Elizabeth Mechcatie

ROCKVILLE, MD. — The majority of a federal advisory panel agreed that the benefits of treatment with lasofoxifene, a selective estrogen receptor modulator, would likely outweigh the risks in some postmenopausal women with osteoporosis.

The Food and Drug Administration's Advisory Committee for Reproductive Health Drugs voted 9–3 (with 1 abstention) that there was a population of postmenopausal women with osteoporosis for whom the benefit of treatment would likely outweigh the risks. Most panelists supported limiting the drug's use to women who are at high risk for fractures but cannot tolerate bisphosphonates.

Dr. Diane Merritt, professor of obstetrics and gynecology at Washington University, St. Louis, said she believed there was a use for lasofoxifene, but that it would be important for physicians who prescribe the drug to appropriately counsel the patient about the associated risks.

Voting no on the risk-benefit question, Dr. Lawrence Nelson, head of the Unit on Integrative Reproductive Medicine at the National Institute of Child Health and Human Development, said that because there was still an open question about greater all-cause mortality in women on the lower dose of lasofoxifene, he found it difficult to identify a group of women to whom he would prescribe this drug. In studies, all-cause mortality was greater in women on the lower dose of lasofoxifene studied, compared with those on the higher dose and those on placebo.

Pfizer Inc. has proposed that lasofoxifene, at a dosage of 0.5 mg per day, be approved for treating osteoporosis in postmenopausal women who are at increased risk of fracture.

In a prospective, double-blind, randomized study of 8,556 postmenopausal women at increased risk of fracture, two doses (0.25 mg per day or 0.5 mg per day) of lasofoxifene were compared with placebo.

The risk of developing a new or worsening radiographic vertebral fracture within 3 years—the study's primary end point—was significantly reduced in the women who were treated with both doses of lasofoxifene, compared with those on placebo. The cumulative relative risk of developing a new or worsening radiographic vertebral fracture through the third year of treatment was reduced by 27% in those on the 0.25-mg dose and by 41% in those on the 0.5-mg dose, compared with placebo.

Within the 3 years of starting treatment, nearly 5% of those on the 0.25-mg dose and nearly 4% of those on the 0.5-mg dose developed a new or worsening radiographic vertebral fracture, compared with 6.4% of those on placebo.

The FDA asked the panel to consider several safety issues associated with the drug that were raised in the study: a numerical increase in all-cause mortality in those treated with 0.25 mg; an increase in venous thromboembolic events (VTEs), particularly pulmonary emboli (PEs); and a significant increase in gynecologic adverse events, including increased endometrial thickness, increased vaginal bleeding, and increased uterine-related procedures.

The majority of the panel (seven panelists) said that they could not determine whether the data regarding all-cause mortality reflected a real increase in mortality in those treated with lasofoxifene; four said they did not believe this was a real increase. The study was extended to 5 years, at which time the all-cause mortality rate was 3.2% (90 women) among those on the 0.25-mg dose, compared with 2.6% (73 women) among those on the 0.5-mg dose (the proposed dose) and 2.3% (65 women) among those on placebo. The causes of death that were more common among those on lasofoxifene were cancer (cancers of the brain, lung, and GI tract) and stroke. (At 5 years, the rate of fatal stroke was 0.4% among those on the 0.25-mg dose and 0.2% among those on the higher dose and those on placebo.)

The all-cause mortality rate was also higher among the women on 0.25 mg in the overall phase II/III program for the drug.

The FDA usually follows the recommendations of its advisory panels. If approved, Pfizer will market lasofoxifene under the trade name Fablyn. Raloxifene, another FDA-approved SERM, is approved for osteoporosis indications.

ROCKVILLE, MD. — The majority of a federal advisory panel agreed that the benefits of treatment with lasofoxifene, a selective estrogen receptor modulator, would likely outweigh the risks in some postmenopausal women with osteoporosis.

The Food and Drug Administration's Advisory Committee for Reproductive Health Drugs voted 9–3 (with 1 abstention) that there was a population of postmenopausal women with osteoporosis for whom the benefit of treatment would likely outweigh the risks. Most panelists supported limiting the drug's use to women who are at high risk for fractures but cannot tolerate bisphosphonates.

Dr. Diane Merritt, professor of obstetrics and gynecology at Washington University, St. Louis, said she believed there was a use for lasofoxifene, but that it would be important for physicians who prescribe the drug to appropriately counsel the patient about the associated risks.

Voting no on the risk-benefit question, Dr. Lawrence Nelson, head of the Unit on Integrative Reproductive Medicine at the National Institute of Child Health and Human Development, said that because there was still an open question about greater all-cause mortality in women on the lower dose of lasofoxifene, he found it difficult to identify a group of women to whom he would prescribe this drug. In studies, all-cause mortality was greater in women on the lower dose of lasofoxifene studied, compared with those on the higher dose and those on placebo.

Pfizer Inc. has proposed that lasofoxifene, at a dosage of 0.5 mg per day, be approved for treating osteoporosis in postmenopausal women who are at increased risk of fracture.

In a prospective, double-blind, randomized study of 8,556 postmenopausal women at increased risk of fracture, two doses (0.25 mg per day or 0.5 mg per day) of lasofoxifene were compared with placebo.

The risk of developing a new or worsening radiographic vertebral fracture within 3 years—the study's primary end point—was significantly reduced in the women who were treated with both doses of lasofoxifene, compared with those on placebo. The cumulative relative risk of developing a new or worsening radiographic vertebral fracture through the third year of treatment was reduced by 27% in those on the 0.25-mg dose and by 41% in those on the 0.5-mg dose, compared with placebo.

Within the 3 years of starting treatment, nearly 5% of those on the 0.25-mg dose and nearly 4% of those on the 0.5-mg dose developed a new or worsening radiographic vertebral fracture, compared with 6.4% of those on placebo.

The FDA asked the panel to consider several safety issues associated with the drug that were raised in the study: a numerical increase in all-cause mortality in those treated with 0.25 mg; an increase in venous thromboembolic events (VTEs), particularly pulmonary emboli (PEs); and a significant increase in gynecologic adverse events, including increased endometrial thickness, increased vaginal bleeding, and increased uterine-related procedures.

The majority of the panel (seven panelists) said that they could not determine whether the data regarding all-cause mortality reflected a real increase in mortality in those treated with lasofoxifene; four said they did not believe this was a real increase. The study was extended to 5 years, at which time the all-cause mortality rate was 3.2% (90 women) among those on the 0.25-mg dose, compared with 2.6% (73 women) among those on the 0.5-mg dose (the proposed dose) and 2.3% (65 women) among those on placebo. The causes of death that were more common among those on lasofoxifene were cancer (cancers of the brain, lung, and GI tract) and stroke. (At 5 years, the rate of fatal stroke was 0.4% among those on the 0.25-mg dose and 0.2% among those on the higher dose and those on placebo.)

The all-cause mortality rate was also higher among the women on 0.25 mg in the overall phase II/III program for the drug.

The FDA usually follows the recommendations of its advisory panels. If approved, Pfizer will market lasofoxifene under the trade name Fablyn. Raloxifene, another FDA-approved SERM, is approved for osteoporosis indications.

ROCKVILLE, MD. — The majority of a federal advisory panel agreed that the benefits of treatment with lasofoxifene, a selective estrogen receptor modulator, would likely outweigh the risks in some postmenopausal women with osteoporosis.

The Food and Drug Administration's Advisory Committee for Reproductive Health Drugs voted 9–3 (with 1 abstention) that there was a population of postmenopausal women with osteoporosis for whom the benefit of treatment would likely outweigh the risks. Most panelists supported limiting the drug's use to women who are at high risk for fractures but cannot tolerate bisphosphonates.

Dr. Diane Merritt, professor of obstetrics and gynecology at Washington University, St. Louis, said she believed there was a use for lasofoxifene, but that it would be important for physicians who prescribe the drug to appropriately counsel the patient about the associated risks.

Voting no on the risk-benefit question, Dr. Lawrence Nelson, head of the Unit on Integrative Reproductive Medicine at the National Institute of Child Health and Human Development, said that because there was still an open question about greater all-cause mortality in women on the lower dose of lasofoxifene, he found it difficult to identify a group of women to whom he would prescribe this drug. In studies, all-cause mortality was greater in women on the lower dose of lasofoxifene studied, compared with those on the higher dose and those on placebo.

Pfizer Inc. has proposed that lasofoxifene, at a dosage of 0.5 mg per day, be approved for treating osteoporosis in postmenopausal women who are at increased risk of fracture.

In a prospective, double-blind, randomized study of 8,556 postmenopausal women at increased risk of fracture, two doses (0.25 mg per day or 0.5 mg per day) of lasofoxifene were compared with placebo.

The risk of developing a new or worsening radiographic vertebral fracture within 3 years—the study's primary end point—was significantly reduced in the women who were treated with both doses of lasofoxifene, compared with those on placebo. The cumulative relative risk of developing a new or worsening radiographic vertebral fracture through the third year of treatment was reduced by 27% in those on the 0.25-mg dose and by 41% in those on the 0.5-mg dose, compared with placebo.

Within the 3 years of starting treatment, nearly 5% of those on the 0.25-mg dose and nearly 4% of those on the 0.5-mg dose developed a new or worsening radiographic vertebral fracture, compared with 6.4% of those on placebo.

The FDA asked the panel to consider several safety issues associated with the drug that were raised in the study: a numerical increase in all-cause mortality in those treated with 0.25 mg; an increase in venous thromboembolic events (VTEs), particularly pulmonary emboli (PEs); and a significant increase in gynecologic adverse events, including increased endometrial thickness, increased vaginal bleeding, and increased uterine-related procedures.

The majority of the panel (seven panelists) said that they could not determine whether the data regarding all-cause mortality reflected a real increase in mortality in those treated with lasofoxifene; four said they did not believe this was a real increase. The study was extended to 5 years, at which time the all-cause mortality rate was 3.2% (90 women) among those on the 0.25-mg dose, compared with 2.6% (73 women) among those on the 0.5-mg dose (the proposed dose) and 2.3% (65 women) among those on placebo. The causes of death that were more common among those on lasofoxifene were cancer (cancers of the brain, lung, and GI tract) and stroke. (At 5 years, the rate of fatal stroke was 0.4% among those on the 0.25-mg dose and 0.2% among those on the higher dose and those on placebo.)

The all-cause mortality rate was also higher among the women on 0.25 mg in the overall phase II/III program for the drug.

The FDA usually follows the recommendations of its advisory panels. If approved, Pfizer will market lasofoxifene under the trade name Fablyn. Raloxifene, another FDA-approved SERM, is approved for osteoporosis indications.

ACIP's recommendations on preventing human rabies are available at www.cdc.gov/mmwr/preview/mmwrhtml/rr5703a1.htmwww.cdc.gov/rabies

Health care providers who prescribe postexposure rabies prophylaxis will be required to confer with public health officials and obtain a confirmation code from their respective state health departments before they can order doses of the vaccine, because of limited supplies of the only rabies vaccine that is available, the Centers for Disease Control and Prevention announced.

An update on rabies vaccine availability posted on the CDC's Web site states that the CDC had been notified by Novartis AG, the manufacturer of the human rabies vaccine RabAvert, that the availability of the vaccine in the “near term” could be affected because the supply was being used “at a higher rate than expected.”

At press time, Sanofi Pasteur, the other supplier of rabies vaccine in the United States, said that it has built a supply of its rabies vaccine, Imovax, “that will enable us to meet our historic demand for the vaccine. However because the [rabies vaccine production] facility is currently shut down for renovation, we are unable to produce additional vaccine to meet increased demand,” according to a company spokesperson. “Renovation [of the facility] is on schedule and we expect to be approved and on schedule to reopen by the fourth quarter of 2009.”

“Judicious and appropriate use of rabies vaccines is crucial to avert a situation in which persons exposed to rabies are put at increased risk due to depleted vaccine supplies,” the CDC statement said.

Both companies are requiring that providers obtain the confirmation code to ensure that thorough risk assessments are done before ordering vaccine for postexposure prophylaxis, according to the CDC.

“These codes should only be released by a state/local health authority that has reviewed the known facts of a given exposure and determined they indicate a sufficient level of exposure risk” as described in the CDC's Advisory Committee on Immunization Practices (ACIP) recommendations on preventing human rabies, which were updated earlier this year.

The CDC statement says that the new requirements will remain in place until vaccine supplies are adequate.

In May, the CDC announced that vaccine would temporarily be unavailable for preexposure prophylaxis. The current statement says that until supplies are adequate, distribution of rabies vaccine for preexposure prophylaxis will require approval from state and federal public health authorities, with priority given to workers in rabies laboratories, animal control officers, veterinary staff, wildlife workers, and other people at risk for occupational rabies exposure, according to the CDC.

The CDC statement also points out that while people with a possible exposure to rabies need to be evaluated as soon as possible and that postexposure prophylaxis (PEP) is an “urgent medical issue,” it is not considered an emergency, and PEP can be delayed until after the animal has had rabies testing “or clinical observation is completed,” an approach that “not only limits administration of PEP to persons with confirmed rabies exposure, but it is also cost saving and conserves limited resources.”

A national working group has been formed to monitor the supply situation and to provide updated recommendations “as the situation evolves,” the CDC said.

ACIP's recommendations on preventing human rabies are available at www.cdc.gov/mmwr/preview/mmwrhtml/rr5703a1.htmwww.cdc.gov/rabies

Health care providers who prescribe postexposure rabies prophylaxis will be required to confer with public health officials and obtain a confirmation code from their respective state health departments before they can order doses of the vaccine, because of limited supplies of the only rabies vaccine that is available, the Centers for Disease Control and Prevention announced.

An update on rabies vaccine availability posted on the CDC's Web site states that the CDC had been notified by Novartis AG, the manufacturer of the human rabies vaccine RabAvert, that the availability of the vaccine in the “near term” could be affected because the supply was being used “at a higher rate than expected.”

At press time, Sanofi Pasteur, the other supplier of rabies vaccine in the United States, said that it has built a supply of its rabies vaccine, Imovax, “that will enable us to meet our historic demand for the vaccine. However because the [rabies vaccine production] facility is currently shut down for renovation, we are unable to produce additional vaccine to meet increased demand,” according to a company spokesperson. “Renovation [of the facility] is on schedule and we expect to be approved and on schedule to reopen by the fourth quarter of 2009.”

“Judicious and appropriate use of rabies vaccines is crucial to avert a situation in which persons exposed to rabies are put at increased risk due to depleted vaccine supplies,” the CDC statement said.

Both companies are requiring that providers obtain the confirmation code to ensure that thorough risk assessments are done before ordering vaccine for postexposure prophylaxis, according to the CDC.

“These codes should only be released by a state/local health authority that has reviewed the known facts of a given exposure and determined they indicate a sufficient level of exposure risk” as described in the CDC's Advisory Committee on Immunization Practices (ACIP) recommendations on preventing human rabies, which were updated earlier this year.

The CDC statement says that the new requirements will remain in place until vaccine supplies are adequate.

In May, the CDC announced that vaccine would temporarily be unavailable for preexposure prophylaxis. The current statement says that until supplies are adequate, distribution of rabies vaccine for preexposure prophylaxis will require approval from state and federal public health authorities, with priority given to workers in rabies laboratories, animal control officers, veterinary staff, wildlife workers, and other people at risk for occupational rabies exposure, according to the CDC.

The CDC statement also points out that while people with a possible exposure to rabies need to be evaluated as soon as possible and that postexposure prophylaxis (PEP) is an “urgent medical issue,” it is not considered an emergency, and PEP can be delayed until after the animal has had rabies testing “or clinical observation is completed,” an approach that “not only limits administration of PEP to persons with confirmed rabies exposure, but it is also cost saving and conserves limited resources.”

A national working group has been formed to monitor the supply situation and to provide updated recommendations “as the situation evolves,” the CDC said.

ACIP's recommendations on preventing human rabies are available at www.cdc.gov/mmwr/preview/mmwrhtml/rr5703a1.htmwww.cdc.gov/rabies

Health care providers who prescribe postexposure rabies prophylaxis will be required to confer with public health officials and obtain a confirmation code from their respective state health departments before they can order doses of the vaccine, because of limited supplies of the only rabies vaccine that is available, the Centers for Disease Control and Prevention announced.

An update on rabies vaccine availability posted on the CDC's Web site states that the CDC had been notified by Novartis AG, the manufacturer of the human rabies vaccine RabAvert, that the availability of the vaccine in the “near term” could be affected because the supply was being used “at a higher rate than expected.”

At press time, Sanofi Pasteur, the other supplier of rabies vaccine in the United States, said that it has built a supply of its rabies vaccine, Imovax, “that will enable us to meet our historic demand for the vaccine. However because the [rabies vaccine production] facility is currently shut down for renovation, we are unable to produce additional vaccine to meet increased demand,” according to a company spokesperson. “Renovation [of the facility] is on schedule and we expect to be approved and on schedule to reopen by the fourth quarter of 2009.”

“Judicious and appropriate use of rabies vaccines is crucial to avert a situation in which persons exposed to rabies are put at increased risk due to depleted vaccine supplies,” the CDC statement said.

Both companies are requiring that providers obtain the confirmation code to ensure that thorough risk assessments are done before ordering vaccine for postexposure prophylaxis, according to the CDC.

“These codes should only be released by a state/local health authority that has reviewed the known facts of a given exposure and determined they indicate a sufficient level of exposure risk” as described in the CDC's Advisory Committee on Immunization Practices (ACIP) recommendations on preventing human rabies, which were updated earlier this year.

The CDC statement says that the new requirements will remain in place until vaccine supplies are adequate.

In May, the CDC announced that vaccine would temporarily be unavailable for preexposure prophylaxis. The current statement says that until supplies are adequate, distribution of rabies vaccine for preexposure prophylaxis will require approval from state and federal public health authorities, with priority given to workers in rabies laboratories, animal control officers, veterinary staff, wildlife workers, and other people at risk for occupational rabies exposure, according to the CDC.

The CDC statement also points out that while people with a possible exposure to rabies need to be evaluated as soon as possible and that postexposure prophylaxis (PEP) is an “urgent medical issue,” it is not considered an emergency, and PEP can be delayed until after the animal has had rabies testing “or clinical observation is completed,” an approach that “not only limits administration of PEP to persons with confirmed rabies exposure, but it is also cost saving and conserves limited resources.”

A national working group has been formed to monitor the supply situation and to provide updated recommendations “as the situation evolves,” the CDC said.

From 2001 through 2006, the number of HIV/AIDS diagnoses among men who have sex with men increased by nearly 9% in 33 states, with particularly high increases among black men and Asian/Pacific Islanders under the age of 25 years, according to the Centers for Disease Control and Prevention.

The CDC analysis of trends in HIV/AIDS diagnoses among men who have sex with men (MSM) estimated that of the 214,379 people who were diagnosed with HIV/AIDS, 46% occurred among MSM and 4% occurred among MSM who also injected illicit drugs.

Diagnoses during this time period dropped in all transmission categories except for MSM (MMWR 2007;57:681–6).

Of the cases diagnosed among MSM, 64% were in men aged 25–44 years.

There was a 12% increase in diagnoses among all black MSM.

Diagnoses among black MSM aged 13–24 years increased by 93%, a rate that was about twofold greater than the rate of increase among white MSM in the same age group.

Asian/Pacific Islanders aged 13–24 years saw the largest proportionate increase.

In this group, HIV/AIDS diagnoses increased by 256% (an estimated annual increase of almost 31%).

Among MSM in this younger age group, the annual percentage increases in diagnoses were statistically significant in all racial/ethnic populations, with the exception of American Indian and Alaska Natives.

“These findings underscore the need for continued effective testing and risk reduction interventions for MSM,” particularly for those younger than age 25 years, according to the report.

As an example, the report cites an intervention targeted to young black MSM in North Carolina (one of the 33 states), implemented by the CDC, in collaboration with the state health department and local organizations, that successfully reduced their high-risk sexual behavior and the number of sex partners with whom they engaged in high-risk sexual behaviors.

Among the limitations of the report, the patients in the included 33 states are not representative of all HIV-positive people in the United States.

However, the racial and ethnic disparities observed are similar to those observed for AIDS patients in all of the states.

From 2001 through 2006, the number of HIV/AIDS diagnoses among men who have sex with men increased by nearly 9% in 33 states, with particularly high increases among black men and Asian/Pacific Islanders under the age of 25 years, according to the Centers for Disease Control and Prevention.

The CDC analysis of trends in HIV/AIDS diagnoses among men who have sex with men (MSM) estimated that of the 214,379 people who were diagnosed with HIV/AIDS, 46% occurred among MSM and 4% occurred among MSM who also injected illicit drugs.

Diagnoses during this time period dropped in all transmission categories except for MSM (MMWR 2007;57:681–6).

Of the cases diagnosed among MSM, 64% were in men aged 25–44 years.

There was a 12% increase in diagnoses among all black MSM.

Diagnoses among black MSM aged 13–24 years increased by 93%, a rate that was about twofold greater than the rate of increase among white MSM in the same age group.

Asian/Pacific Islanders aged 13–24 years saw the largest proportionate increase.

In this group, HIV/AIDS diagnoses increased by 256% (an estimated annual increase of almost 31%).

Among MSM in this younger age group, the annual percentage increases in diagnoses were statistically significant in all racial/ethnic populations, with the exception of American Indian and Alaska Natives.

“These findings underscore the need for continued effective testing and risk reduction interventions for MSM,” particularly for those younger than age 25 years, according to the report.

As an example, the report cites an intervention targeted to young black MSM in North Carolina (one of the 33 states), implemented by the CDC, in collaboration with the state health department and local organizations, that successfully reduced their high-risk sexual behavior and the number of sex partners with whom they engaged in high-risk sexual behaviors.

Among the limitations of the report, the patients in the included 33 states are not representative of all HIV-positive people in the United States.

However, the racial and ethnic disparities observed are similar to those observed for AIDS patients in all of the states.

From 2001 through 2006, the number of HIV/AIDS diagnoses among men who have sex with men increased by nearly 9% in 33 states, with particularly high increases among black men and Asian/Pacific Islanders under the age of 25 years, according to the Centers for Disease Control and Prevention.

The CDC analysis of trends in HIV/AIDS diagnoses among men who have sex with men (MSM) estimated that of the 214,379 people who were diagnosed with HIV/AIDS, 46% occurred among MSM and 4% occurred among MSM who also injected illicit drugs.

Diagnoses during this time period dropped in all transmission categories except for MSM (MMWR 2007;57:681–6).

Of the cases diagnosed among MSM, 64% were in men aged 25–44 years.

There was a 12% increase in diagnoses among all black MSM.

Diagnoses among black MSM aged 13–24 years increased by 93%, a rate that was about twofold greater than the rate of increase among white MSM in the same age group.

Asian/Pacific Islanders aged 13–24 years saw the largest proportionate increase.

In this group, HIV/AIDS diagnoses increased by 256% (an estimated annual increase of almost 31%).

Among MSM in this younger age group, the annual percentage increases in diagnoses were statistically significant in all racial/ethnic populations, with the exception of American Indian and Alaska Natives.

“These findings underscore the need for continued effective testing and risk reduction interventions for MSM,” particularly for those younger than age 25 years, according to the report.

As an example, the report cites an intervention targeted to young black MSM in North Carolina (one of the 33 states), implemented by the CDC, in collaboration with the state health department and local organizations, that successfully reduced their high-risk sexual behavior and the number of sex partners with whom they engaged in high-risk sexual behaviors.

Among the limitations of the report, the patients in the included 33 states are not representative of all HIV-positive people in the United States.

However, the racial and ethnic disparities observed are similar to those observed for AIDS patients in all of the states.

The human papilloma virus vaccine, Gardasil, has been approved for a new claim: preventing vaginal and vulvar cancer caused by HPV types 16 and 18, in females aged 9–26, the Food and Drug Administration announced.

The approval is based on follow-up of more than 15,000 participants in the original studies of Gardasil, which found that about 2 years after vaccination, the vaccine was "highly effective" in preventing precancerous vulvar and vaginal lesions caused by HPV types 16 and 18 among females who tested negative for these two types when the study began. Among females in the control group who did not receive the vaccine, 10 developed precancerous vulvar lesions and nine developed precancerous vaginal lesions, which were related to HPV types 16 or 18, according to the FDA statement announcing the approval.

However, there was no evidence that females who had already been infected with the HPV types in the vaccine derived any benefit from the vaccine.

"While vulvar and vaginal cancers are rare, the opportunity to help prevent them is potentially an important additional benefit from immunization against HPV," Dr. Jesse Goodman, director of the FDA's Center for Biologics Evaluation and Research, said in the statement.

Gardasil, manufactured by Merck & Co., was approved in 2006 in females aged 9–26 years for the prevention of cervical cancer caused by HPV type 16 and 18, precancerous genital lesions caused by HPV types 6, 11, 16, and 18, and genital warts caused by HPV types 6 and 11.

HPV types 16 and 18 cause an estimated 70% of cervical cancers and other cancers related to HPV.

More information on the approval is available at: www.fda.gov/cber/products/gardasil.htm

The human papilloma virus vaccine, Gardasil, has been approved for a new claim: preventing vaginal and vulvar cancer caused by HPV types 16 and 18, in females aged 9–26, the Food and Drug Administration announced.

The approval is based on follow-up of more than 15,000 participants in the original studies of Gardasil, which found that about 2 years after vaccination, the vaccine was "highly effective" in preventing precancerous vulvar and vaginal lesions caused by HPV types 16 and 18 among females who tested negative for these two types when the study began. Among females in the control group who did not receive the vaccine, 10 developed precancerous vulvar lesions and nine developed precancerous vaginal lesions, which were related to HPV types 16 or 18, according to the FDA statement announcing the approval.

However, there was no evidence that females who had already been infected with the HPV types in the vaccine derived any benefit from the vaccine.

"While vulvar and vaginal cancers are rare, the opportunity to help prevent them is potentially an important additional benefit from immunization against HPV," Dr. Jesse Goodman, director of the FDA's Center for Biologics Evaluation and Research, said in the statement.

Gardasil, manufactured by Merck & Co., was approved in 2006 in females aged 9–26 years for the prevention of cervical cancer caused by HPV type 16 and 18, precancerous genital lesions caused by HPV types 6, 11, 16, and 18, and genital warts caused by HPV types 6 and 11.

HPV types 16 and 18 cause an estimated 70% of cervical cancers and other cancers related to HPV.

More information on the approval is available at: www.fda.gov/cber/products/gardasil.htm

The human papilloma virus vaccine, Gardasil, has been approved for a new claim: preventing vaginal and vulvar cancer caused by HPV types 16 and 18, in females aged 9–26, the Food and Drug Administration announced.

The approval is based on follow-up of more than 15,000 participants in the original studies of Gardasil, which found that about 2 years after vaccination, the vaccine was "highly effective" in preventing precancerous vulvar and vaginal lesions caused by HPV types 16 and 18 among females who tested negative for these two types when the study began. Among females in the control group who did not receive the vaccine, 10 developed precancerous vulvar lesions and nine developed precancerous vaginal lesions, which were related to HPV types 16 or 18, according to the FDA statement announcing the approval.

However, there was no evidence that females who had already been infected with the HPV types in the vaccine derived any benefit from the vaccine.

"While vulvar and vaginal cancers are rare, the opportunity to help prevent them is potentially an important additional benefit from immunization against HPV," Dr. Jesse Goodman, director of the FDA's Center for Biologics Evaluation and Research, said in the statement.

Gardasil, manufactured by Merck & Co., was approved in 2006 in females aged 9–26 years for the prevention of cervical cancer caused by HPV type 16 and 18, precancerous genital lesions caused by HPV types 6, 11, 16, and 18, and genital warts caused by HPV types 6 and 11.

HPV types 16 and 18 cause an estimated 70% of cervical cancers and other cancers related to HPV.

More information on the approval is available at: www.fda.gov/cber/products/gardasil.htm

Children who had had an enterovirus 71 infection involving the central nervous system were significantly more likely to have symptoms of attention-deficit/hyperactivity disorder than were matched controls in a prospective study that evaluated children at 3–7 years after the infection.

Although herpes simplex encephalitis and other CNS infections can affect neurodevelopment and cognitive function, the authors said this was the first study to follow up long-term behavioral outcomes or ADHD-related symptoms in children after an enterovirus 71 (EV71) CNS infection.

The findings have “clearly demonstrated the association between the EV71 CNS infection and increased symptoms of inattention, hyperactivity, oppositional defiance, internalizing problems, and increased likelihood of ADHD diagnosis,” said Dr. Susan Shur-Fen Gau of National Taiwan University, Taipei, and her associates.

The results also support their hypothesis that children who have had an EV71 CNS infection “are more likely to have ADHD-related symptoms, regardless of IQ” (Pediatrics 2008;122:e452–8).

The study used standardized mother- and teacher-rated scales to evaluate ADHD symptoms and other emotional and behavioral problems in 51 boys and 35 girls aged 4–16 years who had had an EV71 CNS infection at the mean age of 2.5 years, and in 172 controls who were matched for gender, age, school performance, and parental education levels.

In the children with the infections, CNS involvement had been mild in 42 cases (aseptic meningitis) and severe in 35 cases (encephalitis, poliomyelitislike syndrome, or encephalomyelitis); the other 9 children had cardiopulmonary failure after CNS involvement. The children had been diagnosed with the infections from 1998 to 2003 at Chang Gung Children's Hospital, Taoyuan, Taiwan, and National Taiwan University Hospital. There was an epidemic of EV71 infection in Taiwan in 1998.

Scores on teacher- and mother-rated scales of inattention, hyperactivity-impulsivity, oppositional symptoms, and ADHD index were significantly higher in those with the EV71 infection, compared with controls. In the former group, 20% had elevated ADHD-related symptoms, compared with 3% of controls, a significant difference.

The reserchers said that maternal reports provided some evidence that children with the EV71 CNS infections had more internalizing problems, but that that needs to be studied further. There was no correlation between the age at which the child had the infection, any laboratory data, or the severity of CNS involvement with the severity of ADHD-related symptoms, a finding the researchers said was surprising. They speculated that the infection may involve the prefrontal-striatum-subcortical area of the brain, or another area that is related to the core symptoms of ADHD.

They cited the inability to assess ADHD symptoms in the children before the CNS infection among the study's limitations and said more studies were needed to confirm whether the increase in ADHD symptoms was specific to EV71 or also occurred with other microorganisms. Nevertheless, they concluded that an EV71 CNS infection “may affect long-term regulation of attention and emotion and cause hyperactivity-impulsivity in children” and recommended children with these infections be assessed early to identify and treat ADHD symptoms and emotional and behavioral problems.

The study was supported by a grant from the National Science Council of Taiwan's National Research Program for Genomic Medicine.

Children who had had an enterovirus 71 infection involving the central nervous system were significantly more likely to have symptoms of attention-deficit/hyperactivity disorder than were matched controls in a prospective study that evaluated children at 3–7 years after the infection.

Although herpes simplex encephalitis and other CNS infections can affect neurodevelopment and cognitive function, the authors said this was the first study to follow up long-term behavioral outcomes or ADHD-related symptoms in children after an enterovirus 71 (EV71) CNS infection.

The findings have “clearly demonstrated the association between the EV71 CNS infection and increased symptoms of inattention, hyperactivity, oppositional defiance, internalizing problems, and increased likelihood of ADHD diagnosis,” said Dr. Susan Shur-Fen Gau of National Taiwan University, Taipei, and her associates.

The results also support their hypothesis that children who have had an EV71 CNS infection “are more likely to have ADHD-related symptoms, regardless of IQ” (Pediatrics 2008;122:e452–8).

The study used standardized mother- and teacher-rated scales to evaluate ADHD symptoms and other emotional and behavioral problems in 51 boys and 35 girls aged 4–16 years who had had an EV71 CNS infection at the mean age of 2.5 years, and in 172 controls who were matched for gender, age, school performance, and parental education levels.

In the children with the infections, CNS involvement had been mild in 42 cases (aseptic meningitis) and severe in 35 cases (encephalitis, poliomyelitislike syndrome, or encephalomyelitis); the other 9 children had cardiopulmonary failure after CNS involvement. The children had been diagnosed with the infections from 1998 to 2003 at Chang Gung Children's Hospital, Taoyuan, Taiwan, and National Taiwan University Hospital. There was an epidemic of EV71 infection in Taiwan in 1998.

Scores on teacher- and mother-rated scales of inattention, hyperactivity-impulsivity, oppositional symptoms, and ADHD index were significantly higher in those with the EV71 infection, compared with controls. In the former group, 20% had elevated ADHD-related symptoms, compared with 3% of controls, a significant difference.

The reserchers said that maternal reports provided some evidence that children with the EV71 CNS infections had more internalizing problems, but that that needs to be studied further. There was no correlation between the age at which the child had the infection, any laboratory data, or the severity of CNS involvement with the severity of ADHD-related symptoms, a finding the researchers said was surprising. They speculated that the infection may involve the prefrontal-striatum-subcortical area of the brain, or another area that is related to the core symptoms of ADHD.

They cited the inability to assess ADHD symptoms in the children before the CNS infection among the study's limitations and said more studies were needed to confirm whether the increase in ADHD symptoms was specific to EV71 or also occurred with other microorganisms. Nevertheless, they concluded that an EV71 CNS infection “may affect long-term regulation of attention and emotion and cause hyperactivity-impulsivity in children” and recommended children with these infections be assessed early to identify and treat ADHD symptoms and emotional and behavioral problems.

The study was supported by a grant from the National Science Council of Taiwan's National Research Program for Genomic Medicine.

Children who had had an enterovirus 71 infection involving the central nervous system were significantly more likely to have symptoms of attention-deficit/hyperactivity disorder than were matched controls in a prospective study that evaluated children at 3–7 years after the infection.

Although herpes simplex encephalitis and other CNS infections can affect neurodevelopment and cognitive function, the authors said this was the first study to follow up long-term behavioral outcomes or ADHD-related symptoms in children after an enterovirus 71 (EV71) CNS infection.

The findings have “clearly demonstrated the association between the EV71 CNS infection and increased symptoms of inattention, hyperactivity, oppositional defiance, internalizing problems, and increased likelihood of ADHD diagnosis,” said Dr. Susan Shur-Fen Gau of National Taiwan University, Taipei, and her associates.

The results also support their hypothesis that children who have had an EV71 CNS infection “are more likely to have ADHD-related symptoms, regardless of IQ” (Pediatrics 2008;122:e452–8).

The study used standardized mother- and teacher-rated scales to evaluate ADHD symptoms and other emotional and behavioral problems in 51 boys and 35 girls aged 4–16 years who had had an EV71 CNS infection at the mean age of 2.5 years, and in 172 controls who were matched for gender, age, school performance, and parental education levels.

In the children with the infections, CNS involvement had been mild in 42 cases (aseptic meningitis) and severe in 35 cases (encephalitis, poliomyelitislike syndrome, or encephalomyelitis); the other 9 children had cardiopulmonary failure after CNS involvement. The children had been diagnosed with the infections from 1998 to 2003 at Chang Gung Children's Hospital, Taoyuan, Taiwan, and National Taiwan University Hospital. There was an epidemic of EV71 infection in Taiwan in 1998.

Scores on teacher- and mother-rated scales of inattention, hyperactivity-impulsivity, oppositional symptoms, and ADHD index were significantly higher in those with the EV71 infection, compared with controls. In the former group, 20% had elevated ADHD-related symptoms, compared with 3% of controls, a significant difference.

The reserchers said that maternal reports provided some evidence that children with the EV71 CNS infections had more internalizing problems, but that that needs to be studied further. There was no correlation between the age at which the child had the infection, any laboratory data, or the severity of CNS involvement with the severity of ADHD-related symptoms, a finding the researchers said was surprising. They speculated that the infection may involve the prefrontal-striatum-subcortical area of the brain, or another area that is related to the core symptoms of ADHD.

They cited the inability to assess ADHD symptoms in the children before the CNS infection among the study's limitations and said more studies were needed to confirm whether the increase in ADHD symptoms was specific to EV71 or also occurred with other microorganisms. Nevertheless, they concluded that an EV71 CNS infection “may affect long-term regulation of attention and emotion and cause hyperactivity-impulsivity in children” and recommended children with these infections be assessed early to identify and treat ADHD symptoms and emotional and behavioral problems.

The study was supported by a grant from the National Science Council of Taiwan's National Research Program for Genomic Medicine.

Children who had had an enterovirus 71 infection involving the central nervous system were significantly more likely to have symptoms of attention-deficit/hyperactivity disorder than were matched controls in a prospective study that evaluated children at 3-7 years after the infection.

Although herpes simplex encephalitis and other CNS infections can affect neurodevelopment and cognitive function, the authors said that this is the first study to follow up long-term behavioral outcomes or ADHD-related symptoms in children after an enterovirus 71 (EV71) CNS infection.

The findings have “clearly demonstrated the association between the EV71 CNS infection and increased symptoms of inattention, hyperactivity, oppositional defiance, internalizing problems, and increased likelihood of ADHD diagnosis,” concluded Dr. Susan Shur-Fen Gau of National Taiwan University, Taipei, and her associates.

The results also support their hypothesis that children who have had an EV71 CNS infection “are more likely to have ADHD-related symptoms regardless of IQ” (Pediatrics 2008;122:e452-8).

The study used standardized mother- and teacher-rated scales to evaluate ADHD symptoms and other emotional and behavioral problems in 86 children (51 boys and 35 girls; aged 4-16 years) who had had an EV71 CNS infection at the mean age of 2.5 years, and in 172 controls in the same neighborhoods or schools who were matched for gender, age, school performance, and parental education levels.

Among the children with the infections, CNS involvement had been mild in 42 cases (aseptic meningitis) and was severe in 35 cases (encephalitis, poliomyelitislike syndrome, or encephalomyelitis); the other 9 children had cardiopulmonary failure after CNS involvement.

The children had been diagnosed with the infections from 1998 to 2003 at Chang Gung Children's Hospital, Taoyuan, Taiwan, and National Taiwan University Hospital; there was an epidemic of EV71 infection in Taiwan in 1998.

Scores on teacher-rated and mother-rated scales of inattention, hyperactivity-impulsivity, oppositional symptoms, and ADHD index were significantly higher among the children with the EV71 infection, compared with controls. In the former group, 20% had elevated ADHD-related symptoms, compared with 3% of controls, a significant difference.

The maternal reports provided some evidence that children with the EV71 CNS infections had more internalizing problems, but this needs to be studied further, the investigators said.

There was no correlation between the age at which the child had the EV71 infection, any laboratory data, or the severity of CNS involvement with the severity of ADHD-related symptoms, a finding that the investigators said was surprising. They speculated that the EV71 infection may involve the prefrontal-striatum-subcortical area of the brain, or another area that is related to the core symptoms of ADHD.

The investigators acknowledged some limitations of the study, including the inability to assess ADHD symptoms in the children before the CNS infection, and said that more studies were needed to confirm whether the increase in ADHD symptoms was specific to EV71 or also occurred with other microorganisms.

Nevertheless, they concluded that an EV71 CNS infection “may affect long-term regulation of attention and emotion and cause hyperactivity-impulsivity in children,” and recommended that children with these infections be assessed early to identify ADHD symptoms and emotional and behavioral problems, because “early intervention may prove beneficial for their future performance.”

This work was supported by a grant from the National Science Council of Taiwan's National Research Program for Genomic Medicine.

Children who had had an enterovirus 71 infection involving the central nervous system were significantly more likely to have symptoms of attention-deficit/hyperactivity disorder than were matched controls in a prospective study that evaluated children at 3-7 years after the infection.

Although herpes simplex encephalitis and other CNS infections can affect neurodevelopment and cognitive function, the authors said that this is the first study to follow up long-term behavioral outcomes or ADHD-related symptoms in children after an enterovirus 71 (EV71) CNS infection.

The findings have “clearly demonstrated the association between the EV71 CNS infection and increased symptoms of inattention, hyperactivity, oppositional defiance, internalizing problems, and increased likelihood of ADHD diagnosis,” concluded Dr. Susan Shur-Fen Gau of National Taiwan University, Taipei, and her associates.

The results also support their hypothesis that children who have had an EV71 CNS infection “are more likely to have ADHD-related symptoms regardless of IQ” (Pediatrics 2008;122:e452-8).

The study used standardized mother- and teacher-rated scales to evaluate ADHD symptoms and other emotional and behavioral problems in 86 children (51 boys and 35 girls; aged 4-16 years) who had had an EV71 CNS infection at the mean age of 2.5 years, and in 172 controls in the same neighborhoods or schools who were matched for gender, age, school performance, and parental education levels.

Among the children with the infections, CNS involvement had been mild in 42 cases (aseptic meningitis) and was severe in 35 cases (encephalitis, poliomyelitislike syndrome, or encephalomyelitis); the other 9 children had cardiopulmonary failure after CNS involvement.

The children had been diagnosed with the infections from 1998 to 2003 at Chang Gung Children's Hospital, Taoyuan, Taiwan, and National Taiwan University Hospital; there was an epidemic of EV71 infection in Taiwan in 1998.

Scores on teacher-rated and mother-rated scales of inattention, hyperactivity-impulsivity, oppositional symptoms, and ADHD index were significantly higher among the children with the EV71 infection, compared with controls. In the former group, 20% had elevated ADHD-related symptoms, compared with 3% of controls, a significant difference.

The maternal reports provided some evidence that children with the EV71 CNS infections had more internalizing problems, but this needs to be studied further, the investigators said.

There was no correlation between the age at which the child had the EV71 infection, any laboratory data, or the severity of CNS involvement with the severity of ADHD-related symptoms, a finding that the investigators said was surprising. They speculated that the EV71 infection may involve the prefrontal-striatum-subcortical area of the brain, or another area that is related to the core symptoms of ADHD.

The investigators acknowledged some limitations of the study, including the inability to assess ADHD symptoms in the children before the CNS infection, and said that more studies were needed to confirm whether the increase in ADHD symptoms was specific to EV71 or also occurred with other microorganisms.

Nevertheless, they concluded that an EV71 CNS infection “may affect long-term regulation of attention and emotion and cause hyperactivity-impulsivity in children,” and recommended that children with these infections be assessed early to identify ADHD symptoms and emotional and behavioral problems, because “early intervention may prove beneficial for their future performance.”

This work was supported by a grant from the National Science Council of Taiwan's National Research Program for Genomic Medicine.

Children who had had an enterovirus 71 infection involving the central nervous system were significantly more likely to have symptoms of attention-deficit/hyperactivity disorder than were matched controls in a prospective study that evaluated children at 3-7 years after the infection.

Although herpes simplex encephalitis and other CNS infections can affect neurodevelopment and cognitive function, the authors said that this is the first study to follow up long-term behavioral outcomes or ADHD-related symptoms in children after an enterovirus 71 (EV71) CNS infection.

The findings have “clearly demonstrated the association between the EV71 CNS infection and increased symptoms of inattention, hyperactivity, oppositional defiance, internalizing problems, and increased likelihood of ADHD diagnosis,” concluded Dr. Susan Shur-Fen Gau of National Taiwan University, Taipei, and her associates.

The results also support their hypothesis that children who have had an EV71 CNS infection “are more likely to have ADHD-related symptoms regardless of IQ” (Pediatrics 2008;122:e452-8).

The study used standardized mother- and teacher-rated scales to evaluate ADHD symptoms and other emotional and behavioral problems in 86 children (51 boys and 35 girls; aged 4-16 years) who had had an EV71 CNS infection at the mean age of 2.5 years, and in 172 controls in the same neighborhoods or schools who were matched for gender, age, school performance, and parental education levels.

Among the children with the infections, CNS involvement had been mild in 42 cases (aseptic meningitis) and was severe in 35 cases (encephalitis, poliomyelitislike syndrome, or encephalomyelitis); the other 9 children had cardiopulmonary failure after CNS involvement.

The children had been diagnosed with the infections from 1998 to 2003 at Chang Gung Children's Hospital, Taoyuan, Taiwan, and National Taiwan University Hospital; there was an epidemic of EV71 infection in Taiwan in 1998.

Scores on teacher-rated and mother-rated scales of inattention, hyperactivity-impulsivity, oppositional symptoms, and ADHD index were significantly higher among the children with the EV71 infection, compared with controls. In the former group, 20% had elevated ADHD-related symptoms, compared with 3% of controls, a significant difference.

The maternal reports provided some evidence that children with the EV71 CNS infections had more internalizing problems, but this needs to be studied further, the investigators said.

There was no correlation between the age at which the child had the EV71 infection, any laboratory data, or the severity of CNS involvement with the severity of ADHD-related symptoms, a finding that the investigators said was surprising. They speculated that the EV71 infection may involve the prefrontal-striatum-subcortical area of the brain, or another area that is related to the core symptoms of ADHD.

The investigators acknowledged some limitations of the study, including the inability to assess ADHD symptoms in the children before the CNS infection, and said that more studies were needed to confirm whether the increase in ADHD symptoms was specific to EV71 or also occurred with other microorganisms.

Nevertheless, they concluded that an EV71 CNS infection “may affect long-term regulation of attention and emotion and cause hyperactivity-impulsivity in children,” and recommended that children with these infections be assessed early to identify ADHD symptoms and emotional and behavioral problems, because “early intervention may prove beneficial for their future performance.”

This work was supported by a grant from the National Science Council of Taiwan's National Research Program for Genomic Medicine.

COLLEGE PARK, MD. — Clinical trial data show that the antibiotic telavancin is safe and effective for treating complicated skin and skin-structure infections, including those caused by methicillin-resistant Staphylococcus aureus, the majority of a federal advisory panel agreed.

The Food and Drug Administration's anti-infective drugs advisory committee voted 21–5 regarding the safety and efficacy of telavancin, with those voting in favor saying that despite their concerns about nephrotoxicity, QT prolongation, and possible teratogenic effects associated with the drug, they believed these risks were manageable.

The panel voted 18–5, with 3 abstentions, that there could be clinical situations in which the benefits of telavancin in pregnant women would outweigh its risks. All but one panelist agreed that a risk management strategy was needed to prevent unintended use in pregnant women or in women of childbearing potential.

Theravance Inc., the drug's manufacturer, has developed a risk management plan designed to minimize pregnancy exposures, the risk of nephrotoxicity, and the risk related to QT prolongation, and has proposed that the drug not be used during pregnancy, unless the benefit to the patient outweighs the potential risks to the fetus. The plan also includes recommendations to adjust the dose based on creatinine clearance and to avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.

“I voted 'yes,' because I think vancomycin is a dying drug, and I see vancomycin resistance all the time,” said panelist Dr. W. Kemper Alston, who is at the University of Vermont, Burlington. Those voting “no” on the safety and efficacy question cited concerns about the association of the drug with more than one toxicity.

“Safety concerns in multiple systems, not just one, complicate risk management,” said the acting panel chair, Dr. L. Barth Reller, professor of medicine and pathology, Duke University, Durham, N.C. The mechanism of action was not that different from vancomycin, he added, so it is unclear how much its use would affect the problem of increasing resistance.

The FDA usually follows the advice of its advisory panels, which is not binding. The proposed indication for telavancin is for the treatment of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis.

Telavancin, a bactericidal lipoglycopeptide antibiotic that has bactericidal activity against most gram-positive bacteria, is administered intravenously once daily. It has a dual mechanism of action: It inhibits cell wall synthesis, like vancomycin, but also disrupts the function of the bacterial membrane, according to Theravance.

For approval, the company submitted the results of two double-blind, randomized phase III noninferiority studies of almost 1,800 adults with cSSSI caused by gram-positive bacteria, enrolled in 2005–2006. (Half of the 1,320 patients with microbiological confirmation of pathogens at baseline had MRSA.) The patients were treated with telavancin or vancomycin. The FDA and company analyses indicated that in both studies, treatment with telavancin for 7–14 days was as effective as with vancomycin—the current standard of care.

Adverse events with telavancin were mostly mild or moderate. The rate of renal adverse events among those on telavancin was 3.4%, compared with 1.2% among those on vancomycin; the rate of severe renal adverse events was also higher among those on telavancin (1.2% vs. 0.4%).

Cardiac-related severe adverse events were similar among those on telavancin and vancomycin (11% in both groups). Four patients on telavancin and six on vancomycin had a fatal cardiac event; two deaths in the telavancin group were possibly related to the drug, according to the FDA.

COLLEGE PARK, MD. — Clinical trial data show that the antibiotic telavancin is safe and effective for treating complicated skin and skin-structure infections, including those caused by methicillin-resistant Staphylococcus aureus, the majority of a federal advisory panel agreed.

The Food and Drug Administration's anti-infective drugs advisory committee voted 21–5 regarding the safety and efficacy of telavancin, with those voting in favor saying that despite their concerns about nephrotoxicity, QT prolongation, and possible teratogenic effects associated with the drug, they believed these risks were manageable.

The panel voted 18–5, with 3 abstentions, that there could be clinical situations in which the benefits of telavancin in pregnant women would outweigh its risks. All but one panelist agreed that a risk management strategy was needed to prevent unintended use in pregnant women or in women of childbearing potential.

Theravance Inc., the drug's manufacturer, has developed a risk management plan designed to minimize pregnancy exposures, the risk of nephrotoxicity, and the risk related to QT prolongation, and has proposed that the drug not be used during pregnancy, unless the benefit to the patient outweighs the potential risks to the fetus. The plan also includes recommendations to adjust the dose based on creatinine clearance and to avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.

“I voted 'yes,' because I think vancomycin is a dying drug, and I see vancomycin resistance all the time,” said panelist Dr. W. Kemper Alston, who is at the University of Vermont, Burlington. Those voting “no” on the safety and efficacy question cited concerns about the association of the drug with more than one toxicity.

“Safety concerns in multiple systems, not just one, complicate risk management,” said the acting panel chair, Dr. L. Barth Reller, professor of medicine and pathology, Duke University, Durham, N.C. The mechanism of action was not that different from vancomycin, he added, so it is unclear how much its use would affect the problem of increasing resistance.

The FDA usually follows the advice of its advisory panels, which is not binding. The proposed indication for telavancin is for the treatment of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis.

Telavancin, a bactericidal lipoglycopeptide antibiotic that has bactericidal activity against most gram-positive bacteria, is administered intravenously once daily. It has a dual mechanism of action: It inhibits cell wall synthesis, like vancomycin, but also disrupts the function of the bacterial membrane, according to Theravance.

For approval, the company submitted the results of two double-blind, randomized phase III noninferiority studies of almost 1,800 adults with cSSSI caused by gram-positive bacteria, enrolled in 2005–2006. (Half of the 1,320 patients with microbiological confirmation of pathogens at baseline had MRSA.) The patients were treated with telavancin or vancomycin. The FDA and company analyses indicated that in both studies, treatment with telavancin for 7–14 days was as effective as with vancomycin—the current standard of care.

Adverse events with telavancin were mostly mild or moderate. The rate of renal adverse events among those on telavancin was 3.4%, compared with 1.2% among those on vancomycin; the rate of severe renal adverse events was also higher among those on telavancin (1.2% vs. 0.4%).

Cardiac-related severe adverse events were similar among those on telavancin and vancomycin (11% in both groups). Four patients on telavancin and six on vancomycin had a fatal cardiac event; two deaths in the telavancin group were possibly related to the drug, according to the FDA.

COLLEGE PARK, MD. — Clinical trial data show that the antibiotic telavancin is safe and effective for treating complicated skin and skin-structure infections, including those caused by methicillin-resistant Staphylococcus aureus, the majority of a federal advisory panel agreed.

The Food and Drug Administration's anti-infective drugs advisory committee voted 21–5 regarding the safety and efficacy of telavancin, with those voting in favor saying that despite their concerns about nephrotoxicity, QT prolongation, and possible teratogenic effects associated with the drug, they believed these risks were manageable.

The panel voted 18–5, with 3 abstentions, that there could be clinical situations in which the benefits of telavancin in pregnant women would outweigh its risks. All but one panelist agreed that a risk management strategy was needed to prevent unintended use in pregnant women or in women of childbearing potential.

Theravance Inc., the drug's manufacturer, has developed a risk management plan designed to minimize pregnancy exposures, the risk of nephrotoxicity, and the risk related to QT prolongation, and has proposed that the drug not be used during pregnancy, unless the benefit to the patient outweighs the potential risks to the fetus. The plan also includes recommendations to adjust the dose based on creatinine clearance and to avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.

“I voted 'yes,' because I think vancomycin is a dying drug, and I see vancomycin resistance all the time,” said panelist Dr. W. Kemper Alston, who is at the University of Vermont, Burlington. Those voting “no” on the safety and efficacy question cited concerns about the association of the drug with more than one toxicity.

“Safety concerns in multiple systems, not just one, complicate risk management,” said the acting panel chair, Dr. L. Barth Reller, professor of medicine and pathology, Duke University, Durham, N.C. The mechanism of action was not that different from vancomycin, he added, so it is unclear how much its use would affect the problem of increasing resistance.

The FDA usually follows the advice of its advisory panels, which is not binding. The proposed indication for telavancin is for the treatment of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis.

Telavancin, a bactericidal lipoglycopeptide antibiotic that has bactericidal activity against most gram-positive bacteria, is administered intravenously once daily. It has a dual mechanism of action: It inhibits cell wall synthesis, like vancomycin, but also disrupts the function of the bacterial membrane, according to Theravance.

For approval, the company submitted the results of two double-blind, randomized phase III noninferiority studies of almost 1,800 adults with cSSSI caused by gram-positive bacteria, enrolled in 2005–2006. (Half of the 1,320 patients with microbiological confirmation of pathogens at baseline had MRSA.) The patients were treated with telavancin or vancomycin. The FDA and company analyses indicated that in both studies, treatment with telavancin for 7–14 days was as effective as with vancomycin—the current standard of care.

Adverse events with telavancin were mostly mild or moderate. The rate of renal adverse events among those on telavancin was 3.4%, compared with 1.2% among those on vancomycin; the rate of severe renal adverse events was also higher among those on telavancin (1.2% vs. 0.4%).

Cardiac-related severe adverse events were similar among those on telavancin and vancomycin (11% in both groups). Four patients on telavancin and six on vancomycin had a fatal cardiac event; two deaths in the telavancin group were possibly related to the drug, according to the FDA.

An implantable bronchial valve designed to control prolonged air leaks of the lung after lobectomy, segmentectomy, or lung volume reduction surgery has been approved by the Food and Drug Administration.

The IBV Valve System includes the valve, a catheter for inserting it, and a sizing kit to measure the target area for valve implantation, according to the FDA statement announcing the approval. The system is used to treat patients “who have undergone partial or total removal of a lung lobe or lung volume reduction surgery and who experience prolonged air leaks [present 7 days after surgery] or significant air leaks that may become prolonged,” the FDA said.

The catheter containing the valve is passed through a bronchoscope, and the valve is then placed in the affected area of the lung, where it self-expands and redirects air flow from the diseased regions while allowing secretions and trapped air to pass through, according to Spiration Inc., the manufacturer. The valve expands and contracts with breathing and can be removed during a bronchoscopy.

The valve was approved under the Humanitarian Device Exemption program, which applies to devices for diseases or conditions that affect fewer than 4,000 people in the United States every year.

Approval was based on successful use of the valve in 58 patients with emphysema and 4 patients with prolonged air leaks, according to Spiration.

The company plans to conduct a postapproval study to obtain more safety and efficacy information about the system.

The valve is being studied in a pivotal trial of U.S. patients with severe emphysema.

Patients aged 40–70 years with predominantly upper lobe emphysema and shortness of breath with exertion who have had inadequate responses to available medical treatments and who are either ineligible for or opposed to invasive surgery are being enrolled in the trial, according to Spiration.

The study is comparing response rates and serious adverse events at 6 months among those who have the valve implanted and controls, who undergo a diagnostic bronchoscopy with no valves implanted.

The approval “is an extremely important step for patients with emphysema,” said Dr. Robert James Cerfolio, professor of surgery and chief of the section of thoracic surgery at the University of Alabama at Birmingham, who has had significant experience with these valves.

Dr. Cerfolio said in an interview that several well-designed studies have shown that “in properly selected patients, these one-way valves, which can be easily placed via a bronchoscope and which block the entry of air into emphysematous segments of the lung but allow for mucus exit, improve the breathlessness these patients experience.” These studies include several presented in May 2008 at the American Thoracic Society meeting in Toronto.

“Although the mechanism of action is different than that seen in lung volume reduction surgery, the improvement in dyspnea in these patients may be just as good,” Dr. Cerfolio noted in the interview, adding that the technique entails a 15- to 20-minute bronchoscopy, and thereby avoids the morbidity associated with surgery.

Dr. Cerfolio is an investigator in a study of the implantable bronchial valve.

An implantable bronchial valve designed to control prolonged air leaks of the lung after lobectomy, segmentectomy, or lung volume reduction surgery has been approved by the Food and Drug Administration.

The IBV Valve System includes the valve, a catheter for inserting it, and a sizing kit to measure the target area for valve implantation, according to the FDA statement announcing the approval. The system is used to treat patients “who have undergone partial or total removal of a lung lobe or lung volume reduction surgery and who experience prolonged air leaks [present 7 days after surgery] or significant air leaks that may become prolonged,” the FDA said.

The catheter containing the valve is passed through a bronchoscope, and the valve is then placed in the affected area of the lung, where it self-expands and redirects air flow from the diseased regions while allowing secretions and trapped air to pass through, according to Spiration Inc., the manufacturer. The valve expands and contracts with breathing and can be removed during a bronchoscopy.

The valve was approved under the Humanitarian Device Exemption program, which applies to devices for diseases or conditions that affect fewer than 4,000 people in the United States every year.

Approval was based on successful use of the valve in 58 patients with emphysema and 4 patients with prolonged air leaks, according to Spiration.

The company plans to conduct a postapproval study to obtain more safety and efficacy information about the system.

The valve is being studied in a pivotal trial of U.S. patients with severe emphysema.

Patients aged 40–70 years with predominantly upper lobe emphysema and shortness of breath with exertion who have had inadequate responses to available medical treatments and who are either ineligible for or opposed to invasive surgery are being enrolled in the trial, according to Spiration.

The study is comparing response rates and serious adverse events at 6 months among those who have the valve implanted and controls, who undergo a diagnostic bronchoscopy with no valves implanted.

The approval “is an extremely important step for patients with emphysema,” said Dr. Robert James Cerfolio, professor of surgery and chief of the section of thoracic surgery at the University of Alabama at Birmingham, who has had significant experience with these valves.

Dr. Cerfolio said in an interview that several well-designed studies have shown that “in properly selected patients, these one-way valves, which can be easily placed via a bronchoscope and which block the entry of air into emphysematous segments of the lung but allow for mucus exit, improve the breathlessness these patients experience.” These studies include several presented in May 2008 at the American Thoracic Society meeting in Toronto.

“Although the mechanism of action is different than that seen in lung volume reduction surgery, the improvement in dyspnea in these patients may be just as good,” Dr. Cerfolio noted in the interview, adding that the technique entails a 15- to 20-minute bronchoscopy, and thereby avoids the morbidity associated with surgery.

Dr. Cerfolio is an investigator in a study of the implantable bronchial valve.

An implantable bronchial valve designed to control prolonged air leaks of the lung after lobectomy, segmentectomy, or lung volume reduction surgery has been approved by the Food and Drug Administration.

The IBV Valve System includes the valve, a catheter for inserting it, and a sizing kit to measure the target area for valve implantation, according to the FDA statement announcing the approval. The system is used to treat patients “who have undergone partial or total removal of a lung lobe or lung volume reduction surgery and who experience prolonged air leaks [present 7 days after surgery] or significant air leaks that may become prolonged,” the FDA said.

The catheter containing the valve is passed through a bronchoscope, and the valve is then placed in the affected area of the lung, where it self-expands and redirects air flow from the diseased regions while allowing secretions and trapped air to pass through, according to Spiration Inc., the manufacturer. The valve expands and contracts with breathing and can be removed during a bronchoscopy.

The valve was approved under the Humanitarian Device Exemption program, which applies to devices for diseases or conditions that affect fewer than 4,000 people in the United States every year.

Approval was based on successful use of the valve in 58 patients with emphysema and 4 patients with prolonged air leaks, according to Spiration.

The company plans to conduct a postapproval study to obtain more safety and efficacy information about the system.

The valve is being studied in a pivotal trial of U.S. patients with severe emphysema.

Patients aged 40–70 years with predominantly upper lobe emphysema and shortness of breath with exertion who have had inadequate responses to available medical treatments and who are either ineligible for or opposed to invasive surgery are being enrolled in the trial, according to Spiration.

The study is comparing response rates and serious adverse events at 6 months among those who have the valve implanted and controls, who undergo a diagnostic bronchoscopy with no valves implanted.

The approval “is an extremely important step for patients with emphysema,” said Dr. Robert James Cerfolio, professor of surgery and chief of the section of thoracic surgery at the University of Alabama at Birmingham, who has had significant experience with these valves.

Dr. Cerfolio said in an interview that several well-designed studies have shown that “in properly selected patients, these one-way valves, which can be easily placed via a bronchoscope and which block the entry of air into emphysematous segments of the lung but allow for mucus exit, improve the breathlessness these patients experience.” These studies include several presented in May 2008 at the American Thoracic Society meeting in Toronto.

“Although the mechanism of action is different than that seen in lung volume reduction surgery, the improvement in dyspnea in these patients may be just as good,” Dr. Cerfolio noted in the interview, adding that the technique entails a 15- to 20-minute bronchoscopy, and thereby avoids the morbidity associated with surgery.

Dr. Cerfolio is an investigator in a study of the implantable bronchial valve.

The expanded approval of the currently marketed human papillomavirus vaccine to women aged 27–45 years is being held up, at least until the manufacturer addresses some outstanding issues.

In a statement issued in late June the manufacturer of Gardasil, Merck & Co., announced that the Food and Drug Administration had advised the company that there were issues that precluded approval of the vaccine for the older age group within the time frame that had been specified for the FDA's review to be completed.

The company has discussed the FDA's questions with the agency and at press time was expected to respond to the issues raised, according to Merck's statement. Neither the company nor the FDA elaborated on the specific issues.

In 2006, Gardasil (Human Papillomavirus Quadrivalent [Types 6, 11, 16, 18] Vaccine, Recombinant) was approved for girls and women aged 9–26 years for prevention of cervical cancer, precancerous or dysplastic lesions, and genital warts caused by HPV types 6, 11, 16, and 18.

The FDA designated the review of Gardasil in the older age group as a priority review in March. Data from clinical trials in older women were presented by Merck at the winter meeting of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention. In placebo-controlled studies on Gardasil, including one study of almost 4,000 women aged 24–45 years, two-thirds of the women were negative for all four HPV serotypes in the vaccine, and about one-third were positive for one or more of the HPV vaccine serotypes; only 0.4% of the vaccine recipients and 0.3% of the controls were positive for all four.

Over a mean follow-up of 2.2 years, primary efficacy of the vaccine against persistent infection, cervical intraepithelial neoplasia, or external genital lesions caused by any of the four vaccine strains was 92% among subjects aged 24–34 years and 89% among 35- to 45-year-olds. Efficacy against cervical intraepithelial neoplasia or external genital lesions caused by any of the four vaccine serotypes was 92% (88% for 16 and 18, 100% for 6 and 11). Safety profiles were similar to those seen in the 16- to 26-year-old age group, with no serious vaccine-related adverse events among vaccine recipients.

The expanded approval of the currently marketed human papillomavirus vaccine to women aged 27–45 years is being held up, at least until the manufacturer addresses some outstanding issues.

In a statement issued in late June the manufacturer of Gardasil, Merck & Co., announced that the Food and Drug Administration had advised the company that there were issues that precluded approval of the vaccine for the older age group within the time frame that had been specified for the FDA's review to be completed.

The company has discussed the FDA's questions with the agency and at press time was expected to respond to the issues raised, according to Merck's statement. Neither the company nor the FDA elaborated on the specific issues.

In 2006, Gardasil (Human Papillomavirus Quadrivalent [Types 6, 11, 16, 18] Vaccine, Recombinant) was approved for girls and women aged 9–26 years for prevention of cervical cancer, precancerous or dysplastic lesions, and genital warts caused by HPV types 6, 11, 16, and 18.

The FDA designated the review of Gardasil in the older age group as a priority review in March. Data from clinical trials in older women were presented by Merck at the winter meeting of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention. In placebo-controlled studies on Gardasil, including one study of almost 4,000 women aged 24–45 years, two-thirds of the women were negative for all four HPV serotypes in the vaccine, and about one-third were positive for one or more of the HPV vaccine serotypes; only 0.4% of the vaccine recipients and 0.3% of the controls were positive for all four.

Over a mean follow-up of 2.2 years, primary efficacy of the vaccine against persistent infection, cervical intraepithelial neoplasia, or external genital lesions caused by any of the four vaccine strains was 92% among subjects aged 24–34 years and 89% among 35- to 45-year-olds. Efficacy against cervical intraepithelial neoplasia or external genital lesions caused by any of the four vaccine serotypes was 92% (88% for 16 and 18, 100% for 6 and 11). Safety profiles were similar to those seen in the 16- to 26-year-old age group, with no serious vaccine-related adverse events among vaccine recipients.

The expanded approval of the currently marketed human papillomavirus vaccine to women aged 27–45 years is being held up, at least until the manufacturer addresses some outstanding issues.

In a statement issued in late June the manufacturer of Gardasil, Merck & Co., announced that the Food and Drug Administration had advised the company that there were issues that precluded approval of the vaccine for the older age group within the time frame that had been specified for the FDA's review to be completed.

The company has discussed the FDA's questions with the agency and at press time was expected to respond to the issues raised, according to Merck's statement. Neither the company nor the FDA elaborated on the specific issues.

In 2006, Gardasil (Human Papillomavirus Quadrivalent [Types 6, 11, 16, 18] Vaccine, Recombinant) was approved for girls and women aged 9–26 years for prevention of cervical cancer, precancerous or dysplastic lesions, and genital warts caused by HPV types 6, 11, 16, and 18.

The FDA designated the review of Gardasil in the older age group as a priority review in March. Data from clinical trials in older women were presented by Merck at the winter meeting of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention. In placebo-controlled studies on Gardasil, including one study of almost 4,000 women aged 24–45 years, two-thirds of the women were negative for all four HPV serotypes in the vaccine, and about one-third were positive for one or more of the HPV vaccine serotypes; only 0.4% of the vaccine recipients and 0.3% of the controls were positive for all four.

Over a mean follow-up of 2.2 years, primary efficacy of the vaccine against persistent infection, cervical intraepithelial neoplasia, or external genital lesions caused by any of the four vaccine strains was 92% among subjects aged 24–34 years and 89% among 35- to 45-year-olds. Efficacy against cervical intraepithelial neoplasia or external genital lesions caused by any of the four vaccine serotypes was 92% (88% for 16 and 18, 100% for 6 and 11). Safety profiles were similar to those seen in the 16- to 26-year-old age group, with no serious vaccine-related adverse events among vaccine recipients.

SILVER SPRING, MD. — The Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee voted 8 – 3 that tolvaptan, an oral selective arginine vasopressin (AVP) V2-receptor antagonist administered once a day, be approved for use in the chronic treatment of hypervolemic or euvolemic hyponatremia.

Recommendations of those voting in favor of approval included limiting treatment to patients with very low serum sodium levels, hospitalizing patients at the start of treatment, and conducting postmarketing follow-up of patients on chronic treatment.

The panel also agreed in an 8 – 3 vote that there was adequate evidence that the drug could be expected to produce clinical benefits in the treatment of this group of patients. But several panelists said they were more convinced about the benefits in people whose serum levels were below 130 mEq/L, and that they would not be comfortable using tolvaptan to treat people with higher sodium levels until there was more evidence about whether treatment made a difference for this group.

Most of the panel agreed that there were no safety issues that would affect approvability, although several panelists were concerned about bleeding in cirrhosis patients, thirst, and the need for more long-term data, because it would be used chronically in many patients.

Tolvaptan, a product of Otsuka Pharmaceutical Development and Commercialization Inc., belongs to the “vaptan” class of compounds that blocks the action of AVP in the collecting ducts and induces free water clearance in the body (aquaresis), according to the company.

Because the company is pursuing approval of efficacy claims based on tolvaptan's ability to increase serum sodium levels in patients with hyponatremia, the agency said it held the meeting to obtain guidance from the panel on “how best to define efficacy for products such as tolvaptan, where there may be a clear demonstration of activity,” which in this case is increasing serum sodium concentration, “without a clearly tangible clinical benefit.”

In addition to the hyponatremia indication, the FDA is also reviewing tolvaptan as a treatment for worsening HF, regardless of baseline serum sodium. The panel was not asked to review or vote on the HF indication, which was studied in patients hospitalized for HF in the phase III study, Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST).

Most of the data presented by Otsuka were from two phase III studies of patients with hyponatremia due to all causes, with heart failure, antidiuretic hormone (SIADH), or cirrhosis; their mean age was 61–62 years, the mean serum sodium was 129 mEq/L, and about half had levels below 130 mEq/L.

The studies, SALT-1 and 2, compared daily treatment with 15 mg of tolvaptan a day to placebo and found that treatment improved hyponatremia, prevented worsening of hyponatremia, and maintained superior mean serum sodium concentrations from day 4 and at 30 days, when compared with those on placebo. More than 70% of patients completed the 30-day evaluation. The largest effects were seen in the SIADH patients.

The primary end point was the average daily area under the curve changes in serum sodium concentration from baseline to day 4 (short-term) and from baseline to day 30 (sustained), which were significant in both studies, and in a pooled analysis of the studies. In the pooled analysis, the average daily AUC of mean change from baseline in serum sodium levels was 4.0 mEq/L for those on tolvaptan, compared with 0. 4 mEq/L for those on placebo (from baseline to day 4), and 6.2 mEq/L for those on tolvaptan compared with 1.8 mEq/L for those on placebo (the sustained effect).

The most common adverse effects included excessive thirst and dry mouth. Serious adverse events included more cases of GI bleeding in cirrhotic patients on tolvaptan than those on placebo. Overly rapid correction of serum sodium was seen in some patients, but without neurologic sequelae, said Otsuka.

The company also used two patient-reported outcome scales to measure the clinical impact of changes in sodium level changes on treatment on quality of life measure. The mental component scores of one of the scales, the SF-12, improved and were positively correlated with changes in serum sodium in one of the two studies, but not the other.

Otsuka also presented supportive data on a subgroup of 475 patients with hyponatremia, who were in the EVEREST study of patients hospitalized for HF, who received 30 mg of tolvaptan daily or placebo. Their mean LVEF was 26%, most were male. Those on tolvaptan had a significantly greater rates of normalization of serum sodium on day 1 and at discharge, and significantly fewer treated patients went from mild to severe hyponatremia, said Otsuka. Patients with treated with tolvaptan also reported greater improvements in dyspnea than those on placebo.

Those voting against approval included Dr. Robert Harrington, professor of medicine, in the division of cardiology, Duke University, Durham, N.C., who cited as concerns the lack of data in the outpatient setting, the small amount of long-term data in those on chronic treatment; and bleeding in cirrhotic patients.

Tolvaptan should be studied in a phase III trial in outpatients, managed by clinicians other than renal and endocrine experts, to “mimic how it will be incorporated into practice,” he said.

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

If approved, Otsuka plans to market tolvaptan under the trade name Samska. It would be the second drug approved in this class. In 2005, the FDA approved conivaptan for treating euvolemic hyponatremia in hospitalized patients, but it's administered intravenously.

SILVER SPRING, MD. — The Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee voted 8 – 3 that tolvaptan, an oral selective arginine vasopressin (AVP) V2-receptor antagonist administered once a day, be approved for use in the chronic treatment of hypervolemic or euvolemic hyponatremia.

Recommendations of those voting in favor of approval included limiting treatment to patients with very low serum sodium levels, hospitalizing patients at the start of treatment, and conducting postmarketing follow-up of patients on chronic treatment.

The panel also agreed in an 8 – 3 vote that there was adequate evidence that the drug could be expected to produce clinical benefits in the treatment of this group of patients. But several panelists said they were more convinced about the benefits in people whose serum levels were below 130 mEq/L, and that they would not be comfortable using tolvaptan to treat people with higher sodium levels until there was more evidence about whether treatment made a difference for this group.

Most of the panel agreed that there were no safety issues that would affect approvability, although several panelists were concerned about bleeding in cirrhosis patients, thirst, and the need for more long-term data, because it would be used chronically in many patients.

Tolvaptan, a product of Otsuka Pharmaceutical Development and Commercialization Inc., belongs to the “vaptan” class of compounds that blocks the action of AVP in the collecting ducts and induces free water clearance in the body (aquaresis), according to the company.

Because the company is pursuing approval of efficacy claims based on tolvaptan's ability to increase serum sodium levels in patients with hyponatremia, the agency said it held the meeting to obtain guidance from the panel on “how best to define efficacy for products such as tolvaptan, where there may be a clear demonstration of activity,” which in this case is increasing serum sodium concentration, “without a clearly tangible clinical benefit.”

In addition to the hyponatremia indication, the FDA is also reviewing tolvaptan as a treatment for worsening HF, regardless of baseline serum sodium. The panel was not asked to review or vote on the HF indication, which was studied in patients hospitalized for HF in the phase III study, Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST).

Most of the data presented by Otsuka were from two phase III studies of patients with hyponatremia due to all causes, with heart failure, antidiuretic hormone (SIADH), or cirrhosis; their mean age was 61–62 years, the mean serum sodium was 129 mEq/L, and about half had levels below 130 mEq/L.

The studies, SALT-1 and 2, compared daily treatment with 15 mg of tolvaptan a day to placebo and found that treatment improved hyponatremia, prevented worsening of hyponatremia, and maintained superior mean serum sodium concentrations from day 4 and at 30 days, when compared with those on placebo. More than 70% of patients completed the 30-day evaluation. The largest effects were seen in the SIADH patients.

The primary end point was the average daily area under the curve changes in serum sodium concentration from baseline to day 4 (short-term) and from baseline to day 30 (sustained), which were significant in both studies, and in a pooled analysis of the studies. In the pooled analysis, the average daily AUC of mean change from baseline in serum sodium levels was 4.0 mEq/L for those on tolvaptan, compared with 0. 4 mEq/L for those on placebo (from baseline to day 4), and 6.2 mEq/L for those on tolvaptan compared with 1.8 mEq/L for those on placebo (the sustained effect).

The most common adverse effects included excessive thirst and dry mouth. Serious adverse events included more cases of GI bleeding in cirrhotic patients on tolvaptan than those on placebo. Overly rapid correction of serum sodium was seen in some patients, but without neurologic sequelae, said Otsuka.

The company also used two patient-reported outcome scales to measure the clinical impact of changes in sodium level changes on treatment on quality of life measure. The mental component scores of one of the scales, the SF-12, improved and were positively correlated with changes in serum sodium in one of the two studies, but not the other.

Otsuka also presented supportive data on a subgroup of 475 patients with hyponatremia, who were in the EVEREST study of patients hospitalized for HF, who received 30 mg of tolvaptan daily or placebo. Their mean LVEF was 26%, most were male. Those on tolvaptan had a significantly greater rates of normalization of serum sodium on day 1 and at discharge, and significantly fewer treated patients went from mild to severe hyponatremia, said Otsuka. Patients with treated with tolvaptan also reported greater improvements in dyspnea than those on placebo.

Those voting against approval included Dr. Robert Harrington, professor of medicine, in the division of cardiology, Duke University, Durham, N.C., who cited as concerns the lack of data in the outpatient setting, the small amount of long-term data in those on chronic treatment; and bleeding in cirrhotic patients.

Tolvaptan should be studied in a phase III trial in outpatients, managed by clinicians other than renal and endocrine experts, to “mimic how it will be incorporated into practice,” he said.

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

If approved, Otsuka plans to market tolvaptan under the trade name Samska. It would be the second drug approved in this class. In 2005, the FDA approved conivaptan for treating euvolemic hyponatremia in hospitalized patients, but it's administered intravenously.

SILVER SPRING, MD. — The Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee voted 8 – 3 that tolvaptan, an oral selective arginine vasopressin (AVP) V2-receptor antagonist administered once a day, be approved for use in the chronic treatment of hypervolemic or euvolemic hyponatremia.

Recommendations of those voting in favor of approval included limiting treatment to patients with very low serum sodium levels, hospitalizing patients at the start of treatment, and conducting postmarketing follow-up of patients on chronic treatment.

The panel also agreed in an 8 – 3 vote that there was adequate evidence that the drug could be expected to produce clinical benefits in the treatment of this group of patients. But several panelists said they were more convinced about the benefits in people whose serum levels were below 130 mEq/L, and that they would not be comfortable using tolvaptan to treat people with higher sodium levels until there was more evidence about whether treatment made a difference for this group.

Most of the panel agreed that there were no safety issues that would affect approvability, although several panelists were concerned about bleeding in cirrhosis patients, thirst, and the need for more long-term data, because it would be used chronically in many patients.

Tolvaptan, a product of Otsuka Pharmaceutical Development and Commercialization Inc., belongs to the “vaptan” class of compounds that blocks the action of AVP in the collecting ducts and induces free water clearance in the body (aquaresis), according to the company.

Because the company is pursuing approval of efficacy claims based on tolvaptan's ability to increase serum sodium levels in patients with hyponatremia, the agency said it held the meeting to obtain guidance from the panel on “how best to define efficacy for products such as tolvaptan, where there may be a clear demonstration of activity,” which in this case is increasing serum sodium concentration, “without a clearly tangible clinical benefit.”

In addition to the hyponatremia indication, the FDA is also reviewing tolvaptan as a treatment for worsening HF, regardless of baseline serum sodium. The panel was not asked to review or vote on the HF indication, which was studied in patients hospitalized for HF in the phase III study, Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST).

Most of the data presented by Otsuka were from two phase III studies of patients with hyponatremia due to all causes, with heart failure, antidiuretic hormone (SIADH), or cirrhosis; their mean age was 61–62 years, the mean serum sodium was 129 mEq/L, and about half had levels below 130 mEq/L.

The studies, SALT-1 and 2, compared daily treatment with 15 mg of tolvaptan a day to placebo and found that treatment improved hyponatremia, prevented worsening of hyponatremia, and maintained superior mean serum sodium concentrations from day 4 and at 30 days, when compared with those on placebo. More than 70% of patients completed the 30-day evaluation. The largest effects were seen in the SIADH patients.

The primary end point was the average daily area under the curve changes in serum sodium concentration from baseline to day 4 (short-term) and from baseline to day 30 (sustained), which were significant in both studies, and in a pooled analysis of the studies. In the pooled analysis, the average daily AUC of mean change from baseline in serum sodium levels was 4.0 mEq/L for those on tolvaptan, compared with 0. 4 mEq/L for those on placebo (from baseline to day 4), and 6.2 mEq/L for those on tolvaptan compared with 1.8 mEq/L for those on placebo (the sustained effect).

The most common adverse effects included excessive thirst and dry mouth. Serious adverse events included more cases of GI bleeding in cirrhotic patients on tolvaptan than those on placebo. Overly rapid correction of serum sodium was seen in some patients, but without neurologic sequelae, said Otsuka.

The company also used two patient-reported outcome scales to measure the clinical impact of changes in sodium level changes on treatment on quality of life measure. The mental component scores of one of the scales, the SF-12, improved and were positively correlated with changes in serum sodium in one of the two studies, but not the other.

Otsuka also presented supportive data on a subgroup of 475 patients with hyponatremia, who were in the EVEREST study of patients hospitalized for HF, who received 30 mg of tolvaptan daily or placebo. Their mean LVEF was 26%, most were male. Those on tolvaptan had a significantly greater rates of normalization of serum sodium on day 1 and at discharge, and significantly fewer treated patients went from mild to severe hyponatremia, said Otsuka. Patients with treated with tolvaptan also reported greater improvements in dyspnea than those on placebo.

Those voting against approval included Dr. Robert Harrington, professor of medicine, in the division of cardiology, Duke University, Durham, N.C., who cited as concerns the lack of data in the outpatient setting, the small amount of long-term data in those on chronic treatment; and bleeding in cirrhotic patients.

Tolvaptan should be studied in a phase III trial in outpatients, managed by clinicians other than renal and endocrine experts, to “mimic how it will be incorporated into practice,” he said.

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

If approved, Otsuka plans to market tolvaptan under the trade name Samska. It would be the second drug approved in this class. In 2005, the FDA approved conivaptan for treating euvolemic hyponatremia in hospitalized patients, but it's administered intravenously.