Pulmonary Health Hub

SILVER SPRING, MD. – Reassured by the cardiovascular safety data in a large randomized study, the majority of a Food and Drug Administration advisory panel supported the approval of an inhaled liquid spray formulation of tiotropium bromide in a new delivery device for the long-term maintenance treatment of chronic obstructive pulmonary disease.

At the Aug. 14 meeting of the FDA Pulmonary-Allergy Drugs Advisory Committee, the panel voted 10-3 that the safety and efficacy data supported the approval of tiotropium bromide inhalation spray, at a dose of 5 mcg/day, administered via a device that contains 30 doses, for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations.

If the FDA approves the product, Boehringer Ingelheim plans to market it as Spiriva Respimat. It has been available outside of the United States since 2007 and is now available in more than 85 countries, according to the company.

The panel unanimously voted that the available data supported the efficacy of the Respimat device for the indication. This is the same indication approved for the dry powder formulation of tiotropium in the single dose, breath-actuated HandiHaler device, marketed as Spiriva HandiHaler by Boehringer Ingelheim, approved in 2004 by the FDA. A capsule is inserted into the HandiHaler device for each dose.

Like others voting for approval, Dr. Francis McCormack agreed the data had met the criteria for safety and efficacy required for approval and that the new tiotropium product, Spiriva Respimat, was comparable to the existing Spiriva HandiHaler product. “I’m enthusiastic about being able to offer this delivery device to my patients,” commented Dr. McCormack, professor of medicine and director of the division of pulmonary, critical care, and sleep medicine at the University of Cincinnati.

The Respimat device delivers a 5-mcg dose, and the HandiHaler device delivers an 18-mcg dose, with similar pharmacokinetic effects and systemic exposure, according to the company. Panelists agreed that treatment with the Respimat device was not shown to be more effective than with the HandiHaler, and the company did not have any data showing that compliance was better with the Respimat device.

Those voting in favor of approval were reassured by the results of a large study that addressed concerns about a cardiovascular mortality signal in earlier studies associated with tiotropium Respimat.

Boehringer Ingelheim filed for approval of tiotropium Respimat almost 7 years ago. At that time, the FDA requested more data from the company to support the exacerbation claim and to address the mortality imbalance among those treated with tiotropium Respimat in 48-week, placebo-controlled studies, and concerns over cardiovascular safety raised during the review.

The randomized, double-blind, parallel group study, the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial of more than 17,000 patients with COPD followed for at least 2 years adjudicated the cause of deaths, comparing 2.5 mg and 5 mg of tiotropium in the Respimat device to the tiotropium HandiHaler device. All-cause mortality in the three groups was similar.

Fatal MACE (major adverse cardiovascular events) rates were similar between the treatment groups, noted Dr. Robert Lim, a clinical reviewer in the FDA’s division of pulmonary, allergy, and rheumatology products. While there were numerical differences in two fatal MACE components – cardiac disorders and fatal myocardial infarction – the differences were small.

Panelists said that the imbalance in fatal MIs could be a random finding and was not strong enough to vote against approval. However, some panelists cited lingering concerns about a cardiovascular safety signal in different studies.

Although she voted in favor of approval, Erica H. Brittain, Ph.D., a biostatistician at the National Institute of Allergy and Infectious Diseases, Bethesda, Md., said that she had “lingering unease” about a cardiovascular safety signal cropping up in several studies. But she was confident with the all-cause mortality finding and the “clear-cut” efficacy. However, if the ease-of-use feature of the Respimat inhaler was not important to a patient, Dr. Brittain noted that she would probably recommend the HandiHaler product.

A cardiologist on the panel, Dr. Philip Sager, said that he was reassured by the data, and that overall safety, cardiovascular safety, and “clear efficacy in treating patients with COPD has been demonstrated.” Breaking the MACE endpoint down by subgroups gets complicated, and the MI finding could be “statistical noise,” added Dr. Sager, chair of the scientific programs committee of the Cardiac Safety Research Consortium, San Francisco.

Voting against approval, Sean Hennessy, Pharm.D., director of the Center for Pharmacoepidemiology Research and Training, University of Pennsylvania, Philadelphia, said he remained concerned about cardiac safety and the absence of data showing Respimat provided benefits over the HandiHaler. He referred to the consistent finding of an increased rate of fatal MIs in multiple randomized clinical trials.

The FDA is expected to make a decision on approval by Sept. 21. The agency usually follows the recommendations of its advisory panels. Panel members had no relevant conflicts of interest to disclose.

The TIOSPIR study was published in October 2013 (N. Engl. J. Med. 2013;369:1491-501).

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – Reassured by the cardiovascular safety data in a large randomized study, the majority of a Food and Drug Administration advisory panel supported the approval of an inhaled liquid spray formulation of tiotropium bromide in a new delivery device for the long-term maintenance treatment of chronic obstructive pulmonary disease.

At the Aug. 14 meeting of the FDA Pulmonary-Allergy Drugs Advisory Committee, the panel voted 10-3 that the safety and efficacy data supported the approval of tiotropium bromide inhalation spray, at a dose of 5 mcg/day, administered via a device that contains 30 doses, for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations.

If the FDA approves the product, Boehringer Ingelheim plans to market it as Spiriva Respimat. It has been available outside of the United States since 2007 and is now available in more than 85 countries, according to the company.

The panel unanimously voted that the available data supported the efficacy of the Respimat device for the indication. This is the same indication approved for the dry powder formulation of tiotropium in the single dose, breath-actuated HandiHaler device, marketed as Spiriva HandiHaler by Boehringer Ingelheim, approved in 2004 by the FDA. A capsule is inserted into the HandiHaler device for each dose.

Like others voting for approval, Dr. Francis McCormack agreed the data had met the criteria for safety and efficacy required for approval and that the new tiotropium product, Spiriva Respimat, was comparable to the existing Spiriva HandiHaler product. “I’m enthusiastic about being able to offer this delivery device to my patients,” commented Dr. McCormack, professor of medicine and director of the division of pulmonary, critical care, and sleep medicine at the University of Cincinnati.

The Respimat device delivers a 5-mcg dose, and the HandiHaler device delivers an 18-mcg dose, with similar pharmacokinetic effects and systemic exposure, according to the company. Panelists agreed that treatment with the Respimat device was not shown to be more effective than with the HandiHaler, and the company did not have any data showing that compliance was better with the Respimat device.

Those voting in favor of approval were reassured by the results of a large study that addressed concerns about a cardiovascular mortality signal in earlier studies associated with tiotropium Respimat.

Boehringer Ingelheim filed for approval of tiotropium Respimat almost 7 years ago. At that time, the FDA requested more data from the company to support the exacerbation claim and to address the mortality imbalance among those treated with tiotropium Respimat in 48-week, placebo-controlled studies, and concerns over cardiovascular safety raised during the review.

The randomized, double-blind, parallel group study, the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial of more than 17,000 patients with COPD followed for at least 2 years adjudicated the cause of deaths, comparing 2.5 mg and 5 mg of tiotropium in the Respimat device to the tiotropium HandiHaler device. All-cause mortality in the three groups was similar.

Fatal MACE (major adverse cardiovascular events) rates were similar between the treatment groups, noted Dr. Robert Lim, a clinical reviewer in the FDA’s division of pulmonary, allergy, and rheumatology products. While there were numerical differences in two fatal MACE components – cardiac disorders and fatal myocardial infarction – the differences were small.

Panelists said that the imbalance in fatal MIs could be a random finding and was not strong enough to vote against approval. However, some panelists cited lingering concerns about a cardiovascular safety signal in different studies.

Although she voted in favor of approval, Erica H. Brittain, Ph.D., a biostatistician at the National Institute of Allergy and Infectious Diseases, Bethesda, Md., said that she had “lingering unease” about a cardiovascular safety signal cropping up in several studies. But she was confident with the all-cause mortality finding and the “clear-cut” efficacy. However, if the ease-of-use feature of the Respimat inhaler was not important to a patient, Dr. Brittain noted that she would probably recommend the HandiHaler product.

A cardiologist on the panel, Dr. Philip Sager, said that he was reassured by the data, and that overall safety, cardiovascular safety, and “clear efficacy in treating patients with COPD has been demonstrated.” Breaking the MACE endpoint down by subgroups gets complicated, and the MI finding could be “statistical noise,” added Dr. Sager, chair of the scientific programs committee of the Cardiac Safety Research Consortium, San Francisco.

Voting against approval, Sean Hennessy, Pharm.D., director of the Center for Pharmacoepidemiology Research and Training, University of Pennsylvania, Philadelphia, said he remained concerned about cardiac safety and the absence of data showing Respimat provided benefits over the HandiHaler. He referred to the consistent finding of an increased rate of fatal MIs in multiple randomized clinical trials.

The FDA is expected to make a decision on approval by Sept. 21. The agency usually follows the recommendations of its advisory panels. Panel members had no relevant conflicts of interest to disclose.

The TIOSPIR study was published in October 2013 (N. Engl. J. Med. 2013;369:1491-501).

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – Reassured by the cardiovascular safety data in a large randomized study, the majority of a Food and Drug Administration advisory panel supported the approval of an inhaled liquid spray formulation of tiotropium bromide in a new delivery device for the long-term maintenance treatment of chronic obstructive pulmonary disease.

At the Aug. 14 meeting of the FDA Pulmonary-Allergy Drugs Advisory Committee, the panel voted 10-3 that the safety and efficacy data supported the approval of tiotropium bromide inhalation spray, at a dose of 5 mcg/day, administered via a device that contains 30 doses, for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations.

If the FDA approves the product, Boehringer Ingelheim plans to market it as Spiriva Respimat. It has been available outside of the United States since 2007 and is now available in more than 85 countries, according to the company.

The panel unanimously voted that the available data supported the efficacy of the Respimat device for the indication. This is the same indication approved for the dry powder formulation of tiotropium in the single dose, breath-actuated HandiHaler device, marketed as Spiriva HandiHaler by Boehringer Ingelheim, approved in 2004 by the FDA. A capsule is inserted into the HandiHaler device for each dose.

Like others voting for approval, Dr. Francis McCormack agreed the data had met the criteria for safety and efficacy required for approval and that the new tiotropium product, Spiriva Respimat, was comparable to the existing Spiriva HandiHaler product. “I’m enthusiastic about being able to offer this delivery device to my patients,” commented Dr. McCormack, professor of medicine and director of the division of pulmonary, critical care, and sleep medicine at the University of Cincinnati.

The Respimat device delivers a 5-mcg dose, and the HandiHaler device delivers an 18-mcg dose, with similar pharmacokinetic effects and systemic exposure, according to the company. Panelists agreed that treatment with the Respimat device was not shown to be more effective than with the HandiHaler, and the company did not have any data showing that compliance was better with the Respimat device.

Those voting in favor of approval were reassured by the results of a large study that addressed concerns about a cardiovascular mortality signal in earlier studies associated with tiotropium Respimat.

Boehringer Ingelheim filed for approval of tiotropium Respimat almost 7 years ago. At that time, the FDA requested more data from the company to support the exacerbation claim and to address the mortality imbalance among those treated with tiotropium Respimat in 48-week, placebo-controlled studies, and concerns over cardiovascular safety raised during the review.

The randomized, double-blind, parallel group study, the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial of more than 17,000 patients with COPD followed for at least 2 years adjudicated the cause of deaths, comparing 2.5 mg and 5 mg of tiotropium in the Respimat device to the tiotropium HandiHaler device. All-cause mortality in the three groups was similar.

Fatal MACE (major adverse cardiovascular events) rates were similar between the treatment groups, noted Dr. Robert Lim, a clinical reviewer in the FDA’s division of pulmonary, allergy, and rheumatology products. While there were numerical differences in two fatal MACE components – cardiac disorders and fatal myocardial infarction – the differences were small.

Panelists said that the imbalance in fatal MIs could be a random finding and was not strong enough to vote against approval. However, some panelists cited lingering concerns about a cardiovascular safety signal in different studies.

Although she voted in favor of approval, Erica H. Brittain, Ph.D., a biostatistician at the National Institute of Allergy and Infectious Diseases, Bethesda, Md., said that she had “lingering unease” about a cardiovascular safety signal cropping up in several studies. But she was confident with the all-cause mortality finding and the “clear-cut” efficacy. However, if the ease-of-use feature of the Respimat inhaler was not important to a patient, Dr. Brittain noted that she would probably recommend the HandiHaler product.

A cardiologist on the panel, Dr. Philip Sager, said that he was reassured by the data, and that overall safety, cardiovascular safety, and “clear efficacy in treating patients with COPD has been demonstrated.” Breaking the MACE endpoint down by subgroups gets complicated, and the MI finding could be “statistical noise,” added Dr. Sager, chair of the scientific programs committee of the Cardiac Safety Research Consortium, San Francisco.

Voting against approval, Sean Hennessy, Pharm.D., director of the Center for Pharmacoepidemiology Research and Training, University of Pennsylvania, Philadelphia, said he remained concerned about cardiac safety and the absence of data showing Respimat provided benefits over the HandiHaler. He referred to the consistent finding of an increased rate of fatal MIs in multiple randomized clinical trials.

The FDA is expected to make a decision on approval by Sept. 21. The agency usually follows the recommendations of its advisory panels. Panel members had no relevant conflicts of interest to disclose.

The TIOSPIR study was published in October 2013 (N. Engl. J. Med. 2013;369:1491-501).

emechcatie@frontlinemedcom.com

With no currently accepted benchmarks for what constitutes best in class performance for treating children with asthma, bronchiolitis, and pneumonia, researchers recently set out to determine achievable benchmarks of care for the clinical quality indicators that hospitals can target to measure the care they are delivering.

"Even for the most common pediatric conditions, in which there are clear evidence-based guidelines for care, there continues to be significant variability in how well hospitals follow these guidelines," Dr. Kavita Parikh of the Children’s National Medical Center and George Washington School of Medicine in Washington, and her associates, reported in an article scheduled to appear in the September issue of Pediatrics (2014;134:555-62). "We have demonstrated that administrative data can be used to calculate ABCs [achievable benchmarks of care] for the top three admission diagnoses in pediatric hospital care. These ABCs represent measurable and attainable goals for standardization of care, and they can be the starting point for individual hospitals to evaluate their performance to a national standard."

Administrative data from encounters at 42 hospitals during 2012, including 22,186 asthma, 14,882 bronchiolitis, and 12,983 pneumonia encounters were reviewed. The following achievable benchmarks of care were determined:

• For asthma in children 2-18 years: chest radiograph utilization of 24.5%; antibiotic administration, 6.6%; and ipratropium bromide use greater than 2 days, 0%;

• For bronchiolitis in children 2 months-2 years: chest radiograph utilization of 32.4%; viral testing, 0.6%; antibiotic administration, 18.5%; bronchodilator use greater than 2 days of 0%; and steroid use, 6.4%.

• For pneumonia in children 2 months-18 years: complete blood cell count utilization, 28.8%; viral testing, 1.5%; initial narrow-spectrum antibiotic use, 60.7%; erythrocyte sedimentation rate, 3.5%; and C-reactive protein, 0.1%.

The authors said the study had several limitations. The data was based on outcomes at tertiary care hospitals, so it may not be generalizable to the non–tertiary care hospital setting. The authors also were unable to determine if the utilization occurred in the emergency room or in the inpatient setting.

The authors had no financial disclosures.

gtwachtman@frontlinemedcom.com

With no currently accepted benchmarks for what constitutes best in class performance for treating children with asthma, bronchiolitis, and pneumonia, researchers recently set out to determine achievable benchmarks of care for the clinical quality indicators that hospitals can target to measure the care they are delivering.

"Even for the most common pediatric conditions, in which there are clear evidence-based guidelines for care, there continues to be significant variability in how well hospitals follow these guidelines," Dr. Kavita Parikh of the Children’s National Medical Center and George Washington School of Medicine in Washington, and her associates, reported in an article scheduled to appear in the September issue of Pediatrics (2014;134:555-62). "We have demonstrated that administrative data can be used to calculate ABCs [achievable benchmarks of care] for the top three admission diagnoses in pediatric hospital care. These ABCs represent measurable and attainable goals for standardization of care, and they can be the starting point for individual hospitals to evaluate their performance to a national standard."

Administrative data from encounters at 42 hospitals during 2012, including 22,186 asthma, 14,882 bronchiolitis, and 12,983 pneumonia encounters were reviewed. The following achievable benchmarks of care were determined:

• For asthma in children 2-18 years: chest radiograph utilization of 24.5%; antibiotic administration, 6.6%; and ipratropium bromide use greater than 2 days, 0%;

• For bronchiolitis in children 2 months-2 years: chest radiograph utilization of 32.4%; viral testing, 0.6%; antibiotic administration, 18.5%; bronchodilator use greater than 2 days of 0%; and steroid use, 6.4%.

• For pneumonia in children 2 months-18 years: complete blood cell count utilization, 28.8%; viral testing, 1.5%; initial narrow-spectrum antibiotic use, 60.7%; erythrocyte sedimentation rate, 3.5%; and C-reactive protein, 0.1%.

The authors said the study had several limitations. The data was based on outcomes at tertiary care hospitals, so it may not be generalizable to the non–tertiary care hospital setting. The authors also were unable to determine if the utilization occurred in the emergency room or in the inpatient setting.

The authors had no financial disclosures.

gtwachtman@frontlinemedcom.com

With no currently accepted benchmarks for what constitutes best in class performance for treating children with asthma, bronchiolitis, and pneumonia, researchers recently set out to determine achievable benchmarks of care for the clinical quality indicators that hospitals can target to measure the care they are delivering.

"Even for the most common pediatric conditions, in which there are clear evidence-based guidelines for care, there continues to be significant variability in how well hospitals follow these guidelines," Dr. Kavita Parikh of the Children’s National Medical Center and George Washington School of Medicine in Washington, and her associates, reported in an article scheduled to appear in the September issue of Pediatrics (2014;134:555-62). "We have demonstrated that administrative data can be used to calculate ABCs [achievable benchmarks of care] for the top three admission diagnoses in pediatric hospital care. These ABCs represent measurable and attainable goals for standardization of care, and they can be the starting point for individual hospitals to evaluate their performance to a national standard."

Administrative data from encounters at 42 hospitals during 2012, including 22,186 asthma, 14,882 bronchiolitis, and 12,983 pneumonia encounters were reviewed. The following achievable benchmarks of care were determined:

• For asthma in children 2-18 years: chest radiograph utilization of 24.5%; antibiotic administration, 6.6%; and ipratropium bromide use greater than 2 days, 0%;

• For bronchiolitis in children 2 months-2 years: chest radiograph utilization of 32.4%; viral testing, 0.6%; antibiotic administration, 18.5%; bronchodilator use greater than 2 days of 0%; and steroid use, 6.4%.

• For pneumonia in children 2 months-18 years: complete blood cell count utilization, 28.8%; viral testing, 1.5%; initial narrow-spectrum antibiotic use, 60.7%; erythrocyte sedimentation rate, 3.5%; and C-reactive protein, 0.1%.

The authors said the study had several limitations. The data was based on outcomes at tertiary care hospitals, so it may not be generalizable to the non–tertiary care hospital setting. The authors also were unable to determine if the utilization occurred in the emergency room or in the inpatient setting.

The authors had no financial disclosures.

gtwachtman@frontlinemedcom.com

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of an inhaled liquid spray formulation of tiotropium bromide in a new delivery device for the long-term maintenance of chronic obstructive pulmonary disease.

At a Aug. 14 meeting of the FDA Pulmonary-Allergy Drugs Advisory Committee, the panel voted 10-3 that the safety and efficacy data supported the approval of tiotropium bromide inhalation spray, at a dose of 5 mcg/day, administered via a device that contains 30 doses, for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations.

The panel unanimously voted that the available data supported the efficacy of the device for the indication. This is the same indication approved for the dry powder formulation of tiotropium in the single dose, breath-actuated device, marketed as Spiriva HandiHaler by Boehringer Ingelheim, approved in 2004 by the FDA.

The Respimat device delivers 5-mcg dose and the HandiHaler device delivers 18-mcg dose, with similar pharmacokinetic effects and systemic exposure, according to the company.

Those voting in favor of approval were reassured by the results of a large safety study that addressed concerns about a cardiovascular mortality signal in earlier studies associated with tiotropium Respimat. Boehringer Ingelheim filed for approval of tiotropium Respimat almost 7 years ago; at that time, the FDA requested more data from the company to support the exacerbation claim and to address the mortality imbalance among those treated with tiotropium Respimat in 48-week placebo-controlled studies, and concerns over cardiovascular safety raised during the review.

The safety study of more than 17,000 patients with COPD followed for at least 2 years adjudicated the cause of deaths, comparing 2.5 mg and 5 mg of tiotropium in the Respimat device to the tiotropium HandiHaler device. All-cause mortality in the three groups was similar. There were more fatal MIs in the Respimat-treated patients, but panelists said that this could be a statistical finding and was not strong enough to vote against approval. Some panelists cited lingering concerns about a cardiovascular safety signal in different studies.

If approved, Boehringer Ingelheim plans to market the product as Spiriva Respimat.

The FDA is expected to make a decision on approval by Sept. 21. The agency usually follows the recommendations of its advisory panels. Panel members had no relevant conflicts of interest to disclose.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of an inhaled liquid spray formulation of tiotropium bromide in a new delivery device for the long-term maintenance of chronic obstructive pulmonary disease.

At a Aug. 14 meeting of the FDA Pulmonary-Allergy Drugs Advisory Committee, the panel voted 10-3 that the safety and efficacy data supported the approval of tiotropium bromide inhalation spray, at a dose of 5 mcg/day, administered via a device that contains 30 doses, for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations.

The panel unanimously voted that the available data supported the efficacy of the device for the indication. This is the same indication approved for the dry powder formulation of tiotropium in the single dose, breath-actuated device, marketed as Spiriva HandiHaler by Boehringer Ingelheim, approved in 2004 by the FDA.

The Respimat device delivers 5-mcg dose and the HandiHaler device delivers 18-mcg dose, with similar pharmacokinetic effects and systemic exposure, according to the company.

Those voting in favor of approval were reassured by the results of a large safety study that addressed concerns about a cardiovascular mortality signal in earlier studies associated with tiotropium Respimat. Boehringer Ingelheim filed for approval of tiotropium Respimat almost 7 years ago; at that time, the FDA requested more data from the company to support the exacerbation claim and to address the mortality imbalance among those treated with tiotropium Respimat in 48-week placebo-controlled studies, and concerns over cardiovascular safety raised during the review.

The safety study of more than 17,000 patients with COPD followed for at least 2 years adjudicated the cause of deaths, comparing 2.5 mg and 5 mg of tiotropium in the Respimat device to the tiotropium HandiHaler device. All-cause mortality in the three groups was similar. There were more fatal MIs in the Respimat-treated patients, but panelists said that this could be a statistical finding and was not strong enough to vote against approval. Some panelists cited lingering concerns about a cardiovascular safety signal in different studies.

If approved, Boehringer Ingelheim plans to market the product as Spiriva Respimat.

The FDA is expected to make a decision on approval by Sept. 21. The agency usually follows the recommendations of its advisory panels. Panel members had no relevant conflicts of interest to disclose.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of an inhaled liquid spray formulation of tiotropium bromide in a new delivery device for the long-term maintenance of chronic obstructive pulmonary disease.

At a Aug. 14 meeting of the FDA Pulmonary-Allergy Drugs Advisory Committee, the panel voted 10-3 that the safety and efficacy data supported the approval of tiotropium bromide inhalation spray, at a dose of 5 mcg/day, administered via a device that contains 30 doses, for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations.

The panel unanimously voted that the available data supported the efficacy of the device for the indication. This is the same indication approved for the dry powder formulation of tiotropium in the single dose, breath-actuated device, marketed as Spiriva HandiHaler by Boehringer Ingelheim, approved in 2004 by the FDA.

The Respimat device delivers 5-mcg dose and the HandiHaler device delivers 18-mcg dose, with similar pharmacokinetic effects and systemic exposure, according to the company.

Those voting in favor of approval were reassured by the results of a large safety study that addressed concerns about a cardiovascular mortality signal in earlier studies associated with tiotropium Respimat. Boehringer Ingelheim filed for approval of tiotropium Respimat almost 7 years ago; at that time, the FDA requested more data from the company to support the exacerbation claim and to address the mortality imbalance among those treated with tiotropium Respimat in 48-week placebo-controlled studies, and concerns over cardiovascular safety raised during the review.

The safety study of more than 17,000 patients with COPD followed for at least 2 years adjudicated the cause of deaths, comparing 2.5 mg and 5 mg of tiotropium in the Respimat device to the tiotropium HandiHaler device. All-cause mortality in the three groups was similar. There were more fatal MIs in the Respimat-treated patients, but panelists said that this could be a statistical finding and was not strong enough to vote against approval. Some panelists cited lingering concerns about a cardiovascular safety signal in different studies.

If approved, Boehringer Ingelheim plans to market the product as Spiriva Respimat.

The FDA is expected to make a decision on approval by Sept. 21. The agency usually follows the recommendations of its advisory panels. Panel members had no relevant conflicts of interest to disclose.

emechcatie@frontlinemedcom.com

A Food and Drug Administration proposal to regulate e-cigarettes does not go far enough, the American Society of Clinical Oncology and the American Association for Cancer Research say.

The two societies offered their general support for the agency’s proposed rule that would broaden its regulatory oversight over tobacco products in general, but offered suggestions to take the proposal even further.

©goldy/Thinkstockphotos.com

In the area of e-cigarettes, the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR) called for the agency to regulate both electronic nicotine delivery systems (ENDS) as well as the component parts such as the liquids sold separately as refills for e-cigarettes. Additionally, the FDA "should develop a product standard that would require all e-liquid refill bottles to be childproof, including childproof caps for eye-dropper refill bottles," the societies said in comments they submitted together to the FDA on the proposed changes. "Future research may point to the need for additional product changes for ENDS, including standards regulating design, constituents, nicotine levels, or other chemicals including ENDS vapor, and we encourage [the] FDA to require such changes as appropriate to protect the public health."

The FDA issued its proposed rule in April.

In a statement, Dr. Roy Herbst, chair of the AACR Tobacco and Cancer Subcommittee and chief of medical oncology at Yale Comprehensive Cancer Center of New Haven, Conn., noted that there is "insufficient data on the long-term health consequences of e-cigarettes, their value as tobacco-cessation aids, or their effects on the use of conventional cigarettes. Any benefits of e-cigarettes are most likely to be realized in a regulated environment in which appropriate safeguards can be implemented."

Other areas highlighted by the groups that reach further than the FDA’s current proposal include product labeling, marketing, and product flavoring.

For example, the groups call for the FDA to strengthen its proposal in the sales, marketing, and advertising area by expressly prohibiting "self-service displays of tobacco products in retail establishments; the provision of gifts and other giveaways with purchase of tobacco products; the sale and distribution of items such as hats or t-shirts with tobacco product brand logos; brand-name sponsorship of athletic, musical, or other social or cultural events, or any team entry into those events; and youth-oriented advertising of tobacco products, including the use of cartoon characters in tobacco product advertising, promotion, packaging, or labeling." These would apply to all tobacco products, including e-cigarettes and cigars.

These marketing restrictions would enhance the FDA’s proposal to require manufacturers to submit new product marketing materials for agency review, AACR and ASCO say. The groups also call for stronger age-verification rules related to the Internet purchase of tobacco products.

gtwachtman@frontlinemedcom.com

A Food and Drug Administration proposal to regulate e-cigarettes does not go far enough, the American Society of Clinical Oncology and the American Association for Cancer Research say.

The two societies offered their general support for the agency’s proposed rule that would broaden its regulatory oversight over tobacco products in general, but offered suggestions to take the proposal even further.

©goldy/Thinkstockphotos.com

In the area of e-cigarettes, the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR) called for the agency to regulate both electronic nicotine delivery systems (ENDS) as well as the component parts such as the liquids sold separately as refills for e-cigarettes. Additionally, the FDA "should develop a product standard that would require all e-liquid refill bottles to be childproof, including childproof caps for eye-dropper refill bottles," the societies said in comments they submitted together to the FDA on the proposed changes. "Future research may point to the need for additional product changes for ENDS, including standards regulating design, constituents, nicotine levels, or other chemicals including ENDS vapor, and we encourage [the] FDA to require such changes as appropriate to protect the public health."

The FDA issued its proposed rule in April.

In a statement, Dr. Roy Herbst, chair of the AACR Tobacco and Cancer Subcommittee and chief of medical oncology at Yale Comprehensive Cancer Center of New Haven, Conn., noted that there is "insufficient data on the long-term health consequences of e-cigarettes, their value as tobacco-cessation aids, or their effects on the use of conventional cigarettes. Any benefits of e-cigarettes are most likely to be realized in a regulated environment in which appropriate safeguards can be implemented."

Other areas highlighted by the groups that reach further than the FDA’s current proposal include product labeling, marketing, and product flavoring.

For example, the groups call for the FDA to strengthen its proposal in the sales, marketing, and advertising area by expressly prohibiting "self-service displays of tobacco products in retail establishments; the provision of gifts and other giveaways with purchase of tobacco products; the sale and distribution of items such as hats or t-shirts with tobacco product brand logos; brand-name sponsorship of athletic, musical, or other social or cultural events, or any team entry into those events; and youth-oriented advertising of tobacco products, including the use of cartoon characters in tobacco product advertising, promotion, packaging, or labeling." These would apply to all tobacco products, including e-cigarettes and cigars.

These marketing restrictions would enhance the FDA’s proposal to require manufacturers to submit new product marketing materials for agency review, AACR and ASCO say. The groups also call for stronger age-verification rules related to the Internet purchase of tobacco products.

gtwachtman@frontlinemedcom.com

A Food and Drug Administration proposal to regulate e-cigarettes does not go far enough, the American Society of Clinical Oncology and the American Association for Cancer Research say.

The two societies offered their general support for the agency’s proposed rule that would broaden its regulatory oversight over tobacco products in general, but offered suggestions to take the proposal even further.

©goldy/Thinkstockphotos.com

In the area of e-cigarettes, the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR) called for the agency to regulate both electronic nicotine delivery systems (ENDS) as well as the component parts such as the liquids sold separately as refills for e-cigarettes. Additionally, the FDA "should develop a product standard that would require all e-liquid refill bottles to be childproof, including childproof caps for eye-dropper refill bottles," the societies said in comments they submitted together to the FDA on the proposed changes. "Future research may point to the need for additional product changes for ENDS, including standards regulating design, constituents, nicotine levels, or other chemicals including ENDS vapor, and we encourage [the] FDA to require such changes as appropriate to protect the public health."

The FDA issued its proposed rule in April.

In a statement, Dr. Roy Herbst, chair of the AACR Tobacco and Cancer Subcommittee and chief of medical oncology at Yale Comprehensive Cancer Center of New Haven, Conn., noted that there is "insufficient data on the long-term health consequences of e-cigarettes, their value as tobacco-cessation aids, or their effects on the use of conventional cigarettes. Any benefits of e-cigarettes are most likely to be realized in a regulated environment in which appropriate safeguards can be implemented."

Other areas highlighted by the groups that reach further than the FDA’s current proposal include product labeling, marketing, and product flavoring.

For example, the groups call for the FDA to strengthen its proposal in the sales, marketing, and advertising area by expressly prohibiting "self-service displays of tobacco products in retail establishments; the provision of gifts and other giveaways with purchase of tobacco products; the sale and distribution of items such as hats or t-shirts with tobacco product brand logos; brand-name sponsorship of athletic, musical, or other social or cultural events, or any team entry into those events; and youth-oriented advertising of tobacco products, including the use of cartoon characters in tobacco product advertising, promotion, packaging, or labeling." These would apply to all tobacco products, including e-cigarettes and cigars.

These marketing restrictions would enhance the FDA’s proposal to require manufacturers to submit new product marketing materials for agency review, AACR and ASCO say. The groups also call for stronger age-verification rules related to the Internet purchase of tobacco products.

gtwachtman@frontlinemedcom.com

Just over one-third of college students were at risk for one sleeping disorder, and one in five were at risk for a mental disorder, a recent study found.

"Participants at risk for sleep disorders were more likely to have poor health, lower working memory capacity, and more psychological symptoms than normal sleepers," Megan Petrov of the University of Alabama, Tuscaloosa, and her associates reported in the July issue of the Journal of Adolescence (2014;37:587-97).

The researchers used online questionnaires to assess insomnia symptoms, sleep quality, working memory, and the physical and mental health of 1,684 undergraduate college students at the university. The students, recruited in 2010 and 2011, were primarily women (77%). In addition, most were non-Hispanic white (77%), and the mean body mass index (BMI) was 23.5 plus or minus 4.7.

The researchers found that 36% of the students screened positive for having a sleep disorder, most commonly insomnia, restless legs syndrome, and periodic limb movement disorder, and 6.3% screened positive for at least two sleeping disorders. Only 10% of the students reported having a mental disorder diagnosis, but 20% reported frequent symptoms of sadness and anxiety.

Although nightmares and obstructive sleep apnea were less common, those with nightmares or parasomnias were more likely to have mental disorders. Women had a higher risk than men for sleep disorders – especially insomnia – and were more likely to report mental health problems. Meanwhile, African American respondents had fewer mental health diagnoses but higher BMIs, and were more likely to report having poorer physical health, compared with other ethnic groups.

Overall, the researchers reported that daytime sleepiness and other difficulties in daytime functioning due to sleep disturbances were common among these college students.

"Swift and accurate diagnosis and treatment of sleep disorders, particularly among vulnerable subgroups of college students, may improve academic performance, cognition and working memory, [and] physical and mental health, and reduce dropout rates," the researchers concluded.

The researchers cited several limitations of their study. Because the sample was not selected randomly, it is not possible to generalize the results beyond college students with similar characteristics.

The research did not use external funding, and the authors reported no disclosures.

Just over one-third of college students were at risk for one sleeping disorder, and one in five were at risk for a mental disorder, a recent study found.

"Participants at risk for sleep disorders were more likely to have poor health, lower working memory capacity, and more psychological symptoms than normal sleepers," Megan Petrov of the University of Alabama, Tuscaloosa, and her associates reported in the July issue of the Journal of Adolescence (2014;37:587-97).

The researchers used online questionnaires to assess insomnia symptoms, sleep quality, working memory, and the physical and mental health of 1,684 undergraduate college students at the university. The students, recruited in 2010 and 2011, were primarily women (77%). In addition, most were non-Hispanic white (77%), and the mean body mass index (BMI) was 23.5 plus or minus 4.7.

The researchers found that 36% of the students screened positive for having a sleep disorder, most commonly insomnia, restless legs syndrome, and periodic limb movement disorder, and 6.3% screened positive for at least two sleeping disorders. Only 10% of the students reported having a mental disorder diagnosis, but 20% reported frequent symptoms of sadness and anxiety.

Although nightmares and obstructive sleep apnea were less common, those with nightmares or parasomnias were more likely to have mental disorders. Women had a higher risk than men for sleep disorders – especially insomnia – and were more likely to report mental health problems. Meanwhile, African American respondents had fewer mental health diagnoses but higher BMIs, and were more likely to report having poorer physical health, compared with other ethnic groups.

Overall, the researchers reported that daytime sleepiness and other difficulties in daytime functioning due to sleep disturbances were common among these college students.

"Swift and accurate diagnosis and treatment of sleep disorders, particularly among vulnerable subgroups of college students, may improve academic performance, cognition and working memory, [and] physical and mental health, and reduce dropout rates," the researchers concluded.

The researchers cited several limitations of their study. Because the sample was not selected randomly, it is not possible to generalize the results beyond college students with similar characteristics.

The research did not use external funding, and the authors reported no disclosures.

Just over one-third of college students were at risk for one sleeping disorder, and one in five were at risk for a mental disorder, a recent study found.

"Participants at risk for sleep disorders were more likely to have poor health, lower working memory capacity, and more psychological symptoms than normal sleepers," Megan Petrov of the University of Alabama, Tuscaloosa, and her associates reported in the July issue of the Journal of Adolescence (2014;37:587-97).

The researchers used online questionnaires to assess insomnia symptoms, sleep quality, working memory, and the physical and mental health of 1,684 undergraduate college students at the university. The students, recruited in 2010 and 2011, were primarily women (77%). In addition, most were non-Hispanic white (77%), and the mean body mass index (BMI) was 23.5 plus or minus 4.7.

The researchers found that 36% of the students screened positive for having a sleep disorder, most commonly insomnia, restless legs syndrome, and periodic limb movement disorder, and 6.3% screened positive for at least two sleeping disorders. Only 10% of the students reported having a mental disorder diagnosis, but 20% reported frequent symptoms of sadness and anxiety.

Although nightmares and obstructive sleep apnea were less common, those with nightmares or parasomnias were more likely to have mental disorders. Women had a higher risk than men for sleep disorders – especially insomnia – and were more likely to report mental health problems. Meanwhile, African American respondents had fewer mental health diagnoses but higher BMIs, and were more likely to report having poorer physical health, compared with other ethnic groups.

Overall, the researchers reported that daytime sleepiness and other difficulties in daytime functioning due to sleep disturbances were common among these college students.

"Swift and accurate diagnosis and treatment of sleep disorders, particularly among vulnerable subgroups of college students, may improve academic performance, cognition and working memory, [and] physical and mental health, and reduce dropout rates," the researchers concluded.

The researchers cited several limitations of their study. Because the sample was not selected randomly, it is not possible to generalize the results beyond college students with similar characteristics.

The research did not use external funding, and the authors reported no disclosures.

At least 16 of nearly 54,000 unaccompanied children from Central America have been hospitalized with respiratory diseases, Dr. Edith N. Nyangoma and her associates reported August 15 in Morbidity and Mortality Weekly Report (63(32);698-99).

The cases were in persons aged 14–17 years, and diagnoses included laboratory-confirmed pneumococcal pneumonia with laboratory-confirmed influenza (three cases) and without laboratory-confirmed influenza (four cases), influenza pneumonia (one case), and pneumonia with no identified etiology (eight cases).

Five patients experienced septic shock requiring intensive care. No case was fatal. All six cases for which pneumococcal isolates were available were identified as serotype 5, a serotype included in the 13-valent pneumococcal conjugate vaccine (PCV13) (Prevnar-13, Pfizer). Of the 16 patients identified in this cluster, 11 were tested for influenza viruses; four (36%) were positive (two for influenza A[H1N1]pdm09, one for influenza B, and one for influenza A by rapid test), according to the report.

In response to the findings, officials at the Centers for Disease Control have recommended that all unaccompanied children residing in temporary or standard shelters receive influenza vaccine and PCV13 in addition to routinely recommended vaccines. Among the 2,000 children thus far vaccinated in four affected shelters, there have been no serious adverse events.

Routine annual influenza vaccination is recommended for all persons in the United States who are at least age 6 months, but school-aged children in Central America generally are not targeted for vaccination.

PCV13 is routinely given in the United States at age 2–59 months. It is recommended for the older unaccompanied children because of the unexpected number of pneumococcal pneumonia cases occurring in the context of crowded conditions.

Additional information about the ongoing humanitarian and public health response is available at http://emergency.cdc.gov/children/unaccompanied/index.asp.

At least 16 of nearly 54,000 unaccompanied children from Central America have been hospitalized with respiratory diseases, Dr. Edith N. Nyangoma and her associates reported August 15 in Morbidity and Mortality Weekly Report (63(32);698-99).

The cases were in persons aged 14–17 years, and diagnoses included laboratory-confirmed pneumococcal pneumonia with laboratory-confirmed influenza (three cases) and without laboratory-confirmed influenza (four cases), influenza pneumonia (one case), and pneumonia with no identified etiology (eight cases).

Five patients experienced septic shock requiring intensive care. No case was fatal. All six cases for which pneumococcal isolates were available were identified as serotype 5, a serotype included in the 13-valent pneumococcal conjugate vaccine (PCV13) (Prevnar-13, Pfizer). Of the 16 patients identified in this cluster, 11 were tested for influenza viruses; four (36%) were positive (two for influenza A[H1N1]pdm09, one for influenza B, and one for influenza A by rapid test), according to the report.

In response to the findings, officials at the Centers for Disease Control have recommended that all unaccompanied children residing in temporary or standard shelters receive influenza vaccine and PCV13 in addition to routinely recommended vaccines. Among the 2,000 children thus far vaccinated in four affected shelters, there have been no serious adverse events.

Routine annual influenza vaccination is recommended for all persons in the United States who are at least age 6 months, but school-aged children in Central America generally are not targeted for vaccination.

PCV13 is routinely given in the United States at age 2–59 months. It is recommended for the older unaccompanied children because of the unexpected number of pneumococcal pneumonia cases occurring in the context of crowded conditions.

Additional information about the ongoing humanitarian and public health response is available at http://emergency.cdc.gov/children/unaccompanied/index.asp.

At least 16 of nearly 54,000 unaccompanied children from Central America have been hospitalized with respiratory diseases, Dr. Edith N. Nyangoma and her associates reported August 15 in Morbidity and Mortality Weekly Report (63(32);698-99).

The cases were in persons aged 14–17 years, and diagnoses included laboratory-confirmed pneumococcal pneumonia with laboratory-confirmed influenza (three cases) and without laboratory-confirmed influenza (four cases), influenza pneumonia (one case), and pneumonia with no identified etiology (eight cases).

Five patients experienced septic shock requiring intensive care. No case was fatal. All six cases for which pneumococcal isolates were available were identified as serotype 5, a serotype included in the 13-valent pneumococcal conjugate vaccine (PCV13) (Prevnar-13, Pfizer). Of the 16 patients identified in this cluster, 11 were tested for influenza viruses; four (36%) were positive (two for influenza A[H1N1]pdm09, one for influenza B, and one for influenza A by rapid test), according to the report.

In response to the findings, officials at the Centers for Disease Control have recommended that all unaccompanied children residing in temporary or standard shelters receive influenza vaccine and PCV13 in addition to routinely recommended vaccines. Among the 2,000 children thus far vaccinated in four affected shelters, there have been no serious adverse events.

Routine annual influenza vaccination is recommended for all persons in the United States who are at least age 6 months, but school-aged children in Central America generally are not targeted for vaccination.

PCV13 is routinely given in the United States at age 2–59 months. It is recommended for the older unaccompanied children because of the unexpected number of pneumococcal pneumonia cases occurring in the context of crowded conditions.

Additional information about the ongoing humanitarian and public health response is available at http://emergency.cdc.gov/children/unaccompanied/index.asp.

Shift workers often use drugs to try to sleep during the day or stay awake at night, but limited evidence supports the efficacy of these agents, according to a Cochrane Database review of 15 placebo-controlled studies.

"The evidence was of low quality and mostly from small trials," said Dr. Juha Liira of the Finnish Institute of Occupational Health in Helsinki and her associates. "Both sleep- and alertness-promoting agents have potentially serious adverse effects. Therefore, we need more trials to determine the beneficial and harmful effects of these drugs."

©Monkey Business Images Ltd/Thinkstock

The strongest evidence was for the ability of modafinil and armodafinil to promote wakefulness during shift work, but these drugs can pose substantial risks, the authors said.

The review uncovered low-quality evidence for melatonin as a daytime sleep promoter and for caffeine to enhance nighttime wakefulness, the authors said, adding that hypnotics did not affect sleep length or quality after night work.

For the study, reviewers searched the CENTRAL, MEDLINE, EMBASE, PubMed, and PsycINFO databases through September 2013 and ClinicalTrials.gov up to July 2013. They included all randomized, controlled trials, including crossover trials, of pharmacologic agents in shift workers, whether or not the subjects had sleep problems (Cochrane Database Syst. Rev. 2014 Aug. 12 [doi:10.1002/14651858.CD009776.pub2]) They excluded trials that simulated shift work tasks, noting that such studies probably do not approximate shift work in real life. They also excluded studies of airline and military personnel because melatonin has already been reviewed for jet lag (Cochrane Database Syst. Rev. 2002;2:CD001520).

The search yielded 15 randomized, placebo-controlled trials with a total of 718 participants. Nine trials assessed melatonin, two examined hypnotics, three looked at modafinil or armodafinil, and one assessed caffeine, they reported.

Modafinil (200 mg) and armodafinil (150 mg) improved wakefulness and alertness during night shifts at 3-month follow-up, compared with placebo, the researchers said. But armodafinil cut sleepiness by a mean of just one point on the Karolinska Sleepiness Scale (KSS) (range, 1-9 points; 95% confidence interval, -1.32 to -0.67), and improved reaction time by only 50 ms (95% CI, -85.5 to -15.5 ms), they added. "Modafinil probably has similar effects on sleepiness," the reviewers concluded, noting that the drug decreased sleepiness by 0.9 points on the KSS (95% CI, -1.45 to -0.35) while also heightening alertness in a psychomotor vigilance test.

Armodafinil and modafinil also have been linked to serious skin disorders in postmarketing reports, the researchers emphasized. And the drugs caused headache, nausea, and increased blood pressure in clinical trials, they said.

Caffeine at a dose of 300 mg or 4 mg/kg improved alertness during night shifts when combined with a preshift nap, the reviewers said. But the effect size in the single trial was small, with a mean improvement of only 0.63 points on the KSS (95% CI, -1.09 to -0.17), they added.

Melatonin had only low-quality evidence as a sleep promoter, the reviewers said. A dose of 1-10 mg lengthened daytime sleep by an average of 24 minutes, compared with placebo in seven trials of 263 shift workers (95% CI, 9.82-38.86), and added 17 minutes to nighttime sleep in three trials of 234 participants (95% CI, 3.71-30.22), but did not significantly affect other sleep parameters such as sleep latency, they reported.

The only trial of the hypnotic drug zopiclone (7.5 mg) included just 28 participants and found that the agent did not lengthen daytime sleep significantly more than did placebo (mean difference, 44 minutes; 95% CI, -22.67-110.67), while no trials examined adverse effects of hypnotics in shift workers, the reviewers said.

"We need more and better quality trials on the beneficial and adverse effects and costs of all pharmacological agents that induce sleep or promote alertness in shift workers, both with and without a diagnosis of shift work sleep disorder," Dr. Liira and associates concluded. "We also need systematic reviews of their adverse effects."

Most of the melatonin trials had a high risk of bias, so the reviewers downgraded their rating from a high to a low level of quality, they said. They similarly downgraded trials for armodafinil, modafinil, caffeine, and hypnotics.

The Finnish Institute of Occupational Health pays the salary of Dr. Liira and four coauthors. There were no external funding sources or conflicts of interest.

Shift workers often use drugs to try to sleep during the day or stay awake at night, but limited evidence supports the efficacy of these agents, according to a Cochrane Database review of 15 placebo-controlled studies.

"The evidence was of low quality and mostly from small trials," said Dr. Juha Liira of the Finnish Institute of Occupational Health in Helsinki and her associates. "Both sleep- and alertness-promoting agents have potentially serious adverse effects. Therefore, we need more trials to determine the beneficial and harmful effects of these drugs."

©Monkey Business Images Ltd/Thinkstock

The strongest evidence was for the ability of modafinil and armodafinil to promote wakefulness during shift work, but these drugs can pose substantial risks, the authors said.

The review uncovered low-quality evidence for melatonin as a daytime sleep promoter and for caffeine to enhance nighttime wakefulness, the authors said, adding that hypnotics did not affect sleep length or quality after night work.

For the study, reviewers searched the CENTRAL, MEDLINE, EMBASE, PubMed, and PsycINFO databases through September 2013 and ClinicalTrials.gov up to July 2013. They included all randomized, controlled trials, including crossover trials, of pharmacologic agents in shift workers, whether or not the subjects had sleep problems (Cochrane Database Syst. Rev. 2014 Aug. 12 [doi:10.1002/14651858.CD009776.pub2]) They excluded trials that simulated shift work tasks, noting that such studies probably do not approximate shift work in real life. They also excluded studies of airline and military personnel because melatonin has already been reviewed for jet lag (Cochrane Database Syst. Rev. 2002;2:CD001520).

The search yielded 15 randomized, placebo-controlled trials with a total of 718 participants. Nine trials assessed melatonin, two examined hypnotics, three looked at modafinil or armodafinil, and one assessed caffeine, they reported.

Modafinil (200 mg) and armodafinil (150 mg) improved wakefulness and alertness during night shifts at 3-month follow-up, compared with placebo, the researchers said. But armodafinil cut sleepiness by a mean of just one point on the Karolinska Sleepiness Scale (KSS) (range, 1-9 points; 95% confidence interval, -1.32 to -0.67), and improved reaction time by only 50 ms (95% CI, -85.5 to -15.5 ms), they added. "Modafinil probably has similar effects on sleepiness," the reviewers concluded, noting that the drug decreased sleepiness by 0.9 points on the KSS (95% CI, -1.45 to -0.35) while also heightening alertness in a psychomotor vigilance test.

Armodafinil and modafinil also have been linked to serious skin disorders in postmarketing reports, the researchers emphasized. And the drugs caused headache, nausea, and increased blood pressure in clinical trials, they said.

Caffeine at a dose of 300 mg or 4 mg/kg improved alertness during night shifts when combined with a preshift nap, the reviewers said. But the effect size in the single trial was small, with a mean improvement of only 0.63 points on the KSS (95% CI, -1.09 to -0.17), they added.

Melatonin had only low-quality evidence as a sleep promoter, the reviewers said. A dose of 1-10 mg lengthened daytime sleep by an average of 24 minutes, compared with placebo in seven trials of 263 shift workers (95% CI, 9.82-38.86), and added 17 minutes to nighttime sleep in three trials of 234 participants (95% CI, 3.71-30.22), but did not significantly affect other sleep parameters such as sleep latency, they reported.

The only trial of the hypnotic drug zopiclone (7.5 mg) included just 28 participants and found that the agent did not lengthen daytime sleep significantly more than did placebo (mean difference, 44 minutes; 95% CI, -22.67-110.67), while no trials examined adverse effects of hypnotics in shift workers, the reviewers said.

"We need more and better quality trials on the beneficial and adverse effects and costs of all pharmacological agents that induce sleep or promote alertness in shift workers, both with and without a diagnosis of shift work sleep disorder," Dr. Liira and associates concluded. "We also need systematic reviews of their adverse effects."

Most of the melatonin trials had a high risk of bias, so the reviewers downgraded their rating from a high to a low level of quality, they said. They similarly downgraded trials for armodafinil, modafinil, caffeine, and hypnotics.

The Finnish Institute of Occupational Health pays the salary of Dr. Liira and four coauthors. There were no external funding sources or conflicts of interest.

Shift workers often use drugs to try to sleep during the day or stay awake at night, but limited evidence supports the efficacy of these agents, according to a Cochrane Database review of 15 placebo-controlled studies.

"The evidence was of low quality and mostly from small trials," said Dr. Juha Liira of the Finnish Institute of Occupational Health in Helsinki and her associates. "Both sleep- and alertness-promoting agents have potentially serious adverse effects. Therefore, we need more trials to determine the beneficial and harmful effects of these drugs."

©Monkey Business Images Ltd/Thinkstock

The strongest evidence was for the ability of modafinil and armodafinil to promote wakefulness during shift work, but these drugs can pose substantial risks, the authors said.

The review uncovered low-quality evidence for melatonin as a daytime sleep promoter and for caffeine to enhance nighttime wakefulness, the authors said, adding that hypnotics did not affect sleep length or quality after night work.

For the study, reviewers searched the CENTRAL, MEDLINE, EMBASE, PubMed, and PsycINFO databases through September 2013 and ClinicalTrials.gov up to July 2013. They included all randomized, controlled trials, including crossover trials, of pharmacologic agents in shift workers, whether or not the subjects had sleep problems (Cochrane Database Syst. Rev. 2014 Aug. 12 [doi:10.1002/14651858.CD009776.pub2]) They excluded trials that simulated shift work tasks, noting that such studies probably do not approximate shift work in real life. They also excluded studies of airline and military personnel because melatonin has already been reviewed for jet lag (Cochrane Database Syst. Rev. 2002;2:CD001520).

The search yielded 15 randomized, placebo-controlled trials with a total of 718 participants. Nine trials assessed melatonin, two examined hypnotics, three looked at modafinil or armodafinil, and one assessed caffeine, they reported.

Modafinil (200 mg) and armodafinil (150 mg) improved wakefulness and alertness during night shifts at 3-month follow-up, compared with placebo, the researchers said. But armodafinil cut sleepiness by a mean of just one point on the Karolinska Sleepiness Scale (KSS) (range, 1-9 points; 95% confidence interval, -1.32 to -0.67), and improved reaction time by only 50 ms (95% CI, -85.5 to -15.5 ms), they added. "Modafinil probably has similar effects on sleepiness," the reviewers concluded, noting that the drug decreased sleepiness by 0.9 points on the KSS (95% CI, -1.45 to -0.35) while also heightening alertness in a psychomotor vigilance test.

Armodafinil and modafinil also have been linked to serious skin disorders in postmarketing reports, the researchers emphasized. And the drugs caused headache, nausea, and increased blood pressure in clinical trials, they said.

Caffeine at a dose of 300 mg or 4 mg/kg improved alertness during night shifts when combined with a preshift nap, the reviewers said. But the effect size in the single trial was small, with a mean improvement of only 0.63 points on the KSS (95% CI, -1.09 to -0.17), they added.

Melatonin had only low-quality evidence as a sleep promoter, the reviewers said. A dose of 1-10 mg lengthened daytime sleep by an average of 24 minutes, compared with placebo in seven trials of 263 shift workers (95% CI, 9.82-38.86), and added 17 minutes to nighttime sleep in three trials of 234 participants (95% CI, 3.71-30.22), but did not significantly affect other sleep parameters such as sleep latency, they reported.

The only trial of the hypnotic drug zopiclone (7.5 mg) included just 28 participants and found that the agent did not lengthen daytime sleep significantly more than did placebo (mean difference, 44 minutes; 95% CI, -22.67-110.67), while no trials examined adverse effects of hypnotics in shift workers, the reviewers said.

"We need more and better quality trials on the beneficial and adverse effects and costs of all pharmacological agents that induce sleep or promote alertness in shift workers, both with and without a diagnosis of shift work sleep disorder," Dr. Liira and associates concluded. "We also need systematic reviews of their adverse effects."

Most of the melatonin trials had a high risk of bias, so the reviewers downgraded their rating from a high to a low level of quality, they said. They similarly downgraded trials for armodafinil, modafinil, caffeine, and hypnotics.

The Finnish Institute of Occupational Health pays the salary of Dr. Liira and four coauthors. There were no external funding sources or conflicts of interest.

Adults aged 65 years and older should receive both a conjugate and polysaccharide vaccine against pneumococcal pneumonia, according to a new federal proposal.

By a vote of 13-2, a working group of the Advisory Committee on Immunization Practices agreed that a combination of the pneumococcal 13-valent conjugate vaccine (PCV13) and the 23-valent polysaccharide vaccine (PPSV23) will provide the most complete protection for older patients.

For those who have never been vaccinated against pneumococcal pneumonia, or who aren’t sure of their vaccination status, the preferred sequence would be PCV13 first, followed by the PPSV23 vaccine within a minimum of 6-12 months – although that time frame should be considered a very flexible one. But the recommendation also accommodates people who have already had either vaccine, experts advised at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

Those who have had PCV13 should get the PPSV23 within the 6-12 month framework if possible; the two vaccines should not be coadministered.

Those who have been vaccinated with PPSV23 only should receive the PCV13 at least 1 year later. High-risk patients who require an additional dose can receive another PPSV23 6-12 months after PCV13 vaccination.

The recommendation will be passed on to the full committee at its meeting in late October. It was made in a special interim meeting, during which the committee considered evidence provided by the randomized, controlled CAPITA study, and additional information on how herd immunization effects in younger people could impact the vulnerability of older people.

Although the clinical recommendation was made by a body of the Centers for Disease Control and Prevention, the federal body controlling reimbursement has extant policies that could limit its practical implementation. Medicare currently pays for only one pneumococcal pneumonia vaccine for adults aged 65 years and older. Although the Centers for Medicare & Medicaid Services (CMS) would consider amending that if the recommendation is adopted, any change would not be quick, a representative said.

"If CMS decided to go with a change in coverage for a two-shot regimen, that does take time," said Dr. Joseph Chin, medical officer for the agency’s Coverage and Analysis Group.

In most cases, the initial topic is addressed at the beginning of the year, followed by a period of public comment.

"The final okay is typically given in November, and the change is effective in January," Dr. Chin said.

Results of the CAPITA study, sponsored by Pfizer, which manufactures the vaccine, were released in March.

It concluded that the PCV13 vaccine offered significant protection against community-acquired pneumonia caused by strains in the vaccine, with 45% fewer episodes than in those who got the placebo.

There were also 45% fewer first episodes of nonbacteremic and noninvasive pneumonias and 75% fewer first episodes of invasive pneumonia, compared with placebo. The safety profile was good, and, according to the working group, the cost/benefit analysis is in line with other treatments that are considered cost-effective.

None of the committee members had any personal financial disclosures.

msullivan@frontlinemedcom.com

Adults aged 65 years and older should receive both a conjugate and polysaccharide vaccine against pneumococcal pneumonia, according to a new federal proposal.

By a vote of 13-2, a working group of the Advisory Committee on Immunization Practices agreed that a combination of the pneumococcal 13-valent conjugate vaccine (PCV13) and the 23-valent polysaccharide vaccine (PPSV23) will provide the most complete protection for older patients.

For those who have never been vaccinated against pneumococcal pneumonia, or who aren’t sure of their vaccination status, the preferred sequence would be PCV13 first, followed by the PPSV23 vaccine within a minimum of 6-12 months – although that time frame should be considered a very flexible one. But the recommendation also accommodates people who have already had either vaccine, experts advised at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

Those who have had PCV13 should get the PPSV23 within the 6-12 month framework if possible; the two vaccines should not be coadministered.

Those who have been vaccinated with PPSV23 only should receive the PCV13 at least 1 year later. High-risk patients who require an additional dose can receive another PPSV23 6-12 months after PCV13 vaccination.

The recommendation will be passed on to the full committee at its meeting in late October. It was made in a special interim meeting, during which the committee considered evidence provided by the randomized, controlled CAPITA study, and additional information on how herd immunization effects in younger people could impact the vulnerability of older people.

Although the clinical recommendation was made by a body of the Centers for Disease Control and Prevention, the federal body controlling reimbursement has extant policies that could limit its practical implementation. Medicare currently pays for only one pneumococcal pneumonia vaccine for adults aged 65 years and older. Although the Centers for Medicare & Medicaid Services (CMS) would consider amending that if the recommendation is adopted, any change would not be quick, a representative said.

"If CMS decided to go with a change in coverage for a two-shot regimen, that does take time," said Dr. Joseph Chin, medical officer for the agency’s Coverage and Analysis Group.

In most cases, the initial topic is addressed at the beginning of the year, followed by a period of public comment.

"The final okay is typically given in November, and the change is effective in January," Dr. Chin said.

Results of the CAPITA study, sponsored by Pfizer, which manufactures the vaccine, were released in March.

It concluded that the PCV13 vaccine offered significant protection against community-acquired pneumonia caused by strains in the vaccine, with 45% fewer episodes than in those who got the placebo.

There were also 45% fewer first episodes of nonbacteremic and noninvasive pneumonias and 75% fewer first episodes of invasive pneumonia, compared with placebo. The safety profile was good, and, according to the working group, the cost/benefit analysis is in line with other treatments that are considered cost-effective.

None of the committee members had any personal financial disclosures.

msullivan@frontlinemedcom.com

Adults aged 65 years and older should receive both a conjugate and polysaccharide vaccine against pneumococcal pneumonia, according to a new federal proposal.

By a vote of 13-2, a working group of the Advisory Committee on Immunization Practices agreed that a combination of the pneumococcal 13-valent conjugate vaccine (PCV13) and the 23-valent polysaccharide vaccine (PPSV23) will provide the most complete protection for older patients.

For those who have never been vaccinated against pneumococcal pneumonia, or who aren’t sure of their vaccination status, the preferred sequence would be PCV13 first, followed by the PPSV23 vaccine within a minimum of 6-12 months – although that time frame should be considered a very flexible one. But the recommendation also accommodates people who have already had either vaccine, experts advised at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

Those who have had PCV13 should get the PPSV23 within the 6-12 month framework if possible; the two vaccines should not be coadministered.

Those who have been vaccinated with PPSV23 only should receive the PCV13 at least 1 year later. High-risk patients who require an additional dose can receive another PPSV23 6-12 months after PCV13 vaccination.

The recommendation will be passed on to the full committee at its meeting in late October. It was made in a special interim meeting, during which the committee considered evidence provided by the randomized, controlled CAPITA study, and additional information on how herd immunization effects in younger people could impact the vulnerability of older people.

Although the clinical recommendation was made by a body of the Centers for Disease Control and Prevention, the federal body controlling reimbursement has extant policies that could limit its practical implementation. Medicare currently pays for only one pneumococcal pneumonia vaccine for adults aged 65 years and older. Although the Centers for Medicare & Medicaid Services (CMS) would consider amending that if the recommendation is adopted, any change would not be quick, a representative said.

"If CMS decided to go with a change in coverage for a two-shot regimen, that does take time," said Dr. Joseph Chin, medical officer for the agency’s Coverage and Analysis Group.

In most cases, the initial topic is addressed at the beginning of the year, followed by a period of public comment.

"The final okay is typically given in November, and the change is effective in January," Dr. Chin said.

Results of the CAPITA study, sponsored by Pfizer, which manufactures the vaccine, were released in March.

It concluded that the PCV13 vaccine offered significant protection against community-acquired pneumonia caused by strains in the vaccine, with 45% fewer episodes than in those who got the placebo.

There were also 45% fewer first episodes of nonbacteremic and noninvasive pneumonias and 75% fewer first episodes of invasive pneumonia, compared with placebo. The safety profile was good, and, according to the working group, the cost/benefit analysis is in line with other treatments that are considered cost-effective.

None of the committee members had any personal financial disclosures.

msullivan@frontlinemedcom.com

The Food and Drug Administration has approved a new type of insomnia drug, the orexin receptor antagonist suvorexant (Belsomra).

It is the first drug in the class to be approved. Suvorexant blocks the binding of orexin A and B neuropeptides to orexin receptors, presumably inhibiting activation of neurons to the arousal system.

But it will not be available until the Drug Enforcement Administration makes a final determination of where it should fit on the schedule of controlled products. The FDA recommended scheduling, and the DEA proposed earlier this year that it receive a schedule IV classification under the Controlled Substances Act, according to suvorexant maker Merck.

The company said it expects suvorexant to be available in late 2014 or early 2015.

Merck had applied for approval in 2012. In May 2013, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee had questions about the safety of the company’s proposed starting doses. A few months later, the FDA advised Merck that it should make 10 mg the starting dose for most patients.

The company had not been prepared to manufacture that dose, so went back to work and created several new tablets.

Now, according to Dr. Ellis Unger, director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research, "the FDA has approved Belsomra in four different strengths – 5, 10, 15, and 20 milligrams." Dr. Unger, in a statement, noted that "Using the lowest effective dose can reduce the risk of side effects, such as next-morning drowsiness."

The agency and the company say that suvorexant should only be taken once per night, within a half hour of going to bed and at least 7 hours before the person plans to wake up. Patients should not take more than 20 mg a day.

Drowsiness was the most common side effect. In FDA-required studies of next-day driving performance, patients who took 20 mg had impaired performance. Patients who take 20 mg should be warned about driving or conducting any activities that require mental alertness the next day, said the agency.

The drug also has the potential to lead to what the FDA calls "sleep-driving and other complex behaviors while not being fully awake," including preparing and eating food, making phone calls, or having sex. Patients and their families are urged to call their physician if that type of behavior is observed.

Suvorexant will be dispensed with a Medication Guide for patients that details safety information.

Although the drug was studied in three trials, none involved a comparison with other approved insomnia drugs, so its comparative effectiveness is not known, the FDA said.

aault@frontlinemedcom.com

On Twitter @aliciaault

The Food and Drug Administration has approved a new type of insomnia drug, the orexin receptor antagonist suvorexant (Belsomra).

It is the first drug in the class to be approved. Suvorexant blocks the binding of orexin A and B neuropeptides to orexin receptors, presumably inhibiting activation of neurons to the arousal system.

But it will not be available until the Drug Enforcement Administration makes a final determination of where it should fit on the schedule of controlled products. The FDA recommended scheduling, and the DEA proposed earlier this year that it receive a schedule IV classification under the Controlled Substances Act, according to suvorexant maker Merck.

The company said it expects suvorexant to be available in late 2014 or early 2015.

Merck had applied for approval in 2012. In May 2013, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee had questions about the safety of the company’s proposed starting doses. A few months later, the FDA advised Merck that it should make 10 mg the starting dose for most patients.

The company had not been prepared to manufacture that dose, so went back to work and created several new tablets.

Now, according to Dr. Ellis Unger, director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research, "the FDA has approved Belsomra in four different strengths – 5, 10, 15, and 20 milligrams." Dr. Unger, in a statement, noted that "Using the lowest effective dose can reduce the risk of side effects, such as next-morning drowsiness."

The agency and the company say that suvorexant should only be taken once per night, within a half hour of going to bed and at least 7 hours before the person plans to wake up. Patients should not take more than 20 mg a day.

Drowsiness was the most common side effect. In FDA-required studies of next-day driving performance, patients who took 20 mg had impaired performance. Patients who take 20 mg should be warned about driving or conducting any activities that require mental alertness the next day, said the agency.

The drug also has the potential to lead to what the FDA calls "sleep-driving and other complex behaviors while not being fully awake," including preparing and eating food, making phone calls, or having sex. Patients and their families are urged to call their physician if that type of behavior is observed.

Suvorexant will be dispensed with a Medication Guide for patients that details safety information.

Although the drug was studied in three trials, none involved a comparison with other approved insomnia drugs, so its comparative effectiveness is not known, the FDA said.

aault@frontlinemedcom.com

On Twitter @aliciaault

The Food and Drug Administration has approved a new type of insomnia drug, the orexin receptor antagonist suvorexant (Belsomra).

It is the first drug in the class to be approved. Suvorexant blocks the binding of orexin A and B neuropeptides to orexin receptors, presumably inhibiting activation of neurons to the arousal system.

But it will not be available until the Drug Enforcement Administration makes a final determination of where it should fit on the schedule of controlled products. The FDA recommended scheduling, and the DEA proposed earlier this year that it receive a schedule IV classification under the Controlled Substances Act, according to suvorexant maker Merck.

The company said it expects suvorexant to be available in late 2014 or early 2015.

Merck had applied for approval in 2012. In May 2013, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee had questions about the safety of the company’s proposed starting doses. A few months later, the FDA advised Merck that it should make 10 mg the starting dose for most patients.

The company had not been prepared to manufacture that dose, so went back to work and created several new tablets.

Now, according to Dr. Ellis Unger, director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research, "the FDA has approved Belsomra in four different strengths – 5, 10, 15, and 20 milligrams." Dr. Unger, in a statement, noted that "Using the lowest effective dose can reduce the risk of side effects, such as next-morning drowsiness."

The agency and the company say that suvorexant should only be taken once per night, within a half hour of going to bed and at least 7 hours before the person plans to wake up. Patients should not take more than 20 mg a day.

Drowsiness was the most common side effect. In FDA-required studies of next-day driving performance, patients who took 20 mg had impaired performance. Patients who take 20 mg should be warned about driving or conducting any activities that require mental alertness the next day, said the agency.

The drug also has the potential to lead to what the FDA calls "sleep-driving and other complex behaviors while not being fully awake," including preparing and eating food, making phone calls, or having sex. Patients and their families are urged to call their physician if that type of behavior is observed.

Suvorexant will be dispensed with a Medication Guide for patients that details safety information.

Although the drug was studied in three trials, none involved a comparison with other approved insomnia drugs, so its comparative effectiveness is not known, the FDA said.

aault@frontlinemedcom.com

On Twitter @aliciaault

The high-dose version of the trivalent inactivated influenza vaccine induced higher antibody responses and provided significantly improved protection against the disease in patients aged 65 years and older participating in an industry-sponsored phase III-IV randomized, controlled trial, which was reported online Aug. 14 in the New England Journal of Medicine.

The standard-dose vaccine is less effective in older adults, with an absolute efficacy of approximately 50%, than in adults younger than age 65 years. In comparison, given the findings of this large clinical trial, "the absolute efficacy of the high-dose vaccine would be estimated at 62%, a level of protection similar to that seen with standard-dose vaccines in younger adults," said Dr. Carlos A. DiazGranados of Sanofi Pasteur, Swiftwater, Pa., and his associates.

The high-dose trivalent inactivated vaccine, IIV3-HD (Fluzone High Dose), was licensed for use in the United States in 2009, with a requirement to show clinical benefits. This trial was designed to demonstrate those benefits by comparing its efficacy against that of the standard-dose vaccine (Fluzone) in the elderly.

A total of 31,989 adults aged 65 years and older participated in the double-blind trial at 126 medical centers in the United States and Canada during a 20-month period (two flu seasons). They were randomly assigned to receive a single intramuscular dose of either the standard-dose vaccine, which contains 15 mcg of hemagglutinin/strain (15,998 patients), or the high-dose vaccine, which contains 60 mcg of hemagglutinin/strain (15,991 patients).

Blood samples collected from a subset of approximately one-third of the study participants showed that antibody levels for all three influenza strains were significantly higher in members of the high-dose group than in those in the low-dose group at 28 days after vaccination.

The primary endpoint of the trial was the development of influenzalike illness, together with laboratory-confirmed influenza caused by any viral type, at least 14 days after vaccination. This occurred in 301 patients (1.9%) in the standard-dose group, compared with 228 patients (1.4%) in the high-dose group. Therefore, the efficacy of IIV3-HD relative to the standard-dose vaccine was 24.2%, which met the study criterion for superiority, the researchers stated.

This level of efficacy "indicates that about one-quarter of all breakthrough influenza illnesses could be prevented if IIV3-HD were used" instead of the standard-dose vaccine in this age group, Dr. DiazGranados and his associates said (N. Engl. J. Med. 2014 Aug. 14 [doi:10.1056/NEJMoa1315727]).

In addition, rates of pneumonia, cardiorespiratory conditions, hospitalizations, nonroutine medical office visits, and medication use were lower in the high-dose than in the low-dose group. This suggests that the clinical benefits of IIV3-HD will translate into public health benefits, they said.

The rate of serious adverse events was slightly higher with the standard-dose vaccine (9.0%) than with the high-dose vaccine (8.3%). The rate of withdrawal from the study because of adverse events was identical between the two groups at 0.6%, and none of those events were considered to be related to vaccination.

Three patients who received the high-dose vaccine had serious adverse events considered to be related to vaccination: one developed cranial-nerve VI palsy the day after the injection; one developed hypovolemic shock from diarrhea that started the day after the injection; and one developed acute disseminated encephalomyelitis that began 117 days after vaccination. All of these events resolved over time.

This trial was funded by Sanofi-Pasteur, maker of IIV3-HD, which also was involved in study design and monitoring, data management, and statistical analysis.

The high-dose version of the trivalent inactivated influenza vaccine induced higher antibody responses and provided significantly improved protection against the disease in patients aged 65 years and older participating in an industry-sponsored phase III-IV randomized, controlled trial, which was reported online Aug. 14 in the New England Journal of Medicine.

The standard-dose vaccine is less effective in older adults, with an absolute efficacy of approximately 50%, than in adults younger than age 65 years. In comparison, given the findings of this large clinical trial, "the absolute efficacy of the high-dose vaccine would be estimated at 62%, a level of protection similar to that seen with standard-dose vaccines in younger adults," said Dr. Carlos A. DiazGranados of Sanofi Pasteur, Swiftwater, Pa., and his associates.

The high-dose trivalent inactivated vaccine, IIV3-HD (Fluzone High Dose), was licensed for use in the United States in 2009, with a requirement to show clinical benefits. This trial was designed to demonstrate those benefits by comparing its efficacy against that of the standard-dose vaccine (Fluzone) in the elderly.

A total of 31,989 adults aged 65 years and older participated in the double-blind trial at 126 medical centers in the United States and Canada during a 20-month period (two flu seasons). They were randomly assigned to receive a single intramuscular dose of either the standard-dose vaccine, which contains 15 mcg of hemagglutinin/strain (15,998 patients), or the high-dose vaccine, which contains 60 mcg of hemagglutinin/strain (15,991 patients).

Blood samples collected from a subset of approximately one-third of the study participants showed that antibody levels for all three influenza strains were significantly higher in members of the high-dose group than in those in the low-dose group at 28 days after vaccination.

The primary endpoint of the trial was the development of influenzalike illness, together with laboratory-confirmed influenza caused by any viral type, at least 14 days after vaccination. This occurred in 301 patients (1.9%) in the standard-dose group, compared with 228 patients (1.4%) in the high-dose group. Therefore, the efficacy of IIV3-HD relative to the standard-dose vaccine was 24.2%, which met the study criterion for superiority, the researchers stated.

This level of efficacy "indicates that about one-quarter of all breakthrough influenza illnesses could be prevented if IIV3-HD were used" instead of the standard-dose vaccine in this age group, Dr. DiazGranados and his associates said (N. Engl. J. Med. 2014 Aug. 14 [doi:10.1056/NEJMoa1315727]).

In addition, rates of pneumonia, cardiorespiratory conditions, hospitalizations, nonroutine medical office visits, and medication use were lower in the high-dose than in the low-dose group. This suggests that the clinical benefits of IIV3-HD will translate into public health benefits, they said.

The rate of serious adverse events was slightly higher with the standard-dose vaccine (9.0%) than with the high-dose vaccine (8.3%). The rate of withdrawal from the study because of adverse events was identical between the two groups at 0.6%, and none of those events were considered to be related to vaccination.

Three patients who received the high-dose vaccine had serious adverse events considered to be related to vaccination: one developed cranial-nerve VI palsy the day after the injection; one developed hypovolemic shock from diarrhea that started the day after the injection; and one developed acute disseminated encephalomyelitis that began 117 days after vaccination. All of these events resolved over time.

This trial was funded by Sanofi-Pasteur, maker of IIV3-HD, which also was involved in study design and monitoring, data management, and statistical analysis.

The high-dose version of the trivalent inactivated influenza vaccine induced higher antibody responses and provided significantly improved protection against the disease in patients aged 65 years and older participating in an industry-sponsored phase III-IV randomized, controlled trial, which was reported online Aug. 14 in the New England Journal of Medicine.

The standard-dose vaccine is less effective in older adults, with an absolute efficacy of approximately 50%, than in adults younger than age 65 years. In comparison, given the findings of this large clinical trial, "the absolute efficacy of the high-dose vaccine would be estimated at 62%, a level of protection similar to that seen with standard-dose vaccines in younger adults," said Dr. Carlos A. DiazGranados of Sanofi Pasteur, Swiftwater, Pa., and his associates.

The high-dose trivalent inactivated vaccine, IIV3-HD (Fluzone High Dose), was licensed for use in the United States in 2009, with a requirement to show clinical benefits. This trial was designed to demonstrate those benefits by comparing its efficacy against that of the standard-dose vaccine (Fluzone) in the elderly.

A total of 31,989 adults aged 65 years and older participated in the double-blind trial at 126 medical centers in the United States and Canada during a 20-month period (two flu seasons). They were randomly assigned to receive a single intramuscular dose of either the standard-dose vaccine, which contains 15 mcg of hemagglutinin/strain (15,998 patients), or the high-dose vaccine, which contains 60 mcg of hemagglutinin/strain (15,991 patients).

Blood samples collected from a subset of approximately one-third of the study participants showed that antibody levels for all three influenza strains were significantly higher in members of the high-dose group than in those in the low-dose group at 28 days after vaccination.

The primary endpoint of the trial was the development of influenzalike illness, together with laboratory-confirmed influenza caused by any viral type, at least 14 days after vaccination. This occurred in 301 patients (1.9%) in the standard-dose group, compared with 228 patients (1.4%) in the high-dose group. Therefore, the efficacy of IIV3-HD relative to the standard-dose vaccine was 24.2%, which met the study criterion for superiority, the researchers stated.

This level of efficacy "indicates that about one-quarter of all breakthrough influenza illnesses could be prevented if IIV3-HD were used" instead of the standard-dose vaccine in this age group, Dr. DiazGranados and his associates said (N. Engl. J. Med. 2014 Aug. 14 [doi:10.1056/NEJMoa1315727]).

In addition, rates of pneumonia, cardiorespiratory conditions, hospitalizations, nonroutine medical office visits, and medication use were lower in the high-dose than in the low-dose group. This suggests that the clinical benefits of IIV3-HD will translate into public health benefits, they said.

The rate of serious adverse events was slightly higher with the standard-dose vaccine (9.0%) than with the high-dose vaccine (8.3%). The rate of withdrawal from the study because of adverse events was identical between the two groups at 0.6%, and none of those events were considered to be related to vaccination.

Three patients who received the high-dose vaccine had serious adverse events considered to be related to vaccination: one developed cranial-nerve VI palsy the day after the injection; one developed hypovolemic shock from diarrhea that started the day after the injection; and one developed acute disseminated encephalomyelitis that began 117 days after vaccination. All of these events resolved over time.

This trial was funded by Sanofi-Pasteur, maker of IIV3-HD, which also was involved in study design and monitoring, data management, and statistical analysis.