contribute to reduce the occurrence of harmful effects including AML in young children,” they said.

Major Finding: A significant association between in utero exposure to alcohol and childhood acute myeloid leukemia was noted in five studies of children diagnosed at age 0-4 years (OR 2.68) when compared with nonexposed controls.

Data Source: Meta-analysis of 21 case-control studies.

Disclosures: The authors had no disclosures to report. The study was funded with a grant from the World Cancer Research Fund.

Alcohol intake during pregnancy was associated with a significant increase in the risk of acute myeloid leukemia in children who were exposed during pregnancy, but not with an increased risk of acute lymphoblastic leukemia, in a review and meta-analysis of case-control studies from numerous countries.

The results “indicate that the risk of childhood AML increases with maternal alcohol consumption during pregnancy,” reported Dr. Paule Latino-Martel of the University of Paris XIII and associates (Cancer Epidemiol. Biomarkers Prev. 2010;19:OF1-23).

This was the first meta-analysis the authors were aware of that investigated the role of in utero exposure to alcohol in relation to childhood leukemia. The studies had limitations, they said, and more studies with detailed information on alcohol exposure are needed.

The 21 studies included in the review comprised 20 different study populations, for a total of 8,128 cases and 10,207 controls. Because data collection varied among the studies, only relevant studies were included in categorical and dose-response meta-analyses.

A meta-analysis of nine studies found the significant positive association between maternal alcohol consumption during pregnancy and the risk of childhood acute myeloid leukemia (AML), with an odds ratio of 1.56. Maternal consumption of alcohol during pregnancy was not significantly associated with an increased risk of acute lymphoblastic leukemia (ALL), compared with no exposure.

A few studies included data that made it possible to do a dose-response analysis, which was “consistent with a stronger association with AML compared with ALL.”

For each increase of one drink per week, the increase in odds ratios was 1.04 for ALL and 1.24 for AML, but the authors said that the results were heterogeneous, and no conclusions could be made about the amount of alcohol intake that was associated with an increased risk. More studies with more details on alcohol exposure are needed, they added.

Examining the data on childhood age, the authors found no association between maternal alcohol intake during pregnancy and ALL that was diagnosed at age 0-4 years.

But the association between in utero exposure to alcohol and AML that was diagnosed in children aged 0-4 years was significant in five studies (OR 2.68), which the authors said was “consistent with the potential role of prenatal exposure to alcohol in the etiology of AML.”

“The biological plausibility of this association is supported by the fact that alcoholic beverages are recognized as carcinogenic for humans and are involved in several fetal alcohol-related diseases,” they said.

But the reason why in utero exposure to alcohol “may specifically modify the risk of AML in young children is unknown,” the authors said. They pointed out that the peak of AML cases in children is earlier than that of ALL, which suggests “a stronger association or shorter latency of AML with prenatal exposures.”

With little information in the studies on the type of alcohol consumed, the authors were not able to determine whether maternal consumption of one type of alcohol over another (beer vs. wine vs. spirits) was associated with a greater risk of leukemia.

The data available did not suggest, however, that one type of alcohol posed a greater risk than did another type, they wrote.

Based on a meta-analysis of those studies that provided information on alcohol intake by trimester, the authors found no association between childhood ALL and alcohol consumption during any trimester.

For AML, the data were limited, but in the two studies that included this information, the odds ratio “tended to be slightly higher when alcohol was consumed in the second and third trimesters compared with the first trimester,” they said.

The association between maternal alcohol intake and the risk of childhood leukemia—particularly AML—should be studied further and in large birth cohort studies, they recommended.

Noting that an estimated 12% of pregnant women in the United States drink alcohol during pregnancy (and 30% in Sweden, 52% in France, 59% in Australia, and 60% in Russia), they urged that efforts to reduce alcohol use be directed toward women during pregnancy as well as before they become pregnant, which might help “contribute to reduce the occurrence of harmful effects including AML in young children,” they said.

Major Finding: A significant association between in utero exposure to alcohol and childhood acute myeloid leukemia was noted in five studies of children diagnosed at age 0-4 years (OR 2.68) when compared with nonexposed controls.

Data Source: Meta-analysis of 21 case-control studies.

Disclosures: The authors had no disclosures to report. The study was funded with a grant from the World Cancer Research Fund.

Alcohol intake during pregnancy was associated with a significant increase in the risk of acute myeloid leukemia in children who were exposed during pregnancy, but not with an increased risk of acute lymphoblastic leukemia, in a review and meta-analysis of case-control studies from numerous countries.

The results “indicate that the risk of childhood AML increases with maternal alcohol consumption during pregnancy,” reported Dr. Paule Latino-Martel of the University of Paris XIII and associates (Cancer Epidemiol. Biomarkers Prev. 2010;19:OF1-23).

This was the first meta-analysis the authors were aware of that investigated the role of in utero exposure to alcohol in relation to childhood leukemia. The studies had limitations, they said, and more studies with detailed information on alcohol exposure are needed.

The 21 studies included in the review comprised 20 different study populations, for a total of 8,128 cases and 10,207 controls. Because data collection varied among the studies, only relevant studies were included in categorical and dose-response meta-analyses.

A meta-analysis of nine studies found the significant positive association between maternal alcohol consumption during pregnancy and the risk of childhood acute myeloid leukemia (AML), with an odds ratio of 1.56. Maternal consumption of alcohol during pregnancy was not significantly associated with an increased risk of acute lymphoblastic leukemia (ALL), compared with no exposure.

A few studies included data that made it possible to do a dose-response analysis, which was “consistent with a stronger association with AML compared with ALL.”

For each increase of one drink per week, the increase in odds ratios was 1.04 for ALL and 1.24 for AML, but the authors said that the results were heterogeneous, and no conclusions could be made about the amount of alcohol intake that was associated with an increased risk. More studies with more details on alcohol exposure are needed, they added.

Examining the data on childhood age, the authors found no association between maternal alcohol intake during pregnancy and ALL that was diagnosed at age 0-4 years.

But the association between in utero exposure to alcohol and AML that was diagnosed in children aged 0-4 years was significant in five studies (OR 2.68), which the authors said was “consistent with the potential role of prenatal exposure to alcohol in the etiology of AML.”

“The biological plausibility of this association is supported by the fact that alcoholic beverages are recognized as carcinogenic for humans and are involved in several fetal alcohol-related diseases,” they said.

But the reason why in utero exposure to alcohol “may specifically modify the risk of AML in young children is unknown,” the authors said. They pointed out that the peak of AML cases in children is earlier than that of ALL, which suggests “a stronger association or shorter latency of AML with prenatal exposures.”

With little information in the studies on the type of alcohol consumed, the authors were not able to determine whether maternal consumption of one type of alcohol over another (beer vs. wine vs. spirits) was associated with a greater risk of leukemia.

The data available did not suggest, however, that one type of alcohol posed a greater risk than did another type, they wrote.

Based on a meta-analysis of those studies that provided information on alcohol intake by trimester, the authors found no association between childhood ALL and alcohol consumption during any trimester.

For AML, the data were limited, but in the two studies that included this information, the odds ratio “tended to be slightly higher when alcohol was consumed in the second and third trimesters compared with the first trimester,” they said.

The association between maternal alcohol intake and the risk of childhood leukemia—particularly AML—should be studied further and in large birth cohort studies, they recommended.

Noting that an estimated 12% of pregnant women in the United States drink alcohol during pregnancy (and 30% in Sweden, 52% in France, 59% in Australia, and 60% in Russia), they urged that efforts to reduce alcohol use be directed toward women during pregnancy as well as before they become pregnant, which might help “contribute to reduce the occurrence of harmful effects including AML in young children,” they said.

Improving the appearance of port wine stains usually requires multiple laser treatments, and research is ongoing to improve results, according to Dr. Kristen Kelly.

Port wine stains (PWS) are the most common vascular malformations treated by dermatologists. About 0.3% of newborns have a PWS birthmark, which does not proliferate rapidly, but "may thicken, darken and develop nodules over time," Dr. Kelly said at a cosmetic dermatology seminar sponsored by Skin Disease Education Foundation in Santa Monica, Calif.

Photo courtesy Bernard Choi, Ph.D. and Y-C Huang

Historically, treatments for PWS have included tattoos or radiation, but for almost 30 years laser therapy has been the mainstay of treatment. Although these devices have improved, 2-15 or more laser applications are needed at approximately 4-week intervals for successful treatment of these lesions, said Dr. Kelly of the University of California, Irvine, and the Beckman Laser Institute and Medical Clinic.

The pulsed dye laser is the standard of care for PWS treatment and is the laser that she and her associates use most often. However, "we use different lasers and settings over a course of treatment to try to improve our results," Dr. Kelly said in an interview. The other lasers they use include the 755-nm alexandrite laser and combined 1,064:595-nm laser system, as well as intense pulsed light.

For some patients undergoing treatment of a PWS, preparation may include use of a bleaching cream for several weeks before treatment. Sun protection of the area to be treated is recommended for all patients. She and her associates use general anesthesia for patients with large lesions and for children and infants, although this is not a universal practice among dermatologists, she pointed out.

Eye protection with a corneal shield is very important for patients if treatment involves the periorbital or eyelid area, Dr. Kelly said, noting that proper eye protection is also important for those treating the patient.

During treatment, she recommends using a 585-nm or 595-nm wavelength and 0.45-3 millisecond pulse duration--varying pulse duration and wavelength over time to achieve optimal results. Placing patients in the Trendelenburg position can increase blood flow to the area of the PWS, according to Dr. Kelly, who is also with the university's Vascular Birthmarks and Malformations Diagnostic Treatment Center.

Postoperatively, ice should be applied to the treated area, which should be elevated for the first 1-2 postoperative days. A mild analgesic like acetaminophen should be used for discomfort, she said. An emollient should be applied to the treated area, and patients should protect the treated area from sun exposure. A bleaching cream such as hydroquinone may be started 2-3 weeks after treatment for some patients.

Dr. Kelly said that most PWS birthmarks get lighter but require multiple treatments. Some lesions, however, are resistant to treatment, and complete removal is uncommon.

Research on improving results of PWS - to achieve more complete clearance over a shorter period of time - includes studies of imaging methods like laser speckle imaging (LSI), which is used intraoperatively to evaluate the impact of laser treatment on blood flow to determine if flow to the lesional blood vessel is decreased dramatically or shut down.

"Presumably, a greater reduction in flow is associated with greater damage to the blood vessels," said Dr. Kelly, who, with her associates, is studying whether a greater reduction in blood flow during treatment ultimately leads to better results. "We think it does, but we don't know that for sure yet," she said.

They also are studying whether the use of adjunctive agents after laser treatment improves results. These agents include antiangiogenic agents applied topically or administered orally or intravenously. An early study of imiquimod, an immune modulator with antiangiogenic effects, is underway, she noted.

Dr. Kelly disclosed that she has received research grants from Candela Corp. and Graceway Pharmaceuticals, and has served as a consultant to Lumenis. In addition, Graceway and Genentech have donated products for studies she is conducting.

SDEF and this news organization are both owned by Elsevier.

Improving the appearance of port wine stains usually requires multiple laser treatments, and research is ongoing to improve results, according to Dr. Kristen Kelly.

Port wine stains (PWS) are the most common vascular malformations treated by dermatologists. About 0.3% of newborns have a PWS birthmark, which does not proliferate rapidly, but "may thicken, darken and develop nodules over time," Dr. Kelly said at a cosmetic dermatology seminar sponsored by Skin Disease Education Foundation in Santa Monica, Calif.

Photo courtesy Bernard Choi, Ph.D. and Y-C Huang

Historically, treatments for PWS have included tattoos or radiation, but for almost 30 years laser therapy has been the mainstay of treatment. Although these devices have improved, 2-15 or more laser applications are needed at approximately 4-week intervals for successful treatment of these lesions, said Dr. Kelly of the University of California, Irvine, and the Beckman Laser Institute and Medical Clinic.

The pulsed dye laser is the standard of care for PWS treatment and is the laser that she and her associates use most often. However, "we use different lasers and settings over a course of treatment to try to improve our results," Dr. Kelly said in an interview. The other lasers they use include the 755-nm alexandrite laser and combined 1,064:595-nm laser system, as well as intense pulsed light.

For some patients undergoing treatment of a PWS, preparation may include use of a bleaching cream for several weeks before treatment. Sun protection of the area to be treated is recommended for all patients. She and her associates use general anesthesia for patients with large lesions and for children and infants, although this is not a universal practice among dermatologists, she pointed out.

Eye protection with a corneal shield is very important for patients if treatment involves the periorbital or eyelid area, Dr. Kelly said, noting that proper eye protection is also important for those treating the patient.

During treatment, she recommends using a 585-nm or 595-nm wavelength and 0.45-3 millisecond pulse duration--varying pulse duration and wavelength over time to achieve optimal results. Placing patients in the Trendelenburg position can increase blood flow to the area of the PWS, according to Dr. Kelly, who is also with the university's Vascular Birthmarks and Malformations Diagnostic Treatment Center.

Postoperatively, ice should be applied to the treated area, which should be elevated for the first 1-2 postoperative days. A mild analgesic like acetaminophen should be used for discomfort, she said. An emollient should be applied to the treated area, and patients should protect the treated area from sun exposure. A bleaching cream such as hydroquinone may be started 2-3 weeks after treatment for some patients.

Dr. Kelly said that most PWS birthmarks get lighter but require multiple treatments. Some lesions, however, are resistant to treatment, and complete removal is uncommon.

Research on improving results of PWS - to achieve more complete clearance over a shorter period of time - includes studies of imaging methods like laser speckle imaging (LSI), which is used intraoperatively to evaluate the impact of laser treatment on blood flow to determine if flow to the lesional blood vessel is decreased dramatically or shut down.

"Presumably, a greater reduction in flow is associated with greater damage to the blood vessels," said Dr. Kelly, who, with her associates, is studying whether a greater reduction in blood flow during treatment ultimately leads to better results. "We think it does, but we don't know that for sure yet," she said.

They also are studying whether the use of adjunctive agents after laser treatment improves results. These agents include antiangiogenic agents applied topically or administered orally or intravenously. An early study of imiquimod, an immune modulator with antiangiogenic effects, is underway, she noted.

Dr. Kelly disclosed that she has received research grants from Candela Corp. and Graceway Pharmaceuticals, and has served as a consultant to Lumenis. In addition, Graceway and Genentech have donated products for studies she is conducting.

SDEF and this news organization are both owned by Elsevier.

Improving the appearance of port wine stains usually requires multiple laser treatments, and research is ongoing to improve results, according to Dr. Kristen Kelly.

Port wine stains (PWS) are the most common vascular malformations treated by dermatologists. About 0.3% of newborns have a PWS birthmark, which does not proliferate rapidly, but "may thicken, darken and develop nodules over time," Dr. Kelly said at a cosmetic dermatology seminar sponsored by Skin Disease Education Foundation in Santa Monica, Calif.

Photo courtesy Bernard Choi, Ph.D. and Y-C Huang

Historically, treatments for PWS have included tattoos or radiation, but for almost 30 years laser therapy has been the mainstay of treatment. Although these devices have improved, 2-15 or more laser applications are needed at approximately 4-week intervals for successful treatment of these lesions, said Dr. Kelly of the University of California, Irvine, and the Beckman Laser Institute and Medical Clinic.

The pulsed dye laser is the standard of care for PWS treatment and is the laser that she and her associates use most often. However, "we use different lasers and settings over a course of treatment to try to improve our results," Dr. Kelly said in an interview. The other lasers they use include the 755-nm alexandrite laser and combined 1,064:595-nm laser system, as well as intense pulsed light.

For some patients undergoing treatment of a PWS, preparation may include use of a bleaching cream for several weeks before treatment. Sun protection of the area to be treated is recommended for all patients. She and her associates use general anesthesia for patients with large lesions and for children and infants, although this is not a universal practice among dermatologists, she pointed out.

Eye protection with a corneal shield is very important for patients if treatment involves the periorbital or eyelid area, Dr. Kelly said, noting that proper eye protection is also important for those treating the patient.

During treatment, she recommends using a 585-nm or 595-nm wavelength and 0.45-3 millisecond pulse duration--varying pulse duration and wavelength over time to achieve optimal results. Placing patients in the Trendelenburg position can increase blood flow to the area of the PWS, according to Dr. Kelly, who is also with the university's Vascular Birthmarks and Malformations Diagnostic Treatment Center.

Postoperatively, ice should be applied to the treated area, which should be elevated for the first 1-2 postoperative days. A mild analgesic like acetaminophen should be used for discomfort, she said. An emollient should be applied to the treated area, and patients should protect the treated area from sun exposure. A bleaching cream such as hydroquinone may be started 2-3 weeks after treatment for some patients.

Dr. Kelly said that most PWS birthmarks get lighter but require multiple treatments. Some lesions, however, are resistant to treatment, and complete removal is uncommon.

Research on improving results of PWS - to achieve more complete clearance over a shorter period of time - includes studies of imaging methods like laser speckle imaging (LSI), which is used intraoperatively to evaluate the impact of laser treatment on blood flow to determine if flow to the lesional blood vessel is decreased dramatically or shut down.

"Presumably, a greater reduction in flow is associated with greater damage to the blood vessels," said Dr. Kelly, who, with her associates, is studying whether a greater reduction in blood flow during treatment ultimately leads to better results. "We think it does, but we don't know that for sure yet," she said.

They also are studying whether the use of adjunctive agents after laser treatment improves results. These agents include antiangiogenic agents applied topically or administered orally or intravenously. An early study of imiquimod, an immune modulator with antiangiogenic effects, is underway, she noted.

Dr. Kelly disclosed that she has received research grants from Candela Corp. and Graceway Pharmaceuticals, and has served as a consultant to Lumenis. In addition, Graceway and Genentech have donated products for studies she is conducting.

SDEF and this news organization are both owned by Elsevier.