Elizabeth Mechcatie

SAN FRANCISCO — Hot flashes may not necessarily be a cause of depressive symptoms, according to a study that followed women in the menopausal transition for 10 years.

“We were interested in whether these symptoms were more likely to occur concurrently and which was more likely to come first among women in this transition period,” Mary D. Sammel, Sc.D., the study's lead author, said in an interview. The leading hypothesis is that hot flashes cause sleep problems, which lead to depressive symptoms in menopausal women, continued Dr. Sammel of the Center for Clinical Epidemiology and Biostatistics of the University of Pennsylvania, Philadelphia.

The study evaluated 170 women aged 35–47 who were enrolled in the ongoing Penn Ovarian Aging Study. Previous studies of this cohort had looked at these two symptom processes separately; the current study analyzed these symptoms together, she said at the annual meeting of the American Society for Reproductive Medicine.

At baseline, the women had no hot flashes or depressive symptoms, had had regular periods for the previous 3 months, and had premenopausal reproductive hormone levels. Women were then assessed annually via questionnaire. About half were white, and the rest were African American. Over the 10-year period, more than 60% of the women reported experiencing hot flashes and 50% reported depressive symptoms. About 41% reported that their hot flashes and depressive symptoms started at the same time.

Of the women who reported having both depressive symptoms and hot flashes, nearly 24% experienced depressive symptoms before they had hot flashes, which was a twofold higher rate than would be expected if the two processes were independent, based on statistical probability estimates. Only 8% of the women reported experiencing hot flashes before the development of depressive symptoms, which was less often than would be expected, based on the statistical probability they would occur in this pattern, Dr. Sammel said.

“Both processes have been associated with changes in reproductive hormones, but these patterns of reporting indicate the potential for different underlying mechanisms,” she and her coauthors concluded.

Previous studies of these women in the Penn Ovarian Aging Study cohort—which also includes women who already had menopausal symptoms when they were enrolled—have shown that the prevalence of depressive symptoms increases at the earliest stages of the menopausal transition, when women are experiencing small changes in reproductive hormones. This is followed by a decline in depressive symptoms in later stages of the menopausal transition, she said.

These findings suggest “it is the fluctuating hormones, earlier in the transition, which are more likely to influence depressive stages, and not the dramatic changes in estradiol and FSH, exhibited later in the transition,” Dr. Sammel noted.

SAN FRANCISCO — Hot flashes may not necessarily be a cause of depressive symptoms, according to a study that followed women in the menopausal transition for 10 years.

“We were interested in whether these symptoms were more likely to occur concurrently and which was more likely to come first among women in this transition period,” Mary D. Sammel, Sc.D., the study's lead author, said in an interview. The leading hypothesis is that hot flashes cause sleep problems, which lead to depressive symptoms in menopausal women, continued Dr. Sammel of the Center for Clinical Epidemiology and Biostatistics of the University of Pennsylvania, Philadelphia.

The study evaluated 170 women aged 35–47 who were enrolled in the ongoing Penn Ovarian Aging Study. Previous studies of this cohort had looked at these two symptom processes separately; the current study analyzed these symptoms together, she said at the annual meeting of the American Society for Reproductive Medicine.

At baseline, the women had no hot flashes or depressive symptoms, had had regular periods for the previous 3 months, and had premenopausal reproductive hormone levels. Women were then assessed annually via questionnaire. About half were white, and the rest were African American. Over the 10-year period, more than 60% of the women reported experiencing hot flashes and 50% reported depressive symptoms. About 41% reported that their hot flashes and depressive symptoms started at the same time.

Of the women who reported having both depressive symptoms and hot flashes, nearly 24% experienced depressive symptoms before they had hot flashes, which was a twofold higher rate than would be expected if the two processes were independent, based on statistical probability estimates. Only 8% of the women reported experiencing hot flashes before the development of depressive symptoms, which was less often than would be expected, based on the statistical probability they would occur in this pattern, Dr. Sammel said.

“Both processes have been associated with changes in reproductive hormones, but these patterns of reporting indicate the potential for different underlying mechanisms,” she and her coauthors concluded.

Previous studies of these women in the Penn Ovarian Aging Study cohort—which also includes women who already had menopausal symptoms when they were enrolled—have shown that the prevalence of depressive symptoms increases at the earliest stages of the menopausal transition, when women are experiencing small changes in reproductive hormones. This is followed by a decline in depressive symptoms in later stages of the menopausal transition, she said.

These findings suggest “it is the fluctuating hormones, earlier in the transition, which are more likely to influence depressive stages, and not the dramatic changes in estradiol and FSH, exhibited later in the transition,” Dr. Sammel noted.

SAN FRANCISCO — Hot flashes may not necessarily be a cause of depressive symptoms, according to a study that followed women in the menopausal transition for 10 years.

“We were interested in whether these symptoms were more likely to occur concurrently and which was more likely to come first among women in this transition period,” Mary D. Sammel, Sc.D., the study's lead author, said in an interview. The leading hypothesis is that hot flashes cause sleep problems, which lead to depressive symptoms in menopausal women, continued Dr. Sammel of the Center for Clinical Epidemiology and Biostatistics of the University of Pennsylvania, Philadelphia.

The study evaluated 170 women aged 35–47 who were enrolled in the ongoing Penn Ovarian Aging Study. Previous studies of this cohort had looked at these two symptom processes separately; the current study analyzed these symptoms together, she said at the annual meeting of the American Society for Reproductive Medicine.

At baseline, the women had no hot flashes or depressive symptoms, had had regular periods for the previous 3 months, and had premenopausal reproductive hormone levels. Women were then assessed annually via questionnaire. About half were white, and the rest were African American. Over the 10-year period, more than 60% of the women reported experiencing hot flashes and 50% reported depressive symptoms. About 41% reported that their hot flashes and depressive symptoms started at the same time.

Of the women who reported having both depressive symptoms and hot flashes, nearly 24% experienced depressive symptoms before they had hot flashes, which was a twofold higher rate than would be expected if the two processes were independent, based on statistical probability estimates. Only 8% of the women reported experiencing hot flashes before the development of depressive symptoms, which was less often than would be expected, based on the statistical probability they would occur in this pattern, Dr. Sammel said.

“Both processes have been associated with changes in reproductive hormones, but these patterns of reporting indicate the potential for different underlying mechanisms,” she and her coauthors concluded.

Previous studies of these women in the Penn Ovarian Aging Study cohort—which also includes women who already had menopausal symptoms when they were enrolled—have shown that the prevalence of depressive symptoms increases at the earliest stages of the menopausal transition, when women are experiencing small changes in reproductive hormones. This is followed by a decline in depressive symptoms in later stages of the menopausal transition, she said.

These findings suggest “it is the fluctuating hormones, earlier in the transition, which are more likely to influence depressive stages, and not the dramatic changes in estradiol and FSH, exhibited later in the transition,” Dr. Sammel noted.

Cases of Clostridium difficile-associated disease at children's hospitals increased significantly between 2001 and 2006, but in-hospital mortality and colectomy rates did not increase during that time, in what the authors say is the first study to report “the increasing nationwide burden” of C. difficile-associated disease at freestanding pediatric hospitals.

A significant increase in the use of oral metronidazole to treat C. difficile-associated disease (CDAD) and the preponderance of cases in children with complex medical conditions were among the other notable findings of the retrospective cohort study, conducted at 22 children's hospitals across the United States, according to Dr. Jason Kim of the division of infectious diseases at Children's Hospital of Philadelphia, and his associates (Pediatrics 2008;122:1266-70).

They pointed out that, while the incidence and severity of CDAD in adults had been increasing, the epidemiology of CDAD in the pediatric population has “remained relatively undefined.”

Previous studies were usually done in one center, and provided inconsistent results. But this study was a multicenter trial and documented the largest number of pediatric CDAD cases reported—4,895 cases among children under age 18 years, they said.

The median age of these children was 4 years; CDAD was defined as a hospitalized child with a discharge code for C. difficile infection, a laboratory billing charge for C. difficile toxin assay, and an initial dose of CDAD antimicrobial therapy (oral or parenteral administration of metronidazole or oral vancomycin).

Of the cases, 54% were boys, 76% were white, 26% were aged 1 year or younger, and 5% were under 1 month of age. Most (67%) had at least one complex underlying medical condition, which among children 1 month and younger was most often a cardiovascular condition; a malignancy was the most common condition among the oldest children.

Between 2001 and 2006, the annual rate of CDAD increased from 2.6 to 4.0 cases per 1,000 admissions, a 53% increase. No regional differences in CDAD incidence were detected.

When they analyzed age groups separately, the authors found a marked increase in cases among children ages 1-5 years, from 0.7 to 1.3 cases per 1,000 admissions, an 85% increase. There were increases from 1.2 to 1.8 cases per 1,000 admissions among children ages 5-17 years. But there was no significant difference in the CDAD incidence among children under age 1 year.

Single therapy of oral metronidazole was the most common treatment (61%), use of which increased significantly over the period studied. The use of oral vancomycin, which was used to treat 3.5% of the children, did not increase during the study.

During the period studied, 61 of the children underwent a colectomy, at a median age of 2.1 years, but the rate did not increase during the study.

All-cause mortality among the children with CDAD was 4%, and did not increase, unlike the increase that has been documented in adults, they observed.

The increase in CDAD cases in the hospitalized children could be attributable to more people carrying C. difficile, or to an increase in the more virulent strain of C. difficile, the North American pulsed-field gel electrophoresis type 1 (NAP1), which “is considered a major factor for the recent increase in adults,” Dr. Kim and his associates wrote.

The researchers pointed out that 26% of the cases occurred in children under age 1 year and 5% under age 1 month—a significant proportion of whom “were at an age previously thought to be unaffected by C. difficile toxin.”

Cases of Clostridium difficile-associated disease at children's hospitals increased significantly between 2001 and 2006, but in-hospital mortality and colectomy rates did not increase during that time, in what the authors say is the first study to report “the increasing nationwide burden” of C. difficile-associated disease at freestanding pediatric hospitals.

A significant increase in the use of oral metronidazole to treat C. difficile-associated disease (CDAD) and the preponderance of cases in children with complex medical conditions were among the other notable findings of the retrospective cohort study, conducted at 22 children's hospitals across the United States, according to Dr. Jason Kim of the division of infectious diseases at Children's Hospital of Philadelphia, and his associates (Pediatrics 2008;122:1266-70).

They pointed out that, while the incidence and severity of CDAD in adults had been increasing, the epidemiology of CDAD in the pediatric population has “remained relatively undefined.”

Previous studies were usually done in one center, and provided inconsistent results. But this study was a multicenter trial and documented the largest number of pediatric CDAD cases reported—4,895 cases among children under age 18 years, they said.

The median age of these children was 4 years; CDAD was defined as a hospitalized child with a discharge code for C. difficile infection, a laboratory billing charge for C. difficile toxin assay, and an initial dose of CDAD antimicrobial therapy (oral or parenteral administration of metronidazole or oral vancomycin).

Of the cases, 54% were boys, 76% were white, 26% were aged 1 year or younger, and 5% were under 1 month of age. Most (67%) had at least one complex underlying medical condition, which among children 1 month and younger was most often a cardiovascular condition; a malignancy was the most common condition among the oldest children.

Between 2001 and 2006, the annual rate of CDAD increased from 2.6 to 4.0 cases per 1,000 admissions, a 53% increase. No regional differences in CDAD incidence were detected.

When they analyzed age groups separately, the authors found a marked increase in cases among children ages 1-5 years, from 0.7 to 1.3 cases per 1,000 admissions, an 85% increase. There were increases from 1.2 to 1.8 cases per 1,000 admissions among children ages 5-17 years. But there was no significant difference in the CDAD incidence among children under age 1 year.

Single therapy of oral metronidazole was the most common treatment (61%), use of which increased significantly over the period studied. The use of oral vancomycin, which was used to treat 3.5% of the children, did not increase during the study.

During the period studied, 61 of the children underwent a colectomy, at a median age of 2.1 years, but the rate did not increase during the study.

All-cause mortality among the children with CDAD was 4%, and did not increase, unlike the increase that has been documented in adults, they observed.

The increase in CDAD cases in the hospitalized children could be attributable to more people carrying C. difficile, or to an increase in the more virulent strain of C. difficile, the North American pulsed-field gel electrophoresis type 1 (NAP1), which “is considered a major factor for the recent increase in adults,” Dr. Kim and his associates wrote.

The researchers pointed out that 26% of the cases occurred in children under age 1 year and 5% under age 1 month—a significant proportion of whom “were at an age previously thought to be unaffected by C. difficile toxin.”

Cases of Clostridium difficile-associated disease at children's hospitals increased significantly between 2001 and 2006, but in-hospital mortality and colectomy rates did not increase during that time, in what the authors say is the first study to report “the increasing nationwide burden” of C. difficile-associated disease at freestanding pediatric hospitals.

A significant increase in the use of oral metronidazole to treat C. difficile-associated disease (CDAD) and the preponderance of cases in children with complex medical conditions were among the other notable findings of the retrospective cohort study, conducted at 22 children's hospitals across the United States, according to Dr. Jason Kim of the division of infectious diseases at Children's Hospital of Philadelphia, and his associates (Pediatrics 2008;122:1266-70).

They pointed out that, while the incidence and severity of CDAD in adults had been increasing, the epidemiology of CDAD in the pediatric population has “remained relatively undefined.”

Previous studies were usually done in one center, and provided inconsistent results. But this study was a multicenter trial and documented the largest number of pediatric CDAD cases reported—4,895 cases among children under age 18 years, they said.

The median age of these children was 4 years; CDAD was defined as a hospitalized child with a discharge code for C. difficile infection, a laboratory billing charge for C. difficile toxin assay, and an initial dose of CDAD antimicrobial therapy (oral or parenteral administration of metronidazole or oral vancomycin).

Of the cases, 54% were boys, 76% were white, 26% were aged 1 year or younger, and 5% were under 1 month of age. Most (67%) had at least one complex underlying medical condition, which among children 1 month and younger was most often a cardiovascular condition; a malignancy was the most common condition among the oldest children.

Between 2001 and 2006, the annual rate of CDAD increased from 2.6 to 4.0 cases per 1,000 admissions, a 53% increase. No regional differences in CDAD incidence were detected.

When they analyzed age groups separately, the authors found a marked increase in cases among children ages 1-5 years, from 0.7 to 1.3 cases per 1,000 admissions, an 85% increase. There were increases from 1.2 to 1.8 cases per 1,000 admissions among children ages 5-17 years. But there was no significant difference in the CDAD incidence among children under age 1 year.

Single therapy of oral metronidazole was the most common treatment (61%), use of which increased significantly over the period studied. The use of oral vancomycin, which was used to treat 3.5% of the children, did not increase during the study.

During the period studied, 61 of the children underwent a colectomy, at a median age of 2.1 years, but the rate did not increase during the study.

All-cause mortality among the children with CDAD was 4%, and did not increase, unlike the increase that has been documented in adults, they observed.

The increase in CDAD cases in the hospitalized children could be attributable to more people carrying C. difficile, or to an increase in the more virulent strain of C. difficile, the North American pulsed-field gel electrophoresis type 1 (NAP1), which “is considered a major factor for the recent increase in adults,” Dr. Kim and his associates wrote.

The researchers pointed out that 26% of the cases occurred in children under age 1 year and 5% under age 1 month—a significant proportion of whom “were at an age previously thought to be unaffected by C. difficile toxin.”

COLLEGE PARK, MD. — The Food and Drug Administration has requested that a well-controlled clinical trial with an adequate number of patients with methicillin-resistant Staphylococcus aureus be conducted before the lipoglycopeptide antibiotic oritavancin is approved, according to the manufacturer.

The FDA made the request in a “complete response letter” to Targanta Therapeutics Corp. regarding its application for approval of oritavancin, the company said. The FDA's Anti-Infective Drugs Advisory Committee had voted 10–8 that data from two clinical trials of oritavancin failed to show that it is an effective and safe treatment for complicated skin and skin structure infections (cSSSIs), citing the need for more evidence to prove its efficacy against methicillin-resistant Staphylococcus aureus (MRSA).

Dr. Carol A. Kauffman, chief of infectious diseases, Veterans Affairs Health Care System, Ann Arbor, Mich., was among the majority voting no on the safety and efficacy question. “It may be a wonderful drug,” she said, but more information is needed. She urged the FDA to encourage Targanta to conduct a study of the drug in MRSA patients.

In the letter, the FDA said that the company had not shown the safety and efficacy of oritavancin for the proposed indication, according to Targanta. At the meeting, the FDA panel reviewed two studies submitted by Targanta, which compared oritavancin with vancomycin in approximately 2,000 adults with cSSSIs. Oritavancin inhibits cell wall biosynthesis with a mechanism of action similar to that of vancomycin but also disrupts the membranes of gram-positive bacteria and is active against gram-positive bacteria, including MRSA, according to Targanta.

The company has proposed that oritavancin be approved for treating adults with cSSSIs caused by susceptible isolates of the gram-positive organisms Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, the Streptococcus anginosus group, Streptococcus dysgalactiae, and Enterococcus faecalis (vancomycin-susceptible strains only). The recommended dosing regimen is 200 mg (300 mg for people who weigh more than 110 kg) daily for 3–7 days. It is administered in an intravenous infusion over 60 minutes.

In two randomized, double-blind phase III studies of approximately 2,000 adults with a cSSSI presumed or proved to be caused by gram-positive bacteria, the overall efficacy of once-daily treatment with oritavancin for 3–7 days was similar to a regimen of intravenous vancomycin twice a day for 3–7 days followed by daily oral cephalexin for a total of 10–14 days, with a low rate of relapse, the company said.

One study used a weight-based dose of oritavancin; the larger study used the fixed dose that is the proposed dose. A majority (10 of 18 panelists) voted that the weight-based dosing study did not provide independent evidence that oritavancin is effective for cSSSI, largely because the study was too small, was underpowered, and did not include enough MRSA cases.

In an 11–6 vote with 1 abstention, the panel voted that the larger study provided evidence that oritavancin was effective for cSSSI. However, several of those voting yes said that, while they agreed that the study showed oritavancin's overall effectiveness, they did not believe the study showed the drug was effective against cSSSI due to MRSA specifically. Those voting no expressed concern that there was insufficient evidence that oritavancin is effective against MRSA, the cause of most cases of cSSSI, and because it had not been studied in infections caused by contemporary isolates of MRSA (the study was conducted between 1998 and 2002).

In the fixed-dose study, the efficacy rate was about 12% lower among those infections identified as MRSA in the oritavancin arms, compared with those in the vancomycin arm, according to the FDA's presentation of the data.

The safety profiles of both regimens, including the number of deaths and significant adverse events, were comparable, although the rate of treatment-emergent adverse events was statistically lower among those on oritavancin.

COLLEGE PARK, MD. — The Food and Drug Administration has requested that a well-controlled clinical trial with an adequate number of patients with methicillin-resistant Staphylococcus aureus be conducted before the lipoglycopeptide antibiotic oritavancin is approved, according to the manufacturer.

The FDA made the request in a “complete response letter” to Targanta Therapeutics Corp. regarding its application for approval of oritavancin, the company said. The FDA's Anti-Infective Drugs Advisory Committee had voted 10–8 that data from two clinical trials of oritavancin failed to show that it is an effective and safe treatment for complicated skin and skin structure infections (cSSSIs), citing the need for more evidence to prove its efficacy against methicillin-resistant Staphylococcus aureus (MRSA).

Dr. Carol A. Kauffman, chief of infectious diseases, Veterans Affairs Health Care System, Ann Arbor, Mich., was among the majority voting no on the safety and efficacy question. “It may be a wonderful drug,” she said, but more information is needed. She urged the FDA to encourage Targanta to conduct a study of the drug in MRSA patients.

In the letter, the FDA said that the company had not shown the safety and efficacy of oritavancin for the proposed indication, according to Targanta. At the meeting, the FDA panel reviewed two studies submitted by Targanta, which compared oritavancin with vancomycin in approximately 2,000 adults with cSSSIs. Oritavancin inhibits cell wall biosynthesis with a mechanism of action similar to that of vancomycin but also disrupts the membranes of gram-positive bacteria and is active against gram-positive bacteria, including MRSA, according to Targanta.

The company has proposed that oritavancin be approved for treating adults with cSSSIs caused by susceptible isolates of the gram-positive organisms Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, the Streptococcus anginosus group, Streptococcus dysgalactiae, and Enterococcus faecalis (vancomycin-susceptible strains only). The recommended dosing regimen is 200 mg (300 mg for people who weigh more than 110 kg) daily for 3–7 days. It is administered in an intravenous infusion over 60 minutes.

In two randomized, double-blind phase III studies of approximately 2,000 adults with a cSSSI presumed or proved to be caused by gram-positive bacteria, the overall efficacy of once-daily treatment with oritavancin for 3–7 days was similar to a regimen of intravenous vancomycin twice a day for 3–7 days followed by daily oral cephalexin for a total of 10–14 days, with a low rate of relapse, the company said.

One study used a weight-based dose of oritavancin; the larger study used the fixed dose that is the proposed dose. A majority (10 of 18 panelists) voted that the weight-based dosing study did not provide independent evidence that oritavancin is effective for cSSSI, largely because the study was too small, was underpowered, and did not include enough MRSA cases.

In an 11–6 vote with 1 abstention, the panel voted that the larger study provided evidence that oritavancin was effective for cSSSI. However, several of those voting yes said that, while they agreed that the study showed oritavancin's overall effectiveness, they did not believe the study showed the drug was effective against cSSSI due to MRSA specifically. Those voting no expressed concern that there was insufficient evidence that oritavancin is effective against MRSA, the cause of most cases of cSSSI, and because it had not been studied in infections caused by contemporary isolates of MRSA (the study was conducted between 1998 and 2002).

In the fixed-dose study, the efficacy rate was about 12% lower among those infections identified as MRSA in the oritavancin arms, compared with those in the vancomycin arm, according to the FDA's presentation of the data.

The safety profiles of both regimens, including the number of deaths and significant adverse events, were comparable, although the rate of treatment-emergent adverse events was statistically lower among those on oritavancin.

COLLEGE PARK, MD. — The Food and Drug Administration has requested that a well-controlled clinical trial with an adequate number of patients with methicillin-resistant Staphylococcus aureus be conducted before the lipoglycopeptide antibiotic oritavancin is approved, according to the manufacturer.

The FDA made the request in a “complete response letter” to Targanta Therapeutics Corp. regarding its application for approval of oritavancin, the company said. The FDA's Anti-Infective Drugs Advisory Committee had voted 10–8 that data from two clinical trials of oritavancin failed to show that it is an effective and safe treatment for complicated skin and skin structure infections (cSSSIs), citing the need for more evidence to prove its efficacy against methicillin-resistant Staphylococcus aureus (MRSA).

Dr. Carol A. Kauffman, chief of infectious diseases, Veterans Affairs Health Care System, Ann Arbor, Mich., was among the majority voting no on the safety and efficacy question. “It may be a wonderful drug,” she said, but more information is needed. She urged the FDA to encourage Targanta to conduct a study of the drug in MRSA patients.

In the letter, the FDA said that the company had not shown the safety and efficacy of oritavancin for the proposed indication, according to Targanta. At the meeting, the FDA panel reviewed two studies submitted by Targanta, which compared oritavancin with vancomycin in approximately 2,000 adults with cSSSIs. Oritavancin inhibits cell wall biosynthesis with a mechanism of action similar to that of vancomycin but also disrupts the membranes of gram-positive bacteria and is active against gram-positive bacteria, including MRSA, according to Targanta.

The company has proposed that oritavancin be approved for treating adults with cSSSIs caused by susceptible isolates of the gram-positive organisms Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, the Streptococcus anginosus group, Streptococcus dysgalactiae, and Enterococcus faecalis (vancomycin-susceptible strains only). The recommended dosing regimen is 200 mg (300 mg for people who weigh more than 110 kg) daily for 3–7 days. It is administered in an intravenous infusion over 60 minutes.

In two randomized, double-blind phase III studies of approximately 2,000 adults with a cSSSI presumed or proved to be caused by gram-positive bacteria, the overall efficacy of once-daily treatment with oritavancin for 3–7 days was similar to a regimen of intravenous vancomycin twice a day for 3–7 days followed by daily oral cephalexin for a total of 10–14 days, with a low rate of relapse, the company said.

One study used a weight-based dose of oritavancin; the larger study used the fixed dose that is the proposed dose. A majority (10 of 18 panelists) voted that the weight-based dosing study did not provide independent evidence that oritavancin is effective for cSSSI, largely because the study was too small, was underpowered, and did not include enough MRSA cases.

In an 11–6 vote with 1 abstention, the panel voted that the larger study provided evidence that oritavancin was effective for cSSSI. However, several of those voting yes said that, while they agreed that the study showed oritavancin's overall effectiveness, they did not believe the study showed the drug was effective against cSSSI due to MRSA specifically. Those voting no expressed concern that there was insufficient evidence that oritavancin is effective against MRSA, the cause of most cases of cSSSI, and because it had not been studied in infections caused by contemporary isolates of MRSA (the study was conducted between 1998 and 2002).

In the fixed-dose study, the efficacy rate was about 12% lower among those infections identified as MRSA in the oritavancin arms, compared with those in the vancomycin arm, according to the FDA's presentation of the data.

The safety profiles of both regimens, including the number of deaths and significant adverse events, were comparable, although the rate of treatment-emergent adverse events was statistically lower among those on oritavancin.

COLLEGE PARK, MD. — Clinical trial data indicate 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. Those voting in favor said that while they were concerned 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.

Telavancin was teratogenic in animal studies, which found it was associated with limb malformations in three animal species, but there are no human data available. The FDA's analysis concluded that these findings “strongly” support that these effects are drug-related.

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 avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.

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 at Duke University, Durham, N.C.

The proposed indication for is for the treatment of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, the Streptococcus anginosus group, and Enterococcus faecalis.

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 from 2005 to 2006. (Half of the 1,320 patients with microbiologic confirmation of pathogens at baseline had MRSA.) Patients were treated with telavancin (10 mg/kg IV once daily) or vancomycin (1 g IV every 12 hours).

FDA and company analyses of different outcome measures indicated that in both studies treatment with telavancin for 7–14 days was as effective as treatment with vancomycin. Efficacy against MRSA infections was slightly better among those treated with telavancin, but the difference was not significant.

Telavancin was associated with common adverse events that 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 also was higher among those on telavancin (1.2% vs. 0.4%, respectively). Renal events were associated with comorbidities such as heart failure or kidney disease at baseline, according to Theravance.

The company is recommending that serum creatinine be monitored during treatment and that the potential risks of the drug be weighed against the benefits in patients with moderate or severe renal impairment or conditions that predispose them to kidney dysfunction.

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

In October 2007, the FDA issued an approvable letter for telavancin, which indicated the agency's preparedness to approve the product after the outstanding questions specified in the letter are resolved.

COLLEGE PARK, MD. — Clinical trial data indicate 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. Those voting in favor said that while they were concerned 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.

Telavancin was teratogenic in animal studies, which found it was associated with limb malformations in three animal species, but there are no human data available. The FDA's analysis concluded that these findings “strongly” support that these effects are drug-related.

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 avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.

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 at Duke University, Durham, N.C.

The proposed indication for is for the treatment of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, the Streptococcus anginosus group, and Enterococcus faecalis.

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 from 2005 to 2006. (Half of the 1,320 patients with microbiologic confirmation of pathogens at baseline had MRSA.) Patients were treated with telavancin (10 mg/kg IV once daily) or vancomycin (1 g IV every 12 hours).

FDA and company analyses of different outcome measures indicated that in both studies treatment with telavancin for 7–14 days was as effective as treatment with vancomycin. Efficacy against MRSA infections was slightly better among those treated with telavancin, but the difference was not significant.

Telavancin was associated with common adverse events that 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 also was higher among those on telavancin (1.2% vs. 0.4%, respectively). Renal events were associated with comorbidities such as heart failure or kidney disease at baseline, according to Theravance.

The company is recommending that serum creatinine be monitored during treatment and that the potential risks of the drug be weighed against the benefits in patients with moderate or severe renal impairment or conditions that predispose them to kidney dysfunction.

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

In October 2007, the FDA issued an approvable letter for telavancin, which indicated the agency's preparedness to approve the product after the outstanding questions specified in the letter are resolved.

COLLEGE PARK, MD. — Clinical trial data indicate 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. Those voting in favor said that while they were concerned 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.

Telavancin was teratogenic in animal studies, which found it was associated with limb malformations in three animal species, but there are no human data available. The FDA's analysis concluded that these findings “strongly” support that these effects are drug-related.

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 avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.

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 at Duke University, Durham, N.C.

The proposed indication for is for the treatment of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, the Streptococcus anginosus group, and Enterococcus faecalis.

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 from 2005 to 2006. (Half of the 1,320 patients with microbiologic confirmation of pathogens at baseline had MRSA.) Patients were treated with telavancin (10 mg/kg IV once daily) or vancomycin (1 g IV every 12 hours).

FDA and company analyses of different outcome measures indicated that in both studies treatment with telavancin for 7–14 days was as effective as treatment with vancomycin. Efficacy against MRSA infections was slightly better among those treated with telavancin, but the difference was not significant.

Telavancin was associated with common adverse events that 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 also was higher among those on telavancin (1.2% vs. 0.4%, respectively). Renal events were associated with comorbidities such as heart failure or kidney disease at baseline, according to Theravance.

The company is recommending that serum creatinine be monitored during treatment and that the potential risks of the drug be weighed against the benefits in patients with moderate or severe renal impairment or conditions that predispose them to kidney dysfunction.

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

In October 2007, the FDA issued an approvable letter for telavancin, which indicated the agency's preparedness to approve the product after the outstanding questions specified in the letter are resolved.

SILVER SPRING, MD. — Approval of a long-awaited alternative to allopurinol for people with gout is likely now that febuxostat has received a nearly unanimous vote for support by a federal advisory panel.

The Food and Drug Administration's Arthritis Drugs Advisory Committee voted 12-0, with 1 abstention, recommending approval of the xanthine oxidase inhibitor febuxostat for the treatment of chronic gout, but recommended that studies further evaluating the drug's cardiovascular safety be conducted after approval.

The panel agreed that the available data on febuxostat at doses of 40 mg/day and 80 mg/day provided evidence that it would be useful as a treatment for patients with gout and would meet an unmet need for treating hyp-eruricemia in patients who are intolerant to or allergic to allopurinol and in those patients with renal impairment, who have to take a reduced, less-effective dose of allo-purinol. The panel met last month.

Panelist Dr. John Cush, director of clinical rheumatology, Baylor Research Institute, Baylor College of Medicine, Dallas, said febuxostat would be a useful addition to the available treatments because of its potent urate-lowering effect. The drug requires less dose adjustment than does allopurinol and has been easier to tolerate than is allopurinol.

Like other panelists, he did not believe the issue regarding the potential cardiovascular safety signal seen in the two initial phase III studies of febuxostat had been completely resolved. That could be addressed with postmarketing studies, he said, adding it should not hold up approval.

Because of new legislation, the FDA now has more clout in getting companies to adhere to their postmarketing study commitments, which influenced some panelists to vote for approval. The FDA usually follows the recommendations of its advisory panels, which are not binding.

The manufacturer, Takeda Pharmaceuticals, has proposed that febuxostat, taken orally, at a dosage of 40 mg/day or 80 mg/day, be approved for treating hyperuricemia in patients with gout. The higher dosage would be recommended for patients with higher serum uric acid levels and for patients with tophi. If approved, febuxostat, a nonpurine selective inhibitor of xanthine oxidase that reduces the formation of uric acid, would be the second xanthine oxidase inhibitor approved for gout in the United States. Allopurinol, available since 1964, is a nonselective xanthine oxidase inhibitor.

Takeda presented the results of the phase III study of 2,269 mostly male patients with hyperuricemia, who had had gout for a mean of 11 years, conducted to prospectively evaluate the cardiovascular safety of febuxostat. Their mean age was 53 years; about 20% were older than 65 years, 53% had hypertension, 42% had hyperlipidemia, and 12% had atherosclerotic disease. Patients with mildly or moderately impaired renal function (about 66%) were also enrolled. At 6 months, the rates of cardiovascular events, blindly adjudicated by an independent expert committee, were similar in those on 40 mg/day or 80 mg/day of febuxostat and those on allopurinol (200-300 mg/day).

The FDA asked the company to conduct this study after the agency's review of the two phase III trials that were initially submitted to it for approval in 2004 suggested there was a cardiovascular safety signal associated with the 80-mg and 120-mg doses of febuxostat, compared with allopurinol. In the studies, the rates of cardiovascular thromboembolic events were higher in patients treated with 80 or 120 mg of febuxostat daily, compared with those on allopurinol or placebo, though the number of events was small. The company dropped development of the 120-mg dose and focused on the two lower doses.

The FDA held the panel meeting to review the drug's safety; efficacy was not an issue. In the three phase III studies, which enrolled patients with a diagnosis of gout and a baseline serum uric acid of 8.0 mg/dL or more, the 80-mg dose of febuxostat was significantly more effective than allopurinol, and the 40-mg dose was as effective as allopurinol, in lowering and maintaining serum uric acid below 6.0 mg/dL. Patients in all three groups experienced flares, which were higher in patients on the higher febuxostat doses but gradually decreased over time, said Takeda. The two doses of febuxostat were also effective in patients with renal impairment, who require a lower, usually suboptimal dose of allopurinol, and no safety signal was seen in this population. Febuxostat had no effects on blood pressure, glucose, lipids, or weight.

In two open-label extension studies that followed patients in phase II and the initial phase III studies for 3-5 years, gout flares fell to almost zero, said Takeda.

A cardiologist on the panel, Dr. Robert Harrington, professor of medicine, Duke University, Durham, N.C., said the database on febuxostat was insufficient to draw an inference about cardiovascular risk in patients with cardiovascular disease and that some of the issues regarding cardiovascular risk “still need to be better clarified.” He noted that most of the subjects were middle-aged, overweight men, and that 6 months was not enough time to detect a cardiovascular risk for a drug that will be taken for a lifetime. He said his vote in favor of approval was influenced by the FDA's increased authority in requiring companies to meet their postmarketing study commitments.

The panelist who abstained, Dr. Curt Furberg, professor in the department of public health sciences, Wake Forest University, Winston-Salem, N.C., said that the febuxostat package insert should include a statement in the precautions section that safety in patients with cardiovascular disease was not known. He recommended a long-term trial of febuxostat's safety in people with gout who are at high risk for cardiovascular disease, as well as in older patients and those with cardiovascular disease.

In an interview, Dr. Robert Wortmann, professor of medicine and rheumatology, Dartmouth-Hitchcock Medical Center, Lebanon, N.H., noted that it has been 4 years since febuxostat's manufacturer filed for FDA approval and said the delay has been frustrating for clinicians who treat gout. He was not at the meeting but has been a consultant to Takeda and TAP Pharmaceutical Products Inc., which was acquired by Takeda, since 1998, and was involved in the design of febuxostat studies.

“The No. 1advantage in my opinion is that we [will] now have an alternative xanthine oxidase inhibitor for people who can't tolerate allopurinol,” he said. Another benefit is that it can be used in patients with mild to moderate renal dysfunction, without modifying the dosage, as opposed to allopurinol, he added.

Allopurinol is effective if used appropriately, and it is inexpensive, but it is often underdosed, so many patients on allopurinol do not reach target urate level below 6 mg/dL, he pointed out. Although allopurinol is approved at dosages up to 800 mg/day, most prescriptions are written for 300 mg or less, a dosage that does not adequately control urate in half to two-thirds of patients, he added, noting that there is not much experience with higher allopurinol doses.

The febuxostat studies were conducted in the United States and Canada; about 30% of the patients enrolled were treated by rheumatologists, and the rest were treated by primary care physicians, reflecting clinical practice. Gout is largely diagnosed and managed by primary care and emergency physicians; rheumatologists tend to treat those with more severe gout. If the drug is approved, Takeda plans to market it as Uloric.

SILVER SPRING, MD. — Approval of a long-awaited alternative to allopurinol for people with gout is likely now that febuxostat has received a nearly unanimous vote for support by a federal advisory panel.

The Food and Drug Administration's Arthritis Drugs Advisory Committee voted 12-0, with 1 abstention, recommending approval of the xanthine oxidase inhibitor febuxostat for the treatment of chronic gout, but recommended that studies further evaluating the drug's cardiovascular safety be conducted after approval.

The panel agreed that the available data on febuxostat at doses of 40 mg/day and 80 mg/day provided evidence that it would be useful as a treatment for patients with gout and would meet an unmet need for treating hyp-eruricemia in patients who are intolerant to or allergic to allopurinol and in those patients with renal impairment, who have to take a reduced, less-effective dose of allo-purinol. The panel met last month.

Panelist Dr. John Cush, director of clinical rheumatology, Baylor Research Institute, Baylor College of Medicine, Dallas, said febuxostat would be a useful addition to the available treatments because of its potent urate-lowering effect. The drug requires less dose adjustment than does allopurinol and has been easier to tolerate than is allopurinol.

Like other panelists, he did not believe the issue regarding the potential cardiovascular safety signal seen in the two initial phase III studies of febuxostat had been completely resolved. That could be addressed with postmarketing studies, he said, adding it should not hold up approval.

Because of new legislation, the FDA now has more clout in getting companies to adhere to their postmarketing study commitments, which influenced some panelists to vote for approval. The FDA usually follows the recommendations of its advisory panels, which are not binding.

The manufacturer, Takeda Pharmaceuticals, has proposed that febuxostat, taken orally, at a dosage of 40 mg/day or 80 mg/day, be approved for treating hyperuricemia in patients with gout. The higher dosage would be recommended for patients with higher serum uric acid levels and for patients with tophi. If approved, febuxostat, a nonpurine selective inhibitor of xanthine oxidase that reduces the formation of uric acid, would be the second xanthine oxidase inhibitor approved for gout in the United States. Allopurinol, available since 1964, is a nonselective xanthine oxidase inhibitor.

Takeda presented the results of the phase III study of 2,269 mostly male patients with hyperuricemia, who had had gout for a mean of 11 years, conducted to prospectively evaluate the cardiovascular safety of febuxostat. Their mean age was 53 years; about 20% were older than 65 years, 53% had hypertension, 42% had hyperlipidemia, and 12% had atherosclerotic disease. Patients with mildly or moderately impaired renal function (about 66%) were also enrolled. At 6 months, the rates of cardiovascular events, blindly adjudicated by an independent expert committee, were similar in those on 40 mg/day or 80 mg/day of febuxostat and those on allopurinol (200-300 mg/day).

The FDA asked the company to conduct this study after the agency's review of the two phase III trials that were initially submitted to it for approval in 2004 suggested there was a cardiovascular safety signal associated with the 80-mg and 120-mg doses of febuxostat, compared with allopurinol. In the studies, the rates of cardiovascular thromboembolic events were higher in patients treated with 80 or 120 mg of febuxostat daily, compared with those on allopurinol or placebo, though the number of events was small. The company dropped development of the 120-mg dose and focused on the two lower doses.

The FDA held the panel meeting to review the drug's safety; efficacy was not an issue. In the three phase III studies, which enrolled patients with a diagnosis of gout and a baseline serum uric acid of 8.0 mg/dL or more, the 80-mg dose of febuxostat was significantly more effective than allopurinol, and the 40-mg dose was as effective as allopurinol, in lowering and maintaining serum uric acid below 6.0 mg/dL. Patients in all three groups experienced flares, which were higher in patients on the higher febuxostat doses but gradually decreased over time, said Takeda. The two doses of febuxostat were also effective in patients with renal impairment, who require a lower, usually suboptimal dose of allopurinol, and no safety signal was seen in this population. Febuxostat had no effects on blood pressure, glucose, lipids, or weight.

In two open-label extension studies that followed patients in phase II and the initial phase III studies for 3-5 years, gout flares fell to almost zero, said Takeda.

A cardiologist on the panel, Dr. Robert Harrington, professor of medicine, Duke University, Durham, N.C., said the database on febuxostat was insufficient to draw an inference about cardiovascular risk in patients with cardiovascular disease and that some of the issues regarding cardiovascular risk “still need to be better clarified.” He noted that most of the subjects were middle-aged, overweight men, and that 6 months was not enough time to detect a cardiovascular risk for a drug that will be taken for a lifetime. He said his vote in favor of approval was influenced by the FDA's increased authority in requiring companies to meet their postmarketing study commitments.

The panelist who abstained, Dr. Curt Furberg, professor in the department of public health sciences, Wake Forest University, Winston-Salem, N.C., said that the febuxostat package insert should include a statement in the precautions section that safety in patients with cardiovascular disease was not known. He recommended a long-term trial of febuxostat's safety in people with gout who are at high risk for cardiovascular disease, as well as in older patients and those with cardiovascular disease.

In an interview, Dr. Robert Wortmann, professor of medicine and rheumatology, Dartmouth-Hitchcock Medical Center, Lebanon, N.H., noted that it has been 4 years since febuxostat's manufacturer filed for FDA approval and said the delay has been frustrating for clinicians who treat gout. He was not at the meeting but has been a consultant to Takeda and TAP Pharmaceutical Products Inc., which was acquired by Takeda, since 1998, and was involved in the design of febuxostat studies.

“The No. 1advantage in my opinion is that we [will] now have an alternative xanthine oxidase inhibitor for people who can't tolerate allopurinol,” he said. Another benefit is that it can be used in patients with mild to moderate renal dysfunction, without modifying the dosage, as opposed to allopurinol, he added.

Allopurinol is effective if used appropriately, and it is inexpensive, but it is often underdosed, so many patients on allopurinol do not reach target urate level below 6 mg/dL, he pointed out. Although allopurinol is approved at dosages up to 800 mg/day, most prescriptions are written for 300 mg or less, a dosage that does not adequately control urate in half to two-thirds of patients, he added, noting that there is not much experience with higher allopurinol doses.

The febuxostat studies were conducted in the United States and Canada; about 30% of the patients enrolled were treated by rheumatologists, and the rest were treated by primary care physicians, reflecting clinical practice. Gout is largely diagnosed and managed by primary care and emergency physicians; rheumatologists tend to treat those with more severe gout. If the drug is approved, Takeda plans to market it as Uloric.

SILVER SPRING, MD. — Approval of a long-awaited alternative to allopurinol for people with gout is likely now that febuxostat has received a nearly unanimous vote for support by a federal advisory panel.

The Food and Drug Administration's Arthritis Drugs Advisory Committee voted 12-0, with 1 abstention, recommending approval of the xanthine oxidase inhibitor febuxostat for the treatment of chronic gout, but recommended that studies further evaluating the drug's cardiovascular safety be conducted after approval.

The panel agreed that the available data on febuxostat at doses of 40 mg/day and 80 mg/day provided evidence that it would be useful as a treatment for patients with gout and would meet an unmet need for treating hyp-eruricemia in patients who are intolerant to or allergic to allopurinol and in those patients with renal impairment, who have to take a reduced, less-effective dose of allo-purinol. The panel met last month.

Panelist Dr. John Cush, director of clinical rheumatology, Baylor Research Institute, Baylor College of Medicine, Dallas, said febuxostat would be a useful addition to the available treatments because of its potent urate-lowering effect. The drug requires less dose adjustment than does allopurinol and has been easier to tolerate than is allopurinol.

Like other panelists, he did not believe the issue regarding the potential cardiovascular safety signal seen in the two initial phase III studies of febuxostat had been completely resolved. That could be addressed with postmarketing studies, he said, adding it should not hold up approval.

Because of new legislation, the FDA now has more clout in getting companies to adhere to their postmarketing study commitments, which influenced some panelists to vote for approval. The FDA usually follows the recommendations of its advisory panels, which are not binding.

The manufacturer, Takeda Pharmaceuticals, has proposed that febuxostat, taken orally, at a dosage of 40 mg/day or 80 mg/day, be approved for treating hyperuricemia in patients with gout. The higher dosage would be recommended for patients with higher serum uric acid levels and for patients with tophi. If approved, febuxostat, a nonpurine selective inhibitor of xanthine oxidase that reduces the formation of uric acid, would be the second xanthine oxidase inhibitor approved for gout in the United States. Allopurinol, available since 1964, is a nonselective xanthine oxidase inhibitor.

Takeda presented the results of the phase III study of 2,269 mostly male patients with hyperuricemia, who had had gout for a mean of 11 years, conducted to prospectively evaluate the cardiovascular safety of febuxostat. Their mean age was 53 years; about 20% were older than 65 years, 53% had hypertension, 42% had hyperlipidemia, and 12% had atherosclerotic disease. Patients with mildly or moderately impaired renal function (about 66%) were also enrolled. At 6 months, the rates of cardiovascular events, blindly adjudicated by an independent expert committee, were similar in those on 40 mg/day or 80 mg/day of febuxostat and those on allopurinol (200-300 mg/day).

The FDA asked the company to conduct this study after the agency's review of the two phase III trials that were initially submitted to it for approval in 2004 suggested there was a cardiovascular safety signal associated with the 80-mg and 120-mg doses of febuxostat, compared with allopurinol. In the studies, the rates of cardiovascular thromboembolic events were higher in patients treated with 80 or 120 mg of febuxostat daily, compared with those on allopurinol or placebo, though the number of events was small. The company dropped development of the 120-mg dose and focused on the two lower doses.

The FDA held the panel meeting to review the drug's safety; efficacy was not an issue. In the three phase III studies, which enrolled patients with a diagnosis of gout and a baseline serum uric acid of 8.0 mg/dL or more, the 80-mg dose of febuxostat was significantly more effective than allopurinol, and the 40-mg dose was as effective as allopurinol, in lowering and maintaining serum uric acid below 6.0 mg/dL. Patients in all three groups experienced flares, which were higher in patients on the higher febuxostat doses but gradually decreased over time, said Takeda. The two doses of febuxostat were also effective in patients with renal impairment, who require a lower, usually suboptimal dose of allopurinol, and no safety signal was seen in this population. Febuxostat had no effects on blood pressure, glucose, lipids, or weight.

In two open-label extension studies that followed patients in phase II and the initial phase III studies for 3-5 years, gout flares fell to almost zero, said Takeda.

A cardiologist on the panel, Dr. Robert Harrington, professor of medicine, Duke University, Durham, N.C., said the database on febuxostat was insufficient to draw an inference about cardiovascular risk in patients with cardiovascular disease and that some of the issues regarding cardiovascular risk “still need to be better clarified.” He noted that most of the subjects were middle-aged, overweight men, and that 6 months was not enough time to detect a cardiovascular risk for a drug that will be taken for a lifetime. He said his vote in favor of approval was influenced by the FDA's increased authority in requiring companies to meet their postmarketing study commitments.

The panelist who abstained, Dr. Curt Furberg, professor in the department of public health sciences, Wake Forest University, Winston-Salem, N.C., said that the febuxostat package insert should include a statement in the precautions section that safety in patients with cardiovascular disease was not known. He recommended a long-term trial of febuxostat's safety in people with gout who are at high risk for cardiovascular disease, as well as in older patients and those with cardiovascular disease.

In an interview, Dr. Robert Wortmann, professor of medicine and rheumatology, Dartmouth-Hitchcock Medical Center, Lebanon, N.H., noted that it has been 4 years since febuxostat's manufacturer filed for FDA approval and said the delay has been frustrating for clinicians who treat gout. He was not at the meeting but has been a consultant to Takeda and TAP Pharmaceutical Products Inc., which was acquired by Takeda, since 1998, and was involved in the design of febuxostat studies.

“The No. 1advantage in my opinion is that we [will] now have an alternative xanthine oxidase inhibitor for people who can't tolerate allopurinol,” he said. Another benefit is that it can be used in patients with mild to moderate renal dysfunction, without modifying the dosage, as opposed to allopurinol, he added.

Allopurinol is effective if used appropriately, and it is inexpensive, but it is often underdosed, so many patients on allopurinol do not reach target urate level below 6 mg/dL, he pointed out. Although allopurinol is approved at dosages up to 800 mg/day, most prescriptions are written for 300 mg or less, a dosage that does not adequately control urate in half to two-thirds of patients, he added, noting that there is not much experience with higher allopurinol doses.

The febuxostat studies were conducted in the United States and Canada; about 30% of the patients enrolled were treated by rheumatologists, and the rest were treated by primary care physicians, reflecting clinical practice. Gout is largely diagnosed and managed by primary care and emergency physicians; rheumatologists tend to treat those with more severe gout. If the drug is approved, Takeda plans to market it as Uloric.

COLLEGE PARK, MD. — Clinical trial data indicate 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.

At a November meeting, the Food and Drug Administration's anti-infective drugs advisory committee voted 21-5 regarding the safety and efficacy of telavancin. Those voting in favor said that while they were concerned 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 avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.

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 at Duke University, Durham, N.C. He added that since the mechanism of action was not that different from vancomycin, it was not certain how much its use would affect the problem of increasing resistance.

The FDA usually follows the advice of its advisory panels, which are 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, the 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 from 2005 to 2006. (Half of the 1,320 patients with microbiologic confirmation of pathogens at baseline had MRSA). Patients were treated with telavancin (10 mg/kg IV once daily) or vancomycin (1 g IV every 12 hours).

FDA and company analyses of different outcome measures indicated that in both studies treatment with telavancin for 7-14 days was as effective as treatment with vancomycin—the current standard of care. Efficacy against MRSA infections was slightly better among those treated with telavancin, but the difference was not significant. Cure rates were lower among patients with severe renal impairment.

Telavancin was associated with common adverse events that 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 also was higher among those on telavancin (1.2% vs. 0.4%, respectively). The company is recommending that serum creatinine be monitored during treatment.

COLLEGE PARK, MD. — Clinical trial data indicate 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.

At a November meeting, the Food and Drug Administration's anti-infective drugs advisory committee voted 21-5 regarding the safety and efficacy of telavancin. Those voting in favor said that while they were concerned 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 avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.

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 at Duke University, Durham, N.C. He added that since the mechanism of action was not that different from vancomycin, it was not certain how much its use would affect the problem of increasing resistance.

The FDA usually follows the advice of its advisory panels, which are 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, the 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 from 2005 to 2006. (Half of the 1,320 patients with microbiologic confirmation of pathogens at baseline had MRSA). Patients were treated with telavancin (10 mg/kg IV once daily) or vancomycin (1 g IV every 12 hours).

FDA and company analyses of different outcome measures indicated that in both studies treatment with telavancin for 7-14 days was as effective as treatment with vancomycin—the current standard of care. Efficacy against MRSA infections was slightly better among those treated with telavancin, but the difference was not significant. Cure rates were lower among patients with severe renal impairment.

Telavancin was associated with common adverse events that 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 also was higher among those on telavancin (1.2% vs. 0.4%, respectively). The company is recommending that serum creatinine be monitored during treatment.

COLLEGE PARK, MD. — Clinical trial data indicate 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.

At a November meeting, the Food and Drug Administration's anti-infective drugs advisory committee voted 21-5 regarding the safety and efficacy of telavancin. Those voting in favor said that while they were concerned 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 avoid the drug in patients with conditions such as congenital long QT syndrome and uncompensated heart failure.

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 at Duke University, Durham, N.C. He added that since the mechanism of action was not that different from vancomycin, it was not certain how much its use would affect the problem of increasing resistance.

The FDA usually follows the advice of its advisory panels, which are 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, the 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 from 2005 to 2006. (Half of the 1,320 patients with microbiologic confirmation of pathogens at baseline had MRSA). Patients were treated with telavancin (10 mg/kg IV once daily) or vancomycin (1 g IV every 12 hours).

FDA and company analyses of different outcome measures indicated that in both studies treatment with telavancin for 7-14 days was as effective as treatment with vancomycin—the current standard of care. Efficacy against MRSA infections was slightly better among those treated with telavancin, but the difference was not significant. Cure rates were lower among patients with severe renal impairment.

Telavancin was associated with common adverse events that 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 also was higher among those on telavancin (1.2% vs. 0.4%, respectively). The company is recommending that serum creatinine be monitored during treatment.

Anyone taking an antiepileptic drug during pregnancy can enroll in the North American AED registry at Massachusetts General Hospital by calling 1-888-233-2334.

Exposure to sodium valproate early in pregnancy may increase a child's risk for developing an autism spectrum disorder, judging from preliminary results from an ongoing study on the effects of in utero exposure to antiepileptic drugs.

In the study, those children exposed to valproate early in pregnancy were at a sevenfold greater risk of developing autism spectrum disorder (ASD), compared with children whose mothers did not have epilepsy, reported investigators from the Liverpool and Manchester Neurodevelopment Study Group, England (Neurology 2008;71:1923-4).

“The potential risk for autism in this study was substantial for children whose mothers took valproate while pregnant, but more research needs to be done since these are early findings,” one of the authors, Gus Baker, Ph.D., of the University of Liverpool (England) said in a statement issued by the American Academy of Neurology, which publishes Neurology. “However, women who take valproate while pregnant should be informed of the possible risks of autism and are encouraged to discuss them with their doctor[s]. Those who are taking valproate should not stop their treatment without speaking to their doctor[s] first.”

The study enrolled 620 women in Liverpool and Manchester between 2000 and 2006 and has collected information on 632 live births. Of these births, 296 of the babies were born to women with epilepsy, including 249 who were taking antiepileptic drugs (AEDs) at the beginning of their pregnancies (64 were exposed to valproate, 44 to lamotrigine, 76 to carbamazepine, 14 to other monotherapy treatments, and 51 to polytherapy). The remaining 47 babies were born to mothers with epilepsy who were not taking medication.

Neuropsychological tests were done at ages 1, 3, and 6 years; at the end of the study, most—68%—of the children were aged 6 years and older, about 4% were under age 3 years and about 28% were aged 4-5 years).

Of the 632 children, 9 met the DSM-IV criteria for autism spectrum disorders, the authors reported. Another child with a lack of attention, social difficulties, and other ASD features was included in the analyses as a case of ASD. None of the parents of the children with ASD were aware of a family history of autism or another pervasive developmental disorder.

Of these 10 children, 7 had been exposed to an AED during pregnancy (nearly 3% of the 249 children exposed to AEDs). Of these seven children, four had been exposed to valproate (about 6% of the valproate-exposed children).

One of the remaining 3 children was exposed to valproate in combination with lamotrigine (2% of the 51 exposed to polytherapy), 1 child was exposed to phenytoin (11% of the children on exposed to phenytoin), and 1 child exposed to lamotrigine (2% of the children exposed to lamotrigine).

Of the 336 children who were controls (whose mothers did not have epilepsy), 3 (0.9%) were diagnosed with ASD (one case of autism and two with Asperger's syndrome).

The rate of ASD or features of ASD—6%—among the children exposed to valproate alone during pregnancy was seven times greater than the controls (0.9%) and is higher than the incidence reported in the general population (6/1,000 children), the authors wrote.

No conclusion can be made about the risk associated with lamotrigine or phenytoin exposure, based on one case each, they added. Among the limitations of the study is that many of the children were younger than the average age at which ASD usually is detected and diagnosed, and the results are preliminary and need to be confirmed with more prospective studies, they emphasized.

Dr. Lewis Holmes, director of the North American AED Registry at Massachusetts General Hospital, Boston, said that it has been clear that, anecdotally and in the published literature, the risk of autism is increased among children exposed to valproate in utero. This increased risk also has been seen in thalidomide-exposed babies.

He added that valproate is associated with many other malformations, a high risk for serious IQ deficits, as well as the link to autism, but physicians often only associate it with a greater risk for neural tube defects.

Dr. Gideon Koren, professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto, said that the association between in utero exposure to valproate and ASD has been suspected for awhile. “The present study, being prospective, systematic, and controlled, provides strong evidence for the causative role” of valproate in ASD,” he said in an interview.

Anyone taking an antiepileptic drug during pregnancy can enroll in the North American AED registry at Massachusetts General Hospital by calling 1-888-233-2334.

Exposure to sodium valproate early in pregnancy may increase a child's risk for developing an autism spectrum disorder, judging from preliminary results from an ongoing study on the effects of in utero exposure to antiepileptic drugs.

In the study, those children exposed to valproate early in pregnancy were at a sevenfold greater risk of developing autism spectrum disorder (ASD), compared with children whose mothers did not have epilepsy, reported investigators from the Liverpool and Manchester Neurodevelopment Study Group, England (Neurology 2008;71:1923-4).

“The potential risk for autism in this study was substantial for children whose mothers took valproate while pregnant, but more research needs to be done since these are early findings,” one of the authors, Gus Baker, Ph.D., of the University of Liverpool (England) said in a statement issued by the American Academy of Neurology, which publishes Neurology. “However, women who take valproate while pregnant should be informed of the possible risks of autism and are encouraged to discuss them with their doctor[s]. Those who are taking valproate should not stop their treatment without speaking to their doctor[s] first.”

The study enrolled 620 women in Liverpool and Manchester between 2000 and 2006 and has collected information on 632 live births. Of these births, 296 of the babies were born to women with epilepsy, including 249 who were taking antiepileptic drugs (AEDs) at the beginning of their pregnancies (64 were exposed to valproate, 44 to lamotrigine, 76 to carbamazepine, 14 to other monotherapy treatments, and 51 to polytherapy). The remaining 47 babies were born to mothers with epilepsy who were not taking medication.

Neuropsychological tests were done at ages 1, 3, and 6 years; at the end of the study, most—68%—of the children were aged 6 years and older, about 4% were under age 3 years and about 28% were aged 4-5 years).

Of the 632 children, 9 met the DSM-IV criteria for autism spectrum disorders, the authors reported. Another child with a lack of attention, social difficulties, and other ASD features was included in the analyses as a case of ASD. None of the parents of the children with ASD were aware of a family history of autism or another pervasive developmental disorder.

Of these 10 children, 7 had been exposed to an AED during pregnancy (nearly 3% of the 249 children exposed to AEDs). Of these seven children, four had been exposed to valproate (about 6% of the valproate-exposed children).

One of the remaining 3 children was exposed to valproate in combination with lamotrigine (2% of the 51 exposed to polytherapy), 1 child was exposed to phenytoin (11% of the children on exposed to phenytoin), and 1 child exposed to lamotrigine (2% of the children exposed to lamotrigine).

Of the 336 children who were controls (whose mothers did not have epilepsy), 3 (0.9%) were diagnosed with ASD (one case of autism and two with Asperger's syndrome).

The rate of ASD or features of ASD—6%—among the children exposed to valproate alone during pregnancy was seven times greater than the controls (0.9%) and is higher than the incidence reported in the general population (6/1,000 children), the authors wrote.

No conclusion can be made about the risk associated with lamotrigine or phenytoin exposure, based on one case each, they added. Among the limitations of the study is that many of the children were younger than the average age at which ASD usually is detected and diagnosed, and the results are preliminary and need to be confirmed with more prospective studies, they emphasized.

Dr. Lewis Holmes, director of the North American AED Registry at Massachusetts General Hospital, Boston, said that it has been clear that, anecdotally and in the published literature, the risk of autism is increased among children exposed to valproate in utero. This increased risk also has been seen in thalidomide-exposed babies.

He added that valproate is associated with many other malformations, a high risk for serious IQ deficits, as well as the link to autism, but physicians often only associate it with a greater risk for neural tube defects.

Dr. Gideon Koren, professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto, said that the association between in utero exposure to valproate and ASD has been suspected for awhile. “The present study, being prospective, systematic, and controlled, provides strong evidence for the causative role” of valproate in ASD,” he said in an interview.

Anyone taking an antiepileptic drug during pregnancy can enroll in the North American AED registry at Massachusetts General Hospital by calling 1-888-233-2334.

Exposure to sodium valproate early in pregnancy may increase a child's risk for developing an autism spectrum disorder, judging from preliminary results from an ongoing study on the effects of in utero exposure to antiepileptic drugs.

In the study, those children exposed to valproate early in pregnancy were at a sevenfold greater risk of developing autism spectrum disorder (ASD), compared with children whose mothers did not have epilepsy, reported investigators from the Liverpool and Manchester Neurodevelopment Study Group, England (Neurology 2008;71:1923-4).

“The potential risk for autism in this study was substantial for children whose mothers took valproate while pregnant, but more research needs to be done since these are early findings,” one of the authors, Gus Baker, Ph.D., of the University of Liverpool (England) said in a statement issued by the American Academy of Neurology, which publishes Neurology. “However, women who take valproate while pregnant should be informed of the possible risks of autism and are encouraged to discuss them with their doctor[s]. Those who are taking valproate should not stop their treatment without speaking to their doctor[s] first.”

The study enrolled 620 women in Liverpool and Manchester between 2000 and 2006 and has collected information on 632 live births. Of these births, 296 of the babies were born to women with epilepsy, including 249 who were taking antiepileptic drugs (AEDs) at the beginning of their pregnancies (64 were exposed to valproate, 44 to lamotrigine, 76 to carbamazepine, 14 to other monotherapy treatments, and 51 to polytherapy). The remaining 47 babies were born to mothers with epilepsy who were not taking medication.

Neuropsychological tests were done at ages 1, 3, and 6 years; at the end of the study, most—68%—of the children were aged 6 years and older, about 4% were under age 3 years and about 28% were aged 4-5 years).

Of the 632 children, 9 met the DSM-IV criteria for autism spectrum disorders, the authors reported. Another child with a lack of attention, social difficulties, and other ASD features was included in the analyses as a case of ASD. None of the parents of the children with ASD were aware of a family history of autism or another pervasive developmental disorder.

Of these 10 children, 7 had been exposed to an AED during pregnancy (nearly 3% of the 249 children exposed to AEDs). Of these seven children, four had been exposed to valproate (about 6% of the valproate-exposed children).

One of the remaining 3 children was exposed to valproate in combination with lamotrigine (2% of the 51 exposed to polytherapy), 1 child was exposed to phenytoin (11% of the children on exposed to phenytoin), and 1 child exposed to lamotrigine (2% of the children exposed to lamotrigine).

Of the 336 children who were controls (whose mothers did not have epilepsy), 3 (0.9%) were diagnosed with ASD (one case of autism and two with Asperger's syndrome).

The rate of ASD or features of ASD—6%—among the children exposed to valproate alone during pregnancy was seven times greater than the controls (0.9%) and is higher than the incidence reported in the general population (6/1,000 children), the authors wrote.

No conclusion can be made about the risk associated with lamotrigine or phenytoin exposure, based on one case each, they added. Among the limitations of the study is that many of the children were younger than the average age at which ASD usually is detected and diagnosed, and the results are preliminary and need to be confirmed with more prospective studies, they emphasized.

Dr. Lewis Holmes, director of the North American AED Registry at Massachusetts General Hospital, Boston, said that it has been clear that, anecdotally and in the published literature, the risk of autism is increased among children exposed to valproate in utero. This increased risk also has been seen in thalidomide-exposed babies.

He added that valproate is associated with many other malformations, a high risk for serious IQ deficits, as well as the link to autism, but physicians often only associate it with a greater risk for neural tube defects.

Dr. Gideon Koren, professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto, said that the association between in utero exposure to valproate and ASD has been suspected for awhile. “The present study, being prospective, systematic, and controlled, provides strong evidence for the causative role” of valproate in ASD,” he said in an interview.

The Food and Drug Administration's safety review of bisphosphonates has not found a clear association between treatment with a bisphosphonate and atrial fibrillation.

“Based on the data available at this time, health care professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication,” the FDA stated on its MedWatch Web site.

The review compared data on 19,687 patients treated with a bisphosphonate with 18,358 patients who received placebo, who were followed from 6 months up to 3 years. These data, from the manufacturers of alendronate, ibandronate, risedronate, and zoledronic acid, were provided at the FDA's request in October 2007, after concerns about a possible association between bisphosphonates and an increased risk for serious atrial fibrillation were raised in a study and letter published 5 months earlier in the New England Journal of Medicine (2007;356:1809–22; 2007;356:1895–6).

The review found that cases of atrial fibrillation were “rare,” with two or fewer cases reported in most of the studies. The absolute difference in rates of atrial fibrillation between each bisphosphonate and placebo arm ranged from 0 to 3 cases/1,000 people, according to the FDA.

In a large zoledronic acid study, however, the rate of serious atrial fibrillation cases was significantly higher among treated patients. But “across all studies, no clear association between overall bisphosphonate exposure and rate of serious or nonserious atrial fibrillation was observed,” the FDA statement said. In addition, increasing the dose or duration of treatment was not associated with an increased rate of atrial fibrillation. (The label for zoledronic acid, given intravenously once a year for osteoporosis, includes information about the increased risk for serious atrial fibrillation.)

The statement said that the FDA is aware of “discordant results” from the literature and epidemiologic studies of the incidence and clinical course of atrial fibrillation in patients taking bisphosphonates and is “exploring the feasibility of conducting additional epidemiologic studies to examine this issue.” The FDA also continues to monitor postmarketing reports of atrial fibrillation in people treated with bisphosphonates, which are approved for treating osteoporosis, Paget disease, and some cancer-related indications.

In the 2007 studies, 1.3% of the women on Reclast and 1.5% of those on Fosamax developed serious atrial fibrillation (life threatening or resulting in hospitalization), compared with 0.5% and 1.0%, respectively, of those on placebo. When combined, rates of serious and nonserious cases of atrial fibrillation were not significantly different in the treatment and placebo groups. The patients were women aged 65–89 years with osteoporosis.

The bisphosphonates approved by the FDA are alendronate (Fosamax, Fosamax plus D), etidronate (Didronel), ibandronate (Boniva), pamidronate (Aredia), risedronate (Actonel, Actonel with calcium), tiludronate (Skelid), and zoledronic acid (Reclast, Zometa).

The FDA statement is available at www.fda.gov/medwatch/safety/2008/safety08.htm#bisphosphonates2www.fda.gov/MedWatch/report.htm

The Food and Drug Administration's safety review of bisphosphonates has not found a clear association between treatment with a bisphosphonate and atrial fibrillation.

“Based on the data available at this time, health care professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication,” the FDA stated on its MedWatch Web site.

The review compared data on 19,687 patients treated with a bisphosphonate with 18,358 patients who received placebo, who were followed from 6 months up to 3 years. These data, from the manufacturers of alendronate, ibandronate, risedronate, and zoledronic acid, were provided at the FDA's request in October 2007, after concerns about a possible association between bisphosphonates and an increased risk for serious atrial fibrillation were raised in a study and letter published 5 months earlier in the New England Journal of Medicine (2007;356:1809–22; 2007;356:1895–6).

The review found that cases of atrial fibrillation were “rare,” with two or fewer cases reported in most of the studies. The absolute difference in rates of atrial fibrillation between each bisphosphonate and placebo arm ranged from 0 to 3 cases/1,000 people, according to the FDA.

In a large zoledronic acid study, however, the rate of serious atrial fibrillation cases was significantly higher among treated patients. But “across all studies, no clear association between overall bisphosphonate exposure and rate of serious or nonserious atrial fibrillation was observed,” the FDA statement said. In addition, increasing the dose or duration of treatment was not associated with an increased rate of atrial fibrillation. (The label for zoledronic acid, given intravenously once a year for osteoporosis, includes information about the increased risk for serious atrial fibrillation.)

The statement said that the FDA is aware of “discordant results” from the literature and epidemiologic studies of the incidence and clinical course of atrial fibrillation in patients taking bisphosphonates and is “exploring the feasibility of conducting additional epidemiologic studies to examine this issue.” The FDA also continues to monitor postmarketing reports of atrial fibrillation in people treated with bisphosphonates, which are approved for treating osteoporosis, Paget disease, and some cancer-related indications.

In the 2007 studies, 1.3% of the women on Reclast and 1.5% of those on Fosamax developed serious atrial fibrillation (life threatening or resulting in hospitalization), compared with 0.5% and 1.0%, respectively, of those on placebo. When combined, rates of serious and nonserious cases of atrial fibrillation were not significantly different in the treatment and placebo groups. The patients were women aged 65–89 years with osteoporosis.

The bisphosphonates approved by the FDA are alendronate (Fosamax, Fosamax plus D), etidronate (Didronel), ibandronate (Boniva), pamidronate (Aredia), risedronate (Actonel, Actonel with calcium), tiludronate (Skelid), and zoledronic acid (Reclast, Zometa).

The FDA statement is available at www.fda.gov/medwatch/safety/2008/safety08.htm#bisphosphonates2www.fda.gov/MedWatch/report.htm

The Food and Drug Administration's safety review of bisphosphonates has not found a clear association between treatment with a bisphosphonate and atrial fibrillation.

“Based on the data available at this time, health care professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication,” the FDA stated on its MedWatch Web site.

The review compared data on 19,687 patients treated with a bisphosphonate with 18,358 patients who received placebo, who were followed from 6 months up to 3 years. These data, from the manufacturers of alendronate, ibandronate, risedronate, and zoledronic acid, were provided at the FDA's request in October 2007, after concerns about a possible association between bisphosphonates and an increased risk for serious atrial fibrillation were raised in a study and letter published 5 months earlier in the New England Journal of Medicine (2007;356:1809–22; 2007;356:1895–6).

The review found that cases of atrial fibrillation were “rare,” with two or fewer cases reported in most of the studies. The absolute difference in rates of atrial fibrillation between each bisphosphonate and placebo arm ranged from 0 to 3 cases/1,000 people, according to the FDA.

In a large zoledronic acid study, however, the rate of serious atrial fibrillation cases was significantly higher among treated patients. But “across all studies, no clear association between overall bisphosphonate exposure and rate of serious or nonserious atrial fibrillation was observed,” the FDA statement said. In addition, increasing the dose or duration of treatment was not associated with an increased rate of atrial fibrillation. (The label for zoledronic acid, given intravenously once a year for osteoporosis, includes information about the increased risk for serious atrial fibrillation.)

The statement said that the FDA is aware of “discordant results” from the literature and epidemiologic studies of the incidence and clinical course of atrial fibrillation in patients taking bisphosphonates and is “exploring the feasibility of conducting additional epidemiologic studies to examine this issue.” The FDA also continues to monitor postmarketing reports of atrial fibrillation in people treated with bisphosphonates, which are approved for treating osteoporosis, Paget disease, and some cancer-related indications.

In the 2007 studies, 1.3% of the women on Reclast and 1.5% of those on Fosamax developed serious atrial fibrillation (life threatening or resulting in hospitalization), compared with 0.5% and 1.0%, respectively, of those on placebo. When combined, rates of serious and nonserious cases of atrial fibrillation were not significantly different in the treatment and placebo groups. The patients were women aged 65–89 years with osteoporosis.

The bisphosphonates approved by the FDA are alendronate (Fosamax, Fosamax plus D), etidronate (Didronel), ibandronate (Boniva), pamidronate (Aredia), risedronate (Actonel, Actonel with calcium), tiludronate (Skelid), and zoledronic acid (Reclast, Zometa).

The FDA statement is available at www.fda.gov/medwatch/safety/2008/safety08.htm#bisphosphonates2www.fda.gov/MedWatch/report.htm

The Food and Drug Administration has approved a revised indication and several label additions for the angina drug ranolazine, including a statement that the drug reduced hemoglobin A_1c in people with diabetes.

The indication is still for “the treatment of chronic angina, but “the second-line restriction on the use of ranolazine to treat patients with chronic angina has been removed,” according to an announcement issued by the FDA.

Previously, the indication was for treatment of chronic angina, but with the added statement that it should be reserved for patients who have not had an adequate response with other antianginal drugs, because ranolazine increases the QT interval.

The additional statement has been removed from the revised label, with the information about the QT interval prolongation now in the warnings and precaution section.

Also added to the label is a statement that cites the significantly lower rate of arrhythmias in patients with coronary heart disease who were treated with ranolazine in the MERLIN-TIMI 36 trial, compared with those on placebo, CV Therapeutics Inc. noted in its announcement of the approval.

The indications section of the revised label also says that the drug can be used with β-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

CV Therapeutics markets ranolazine in extended-release tablet form as Ranexa, which was approved in January 2006.

Ranolazine has antianginal and anti-ischemic effects, but its exact mechanism of action is not known, according to the label.

In a statement, the company said that data from the MERLIN-TIMI 36 trial were submitted to the FDA in September 2007, as part of its supplemental application. The revised label includes the statement that in the study—which compared ranolazine to placebo in more than 6,000 patients with acute coronary syndrome—no benefit was seen on outcome measures, but that the study was “somewhat reassuring regarding proarrhythmic risks, as ventricular arrhythmias were less common on ranolazine.”

The incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) was 80% among those treated with ranolazine, compared with 87% of those on placebo, a significant difference, according to the label. However, the label also states that the difference in arrhythmias did not result in lower mortality, or reductions in arrhythmia hospitalizations or arrhythmia symptoms.

The label notes that there were no proarrhythmic effects seen on 7-day Holter recordings in 3,162 patients with acute coronary syndrome who were treated with ranolazine.

The revised label also includes the statement that ranolazine “produces small reductions in [hemoglobin A_1c] in patients with diabetes, the clinical significance of which is unknown,” and that the drug “should not be considered a treatment for diabetes.”

The Food and Drug Administration has approved a revised indication and several label additions for the angina drug ranolazine, including a statement that the drug reduced hemoglobin A_1c in people with diabetes.

The indication is still for “the treatment of chronic angina, but “the second-line restriction on the use of ranolazine to treat patients with chronic angina has been removed,” according to an announcement issued by the FDA.

Previously, the indication was for treatment of chronic angina, but with the added statement that it should be reserved for patients who have not had an adequate response with other antianginal drugs, because ranolazine increases the QT interval.

The additional statement has been removed from the revised label, with the information about the QT interval prolongation now in the warnings and precaution section.

Also added to the label is a statement that cites the significantly lower rate of arrhythmias in patients with coronary heart disease who were treated with ranolazine in the MERLIN-TIMI 36 trial, compared with those on placebo, CV Therapeutics Inc. noted in its announcement of the approval.

The indications section of the revised label also says that the drug can be used with β-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

CV Therapeutics markets ranolazine in extended-release tablet form as Ranexa, which was approved in January 2006.

Ranolazine has antianginal and anti-ischemic effects, but its exact mechanism of action is not known, according to the label.

In a statement, the company said that data from the MERLIN-TIMI 36 trial were submitted to the FDA in September 2007, as part of its supplemental application. The revised label includes the statement that in the study—which compared ranolazine to placebo in more than 6,000 patients with acute coronary syndrome—no benefit was seen on outcome measures, but that the study was “somewhat reassuring regarding proarrhythmic risks, as ventricular arrhythmias were less common on ranolazine.”

The incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) was 80% among those treated with ranolazine, compared with 87% of those on placebo, a significant difference, according to the label. However, the label also states that the difference in arrhythmias did not result in lower mortality, or reductions in arrhythmia hospitalizations or arrhythmia symptoms.

The label notes that there were no proarrhythmic effects seen on 7-day Holter recordings in 3,162 patients with acute coronary syndrome who were treated with ranolazine.

The revised label also includes the statement that ranolazine “produces small reductions in [hemoglobin A_1c] in patients with diabetes, the clinical significance of which is unknown,” and that the drug “should not be considered a treatment for diabetes.”

The Food and Drug Administration has approved a revised indication and several label additions for the angina drug ranolazine, including a statement that the drug reduced hemoglobin A_1c in people with diabetes.

The indication is still for “the treatment of chronic angina, but “the second-line restriction on the use of ranolazine to treat patients with chronic angina has been removed,” according to an announcement issued by the FDA.

Previously, the indication was for treatment of chronic angina, but with the added statement that it should be reserved for patients who have not had an adequate response with other antianginal drugs, because ranolazine increases the QT interval.

The additional statement has been removed from the revised label, with the information about the QT interval prolongation now in the warnings and precaution section.

Also added to the label is a statement that cites the significantly lower rate of arrhythmias in patients with coronary heart disease who were treated with ranolazine in the MERLIN-TIMI 36 trial, compared with those on placebo, CV Therapeutics Inc. noted in its announcement of the approval.

The indications section of the revised label also says that the drug can be used with β-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

CV Therapeutics markets ranolazine in extended-release tablet form as Ranexa, which was approved in January 2006.

Ranolazine has antianginal and anti-ischemic effects, but its exact mechanism of action is not known, according to the label.

In a statement, the company said that data from the MERLIN-TIMI 36 trial were submitted to the FDA in September 2007, as part of its supplemental application. The revised label includes the statement that in the study—which compared ranolazine to placebo in more than 6,000 patients with acute coronary syndrome—no benefit was seen on outcome measures, but that the study was “somewhat reassuring regarding proarrhythmic risks, as ventricular arrhythmias were less common on ranolazine.”

The incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) was 80% among those treated with ranolazine, compared with 87% of those on placebo, a significant difference, according to the label. However, the label also states that the difference in arrhythmias did not result in lower mortality, or reductions in arrhythmia hospitalizations or arrhythmia symptoms.

The label notes that there were no proarrhythmic effects seen on 7-day Holter recordings in 3,162 patients with acute coronary syndrome who were treated with ranolazine.

The revised label also includes the statement that ranolazine “produces small reductions in [hemoglobin A_1c] in patients with diabetes, the clinical significance of which is unknown,” and that the drug “should not be considered a treatment for diabetes.”

The label of the immunomodulator efalizumab will soon have a black box warning describing the potential risks of progressive multifocal leukoencephalopathy and other life-threatening infections, because of postmarketing reports of these serious infections, the Food and Drug Administration announced last month

Some cases have required hospitalization and some have been fatal, according to a statement issued by the FDA. In addition to progressive multifocal leukoencephalopathy (PML), the boxed warning will list bacterial sepsis, viral meningitis, invasive fungal disease, and other opportunistic infections as risks associated with efalizumab (Raptiva).

The FDA has also requested that Genentech, the manufacturer of efalizumab, submit plans for a risk evaluation and mitigation strategy. Under legislation passed in 2007, the agency can require manufacturers to make safety labeling changes, and to plan a strategy for evaluating and managing a drug's risks, to ensure that the benefits of a drug outweigh its risks, when a safety issue is identified.

“Doctors and other prescribers should carefully evaluate and weigh the risk/benefit profile of Raptiva for patients who would be more susceptible to these risks,” Dr. Janet Woodcock, the director of the FDA's Center for Drug Evaluation and Research, said in the statement.

In a letter sent to health care professionals, Genentech described a case of PML in a patient treated with efalizumab for psoriasis, the first confirmed case associated with the immunosuppressive human monoclonal antibody.

The patient is a 70-year-old man, who had been treated with efalizumab for chronic plaque psoriasis for more than 4 years. He is currently hospitalized, a spokesperson for Genentech said.

PML is a rare, often fatal progressive disorder that affects the central nervous system. It is caused by activation of the JC virus, which is latent in more than 80% of healthy adults and usually causes disease only in immunocompromised patients.

“Physicians should consider PML in any patient treated with Raptiva who presents with new onset neurologic manifestations” and should also consider a brain MRI, lumbar puncture, and consultation with a neurologist, the letter advises. Efalizumab should be stopped in any patient who develops PML, and antiviral therapy and other appropriate treatments should be considered, the letter adds.

The label of the immunomodulator efalizumab will soon have a black box warning describing the potential risks of progressive multifocal leukoencephalopathy and other life-threatening infections, because of postmarketing reports of these serious infections, the Food and Drug Administration announced last month

Some cases have required hospitalization and some have been fatal, according to a statement issued by the FDA. In addition to progressive multifocal leukoencephalopathy (PML), the boxed warning will list bacterial sepsis, viral meningitis, invasive fungal disease, and other opportunistic infections as risks associated with efalizumab (Raptiva).

The FDA has also requested that Genentech, the manufacturer of efalizumab, submit plans for a risk evaluation and mitigation strategy. Under legislation passed in 2007, the agency can require manufacturers to make safety labeling changes, and to plan a strategy for evaluating and managing a drug's risks, to ensure that the benefits of a drug outweigh its risks, when a safety issue is identified.

“Doctors and other prescribers should carefully evaluate and weigh the risk/benefit profile of Raptiva for patients who would be more susceptible to these risks,” Dr. Janet Woodcock, the director of the FDA's Center for Drug Evaluation and Research, said in the statement.

In a letter sent to health care professionals, Genentech described a case of PML in a patient treated with efalizumab for psoriasis, the first confirmed case associated with the immunosuppressive human monoclonal antibody.

The patient is a 70-year-old man, who had been treated with efalizumab for chronic plaque psoriasis for more than 4 years. He is currently hospitalized, a spokesperson for Genentech said.

PML is a rare, often fatal progressive disorder that affects the central nervous system. It is caused by activation of the JC virus, which is latent in more than 80% of healthy adults and usually causes disease only in immunocompromised patients.

“Physicians should consider PML in any patient treated with Raptiva who presents with new onset neurologic manifestations” and should also consider a brain MRI, lumbar puncture, and consultation with a neurologist, the letter advises. Efalizumab should be stopped in any patient who develops PML, and antiviral therapy and other appropriate treatments should be considered, the letter adds.

The label of the immunomodulator efalizumab will soon have a black box warning describing the potential risks of progressive multifocal leukoencephalopathy and other life-threatening infections, because of postmarketing reports of these serious infections, the Food and Drug Administration announced last month

Some cases have required hospitalization and some have been fatal, according to a statement issued by the FDA. In addition to progressive multifocal leukoencephalopathy (PML), the boxed warning will list bacterial sepsis, viral meningitis, invasive fungal disease, and other opportunistic infections as risks associated with efalizumab (Raptiva).

The FDA has also requested that Genentech, the manufacturer of efalizumab, submit plans for a risk evaluation and mitigation strategy. Under legislation passed in 2007, the agency can require manufacturers to make safety labeling changes, and to plan a strategy for evaluating and managing a drug's risks, to ensure that the benefits of a drug outweigh its risks, when a safety issue is identified.

“Doctors and other prescribers should carefully evaluate and weigh the risk/benefit profile of Raptiva for patients who would be more susceptible to these risks,” Dr. Janet Woodcock, the director of the FDA's Center for Drug Evaluation and Research, said in the statement.

In a letter sent to health care professionals, Genentech described a case of PML in a patient treated with efalizumab for psoriasis, the first confirmed case associated with the immunosuppressive human monoclonal antibody.

The patient is a 70-year-old man, who had been treated with efalizumab for chronic plaque psoriasis for more than 4 years. He is currently hospitalized, a spokesperson for Genentech said.

PML is a rare, often fatal progressive disorder that affects the central nervous system. It is caused by activation of the JC virus, which is latent in more than 80% of healthy adults and usually causes disease only in immunocompromised patients.

“Physicians should consider PML in any patient treated with Raptiva who presents with new onset neurologic manifestations” and should also consider a brain MRI, lumbar puncture, and consultation with a neurologist, the letter advises. Efalizumab should be stopped in any patient who develops PML, and antiviral therapy and other appropriate treatments should be considered, the letter adds.