Elizabeth Mechcatie

BETHESDA, MD. — HIV-infected women shed more human papilloma virus, have higher rates of high-grade cervical intraepithelial neoplasia, and are diagnosed more frequently with vulvar intraepithelial neoplasia (VIN) than are women who are not infected, Thomas C. Wright Jr., M.D., said at a conference on vulvovaginal diseases.

Women infected with HIV have an increased rate of human papilloma virus (HPV) shedding that is generally estimated at about four times that of HIV-negative women, said Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Among HPV-infected women, those who are also infected with HIV have more HPV types than do women without HIV. In one study conducted in New York City, 31% of HIV-positive women had more than one HPV type, vs. 9% of HIV-negative women. A total of 16% and 14% had HPV 16 and HPV 18, respectively, in the HIV-positive group vs. 6% and 3%, respectively, in HIV-negative women.

Studies conducted in the 1990s determined that the distribution of HPV types in women without cervical intraepithelial neoplasia (CIN) tend to be the same in those who are HIV positive and those who are HIV negative. But women with biopsy-confirmed CIN 2,3 who are HIV positive “tend to be more heterogenous for high-risk [HPV] types” he said.

Types 16 and 18, which tend to be the most common high-risk HPV types in the general population and appear to be more aggressive than other high-risk HPV types, are found in considerable numbers of CIN 2,3 cases in both HIV-infected and uninfected women. However, in HIV-infected women, the other HPV types that can cause cancer “may become a little more pathogenic” as the immune system deteriorates, Dr. Wright noted.

Viral load and CD4 counts have both been found to be markers for patients who shed HPV: The Women's Interagency HIV Study (WIHS) published in 1999 found that HPV was detected more frequently in women with low (under 200) CD4 counts, regardless of their HIV viral load. Similarly, women with a high HIV viral load, even with a higher CD4 count, will have high rates of HPV shedding, Dr. Wright said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

For more than a decade, it has been clear that the prevalence of CIN among HIV-positive women is high, estimated at two to four times higher than among noninfected women. He referred to four large prospective follow-up studies, including one he and his associates conducted in New York City, which found that the rates of abnormal cytology in HIV-positive women ranged from 30% to 40%, vs. 8% to 20% among HIV-negative women.

In his study, 7% of the HIV-positive women had high-grade CIN (CIN 2,3), vs. 1% of the HIV-negative women. Over a 3-year follow-up, 20% of the HIV-positive women developed biopsy-confirmed CIN, increasing to 30% over 6 years. Predictably, a woman with low CD4 counts is more likely to develop CIN, Dr. Wright said, adding that a woman with low CD4 counts who is followed for 48 months has a 40% chance of developing biopsy-confirmed CIN.

In HIV-infected women condylomas are very common. Vulvar condylomas in this population are numerous and multifocal, and tend to respond poorly to standard treatments, he said. Although VIN is less common than is CIN, VIN is much more common in HIV-infected women compared with uninfected women.

In a study published this year of 1,778 HIV-infected women and 500 HIV-negative women followed for 8 years, incident condylomas were detected in 23% of HIV-positive women vs. 7% of HIV-negative women. In the WIHS study published this year, risk factors for condylomas identified among HIV-positive women were cytologic abnormalities, HPV, smoking, no HAART (highly active antiretroviral therapy), and a low CD4 count, he said.

Now that HAART is used so widely, there is much less cervical and vulvar disease in HIV-infected patients, Dr. Wright observed. At one point, a large proportion of the patients he saw at the Columbia colposcopy clinic were HIV positive, but those numbers have markedly dropped now that most are on HAART, which has been shown to reduce the incidence of condylomas.

VIN, however, is clearly an increasing problem in this population, he said. Because women in the HIV clinic are well screened and treated with loop electrosurgical excision procedure when CIN is detected, cervical cancer is less common. In contrast, “we continue to identify vulvar cancers,” since screening and treating for VIN lesions is not as thorough.

In a study that followed cervical disease in HIV-positive and HIV-negative women, he and his coinvestigators have found that about 4% of HIV-positive women developed biopsy-confirmed VIN over 60 months vs. less than 1% of HIV-negative women. And, as with cervical disease, the risk was higher with lower CD4 counts, where almost 20% of those with CD4 counts under 200 developed biopsy-confirmed VIN.

In the WIHS study, incident VIN 2,3 was detected in 8% of HIV-positive women during follow-up and 2% of HIV-negative women, “a relatively high attack rate” of 1.52 per 100 person-years among HIV-positive women, vs. 0.36 per 100 person-years for HIV-negative women. This indicates that about 1% of HIV-positive women will develop biopsy-confirmed VIN every year, Dr. Wright pointed out.

In the WIHS study, the risk of VIN 2,3 was increased in women with cytologic abnormalities and high-risk HPV types. However, HAART use and CD4 counts did not have a significant impact on incidence, so while HAART is effective in reducing condylomas and CIN, “we're not seeing the same dramatic impact of HAART on VIN incidence, in the studies that have been reported.”

Based on these findings, he recommended a high level of awareness of vulvar disease in HIV-infected patients. When an HIV- positive patient is referred with an ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesions) Pap, “be absolutely certain that you do a very careful inspection of the vulva, and do liberal biopsies” of anything that looks abnormal.

BETHESDA, MD. — HIV-infected women shed more human papilloma virus, have higher rates of high-grade cervical intraepithelial neoplasia, and are diagnosed more frequently with vulvar intraepithelial neoplasia (VIN) than are women who are not infected, Thomas C. Wright Jr., M.D., said at a conference on vulvovaginal diseases.

Women infected with HIV have an increased rate of human papilloma virus (HPV) shedding that is generally estimated at about four times that of HIV-negative women, said Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Among HPV-infected women, those who are also infected with HIV have more HPV types than do women without HIV. In one study conducted in New York City, 31% of HIV-positive women had more than one HPV type, vs. 9% of HIV-negative women. A total of 16% and 14% had HPV 16 and HPV 18, respectively, in the HIV-positive group vs. 6% and 3%, respectively, in HIV-negative women.

Studies conducted in the 1990s determined that the distribution of HPV types in women without cervical intraepithelial neoplasia (CIN) tend to be the same in those who are HIV positive and those who are HIV negative. But women with biopsy-confirmed CIN 2,3 who are HIV positive “tend to be more heterogenous for high-risk [HPV] types” he said.

Types 16 and 18, which tend to be the most common high-risk HPV types in the general population and appear to be more aggressive than other high-risk HPV types, are found in considerable numbers of CIN 2,3 cases in both HIV-infected and uninfected women. However, in HIV-infected women, the other HPV types that can cause cancer “may become a little more pathogenic” as the immune system deteriorates, Dr. Wright noted.

Viral load and CD4 counts have both been found to be markers for patients who shed HPV: The Women's Interagency HIV Study (WIHS) published in 1999 found that HPV was detected more frequently in women with low (under 200) CD4 counts, regardless of their HIV viral load. Similarly, women with a high HIV viral load, even with a higher CD4 count, will have high rates of HPV shedding, Dr. Wright said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

For more than a decade, it has been clear that the prevalence of CIN among HIV-positive women is high, estimated at two to four times higher than among noninfected women. He referred to four large prospective follow-up studies, including one he and his associates conducted in New York City, which found that the rates of abnormal cytology in HIV-positive women ranged from 30% to 40%, vs. 8% to 20% among HIV-negative women.

In his study, 7% of the HIV-positive women had high-grade CIN (CIN 2,3), vs. 1% of the HIV-negative women. Over a 3-year follow-up, 20% of the HIV-positive women developed biopsy-confirmed CIN, increasing to 30% over 6 years. Predictably, a woman with low CD4 counts is more likely to develop CIN, Dr. Wright said, adding that a woman with low CD4 counts who is followed for 48 months has a 40% chance of developing biopsy-confirmed CIN.

In HIV-infected women condylomas are very common. Vulvar condylomas in this population are numerous and multifocal, and tend to respond poorly to standard treatments, he said. Although VIN is less common than is CIN, VIN is much more common in HIV-infected women compared with uninfected women.

In a study published this year of 1,778 HIV-infected women and 500 HIV-negative women followed for 8 years, incident condylomas were detected in 23% of HIV-positive women vs. 7% of HIV-negative women. In the WIHS study published this year, risk factors for condylomas identified among HIV-positive women were cytologic abnormalities, HPV, smoking, no HAART (highly active antiretroviral therapy), and a low CD4 count, he said.

Now that HAART is used so widely, there is much less cervical and vulvar disease in HIV-infected patients, Dr. Wright observed. At one point, a large proportion of the patients he saw at the Columbia colposcopy clinic were HIV positive, but those numbers have markedly dropped now that most are on HAART, which has been shown to reduce the incidence of condylomas.

VIN, however, is clearly an increasing problem in this population, he said. Because women in the HIV clinic are well screened and treated with loop electrosurgical excision procedure when CIN is detected, cervical cancer is less common. In contrast, “we continue to identify vulvar cancers,” since screening and treating for VIN lesions is not as thorough.

In a study that followed cervical disease in HIV-positive and HIV-negative women, he and his coinvestigators have found that about 4% of HIV-positive women developed biopsy-confirmed VIN over 60 months vs. less than 1% of HIV-negative women. And, as with cervical disease, the risk was higher with lower CD4 counts, where almost 20% of those with CD4 counts under 200 developed biopsy-confirmed VIN.

In the WIHS study, incident VIN 2,3 was detected in 8% of HIV-positive women during follow-up and 2% of HIV-negative women, “a relatively high attack rate” of 1.52 per 100 person-years among HIV-positive women, vs. 0.36 per 100 person-years for HIV-negative women. This indicates that about 1% of HIV-positive women will develop biopsy-confirmed VIN every year, Dr. Wright pointed out.

In the WIHS study, the risk of VIN 2,3 was increased in women with cytologic abnormalities and high-risk HPV types. However, HAART use and CD4 counts did not have a significant impact on incidence, so while HAART is effective in reducing condylomas and CIN, “we're not seeing the same dramatic impact of HAART on VIN incidence, in the studies that have been reported.”

Based on these findings, he recommended a high level of awareness of vulvar disease in HIV-infected patients. When an HIV- positive patient is referred with an ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesions) Pap, “be absolutely certain that you do a very careful inspection of the vulva, and do liberal biopsies” of anything that looks abnormal.

BETHESDA, MD. — HIV-infected women shed more human papilloma virus, have higher rates of high-grade cervical intraepithelial neoplasia, and are diagnosed more frequently with vulvar intraepithelial neoplasia (VIN) than are women who are not infected, Thomas C. Wright Jr., M.D., said at a conference on vulvovaginal diseases.

Women infected with HIV have an increased rate of human papilloma virus (HPV) shedding that is generally estimated at about four times that of HIV-negative women, said Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Among HPV-infected women, those who are also infected with HIV have more HPV types than do women without HIV. In one study conducted in New York City, 31% of HIV-positive women had more than one HPV type, vs. 9% of HIV-negative women. A total of 16% and 14% had HPV 16 and HPV 18, respectively, in the HIV-positive group vs. 6% and 3%, respectively, in HIV-negative women.

Studies conducted in the 1990s determined that the distribution of HPV types in women without cervical intraepithelial neoplasia (CIN) tend to be the same in those who are HIV positive and those who are HIV negative. But women with biopsy-confirmed CIN 2,3 who are HIV positive “tend to be more heterogenous for high-risk [HPV] types” he said.

Types 16 and 18, which tend to be the most common high-risk HPV types in the general population and appear to be more aggressive than other high-risk HPV types, are found in considerable numbers of CIN 2,3 cases in both HIV-infected and uninfected women. However, in HIV-infected women, the other HPV types that can cause cancer “may become a little more pathogenic” as the immune system deteriorates, Dr. Wright noted.

Viral load and CD4 counts have both been found to be markers for patients who shed HPV: The Women's Interagency HIV Study (WIHS) published in 1999 found that HPV was detected more frequently in women with low (under 200) CD4 counts, regardless of their HIV viral load. Similarly, women with a high HIV viral load, even with a higher CD4 count, will have high rates of HPV shedding, Dr. Wright said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

For more than a decade, it has been clear that the prevalence of CIN among HIV-positive women is high, estimated at two to four times higher than among noninfected women. He referred to four large prospective follow-up studies, including one he and his associates conducted in New York City, which found that the rates of abnormal cytology in HIV-positive women ranged from 30% to 40%, vs. 8% to 20% among HIV-negative women.

In his study, 7% of the HIV-positive women had high-grade CIN (CIN 2,3), vs. 1% of the HIV-negative women. Over a 3-year follow-up, 20% of the HIV-positive women developed biopsy-confirmed CIN, increasing to 30% over 6 years. Predictably, a woman with low CD4 counts is more likely to develop CIN, Dr. Wright said, adding that a woman with low CD4 counts who is followed for 48 months has a 40% chance of developing biopsy-confirmed CIN.

In HIV-infected women condylomas are very common. Vulvar condylomas in this population are numerous and multifocal, and tend to respond poorly to standard treatments, he said. Although VIN is less common than is CIN, VIN is much more common in HIV-infected women compared with uninfected women.

In a study published this year of 1,778 HIV-infected women and 500 HIV-negative women followed for 8 years, incident condylomas were detected in 23% of HIV-positive women vs. 7% of HIV-negative women. In the WIHS study published this year, risk factors for condylomas identified among HIV-positive women were cytologic abnormalities, HPV, smoking, no HAART (highly active antiretroviral therapy), and a low CD4 count, he said.

Now that HAART is used so widely, there is much less cervical and vulvar disease in HIV-infected patients, Dr. Wright observed. At one point, a large proportion of the patients he saw at the Columbia colposcopy clinic were HIV positive, but those numbers have markedly dropped now that most are on HAART, which has been shown to reduce the incidence of condylomas.

VIN, however, is clearly an increasing problem in this population, he said. Because women in the HIV clinic are well screened and treated with loop electrosurgical excision procedure when CIN is detected, cervical cancer is less common. In contrast, “we continue to identify vulvar cancers,” since screening and treating for VIN lesions is not as thorough.

In a study that followed cervical disease in HIV-positive and HIV-negative women, he and his coinvestigators have found that about 4% of HIV-positive women developed biopsy-confirmed VIN over 60 months vs. less than 1% of HIV-negative women. And, as with cervical disease, the risk was higher with lower CD4 counts, where almost 20% of those with CD4 counts under 200 developed biopsy-confirmed VIN.

In the WIHS study, incident VIN 2,3 was detected in 8% of HIV-positive women during follow-up and 2% of HIV-negative women, “a relatively high attack rate” of 1.52 per 100 person-years among HIV-positive women, vs. 0.36 per 100 person-years for HIV-negative women. This indicates that about 1% of HIV-positive women will develop biopsy-confirmed VIN every year, Dr. Wright pointed out.

In the WIHS study, the risk of VIN 2,3 was increased in women with cytologic abnormalities and high-risk HPV types. However, HAART use and CD4 counts did not have a significant impact on incidence, so while HAART is effective in reducing condylomas and CIN, “we're not seeing the same dramatic impact of HAART on VIN incidence, in the studies that have been reported.”

Based on these findings, he recommended a high level of awareness of vulvar disease in HIV-infected patients. When an HIV- positive patient is referred with an ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesions) Pap, “be absolutely certain that you do a very careful inspection of the vulva, and do liberal biopsies” of anything that looks abnormal.

WASHINGTON — The prevalence of urinary tract infections in women resistant to standard treatment has been increasing, but there are indications that the increase has begun to level off, Patricia D. Brown, M.D., said at an update on sexually transmitted infections.

Emerging uropathogenic Escherichia coli antimicrobial resistance—particularly to the front-line, first choice treatment of urinary tract infections (UTIs), trimethoprim-sulfamethoxazole (TMP-SMX)—has been documented worldwide. However, much of the data are based on passive surveillance, which can overestimate prevalence, because women with acute, uncomplicated UTIs often do not have cultures performed, so these cases are not reported, said Dr. Brown of Wayne State University, Detroit.

Women who do have a culture have complicated disease and fail treatment, leading to overestimates of true prevalence, she added. Still, passive surveillance can provide information on trends.

In the United States, active surveillance has been conducted in specific geographic areas, where the true prevalence may not reflect that of other geographic areas, Dr. Brown said at the meeting, sponsored by OB.GYN. NEWS, FAMILY PRACTICE NEWS, and Boston University.

Recent studies indicate that TMP-SMX resistance “may be leveling off” after peaking at about 25%, which is probably because of the reduced use of this treatment, she said. But as the use of TMP-SMX for UTIs has decreased, resistance to other antimicrobial agents has been increasing.

In 890 isolates from women with UTIs in the United States who were a part of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, the prevalence of TMP-SMX resistance was about 23%. Resistance to ampicillin was 38%, and resistance to levofloxacin was nearly 7%.

As the use of TMP-SMX has dropped, the use of fluoroquinolones has increased, Dr. Brown said, noting that rates of resistance to β-lactams such as ampicillin have been high for some time.

In the NAUTICA study, resistance to nitrofurantoin was only 1.8%, which she said was “remarkable,” considering that it has been available for about 50 years. But that rate has probably remained so low because the agent has several mechanisms of action and is indicated only for cystitis, she noted.

There are several clinical implications of these resistance trends: In treatment studies of pyelonephritis, antimicrobial resistance has clearly been shown to increase the risks of both clinical and microbiologic failure, she said. She cited a retrospective cohort study of women with acute uncomplicated cystitis, in which the risk of clinical failure was 45.4%, and a prospective study in Israel of empiric TMP-SMX in an area where the prevalence of resistance was high, in which the risk of clinical failure was 46%.

Identifying risk factors for resistance can help guide antibiotic choice, she said, referring to the difficulty facing clinicians, who usually do not have access to resistance trends and who likely will be given an overestimate of resistance if they call their local microbiology lab.

Results of retrospective case-control studies have identified potential risk factors for infection with a uropathogen resistant to TMP-SMX. Two risk factors found in every such study include recent antibiotic use and recent hospitalization, she said. Recent travel to underdeveloped countries has been identified as an independent risk factor in several studies.

The standard treatment of uncomplicated cystitis is 3 days of double-strength formulations of TMP-SMX twice a day. Avoid empiric treatment with TMP-SMX in patients who have recently been hospitalized or have taken antibiotics in the previous 3 months, she said.

Alternative treatments for those with risk factors for resistance are a 7-day course of nitrofurantoin or a 3-day course of a fluoroquinolone. The major drawback of the former is that a full-week course is necessary.

As for the fluoroquinolones, ciprofloxacin is available in generic formulations, so the drug is less expensive. The Food and Drug Administration has approved gatifloxacin as a single-dose treatment for uncomplicated cystitis. One fluoroquinolone that should not be used for UTI is moxifloxacin, which is indicated for respiratory infections, because treatment results in low levels of the drug in the urinary tract.

A single dose of fosfomycin is another alternative, but this is considered a second-line treatment because the efficacy is not that high and it is expensive. One benefit, however, is that resistance to this agent appears to be low, Dr. Brown said.

Short-course treatment is not appropriate for complicated cystitis, which should be treated with a 7-day course of therapy, she said. Avoid empiric TMP-SMX treatment in patients who have recently been treated with antibiotics or have recently been hospitalized, as you would for patients with uncomplicated cystitis. Culture all patients, and adjust treatment based on susceptibility data, she said.

As many as 25% of women with acute cystitis can develop frequent, recurrent UTIs, which are reinfections, not relapses. (Fewer than 5% of these women have a correctable structural or functional abnormality of the urinary tract.)

WASHINGTON — The prevalence of urinary tract infections in women resistant to standard treatment has been increasing, but there are indications that the increase has begun to level off, Patricia D. Brown, M.D., said at an update on sexually transmitted infections.

Emerging uropathogenic Escherichia coli antimicrobial resistance—particularly to the front-line, first choice treatment of urinary tract infections (UTIs), trimethoprim-sulfamethoxazole (TMP-SMX)—has been documented worldwide. However, much of the data are based on passive surveillance, which can overestimate prevalence, because women with acute, uncomplicated UTIs often do not have cultures performed, so these cases are not reported, said Dr. Brown of Wayne State University, Detroit.

Women who do have a culture have complicated disease and fail treatment, leading to overestimates of true prevalence, she added. Still, passive surveillance can provide information on trends.

In the United States, active surveillance has been conducted in specific geographic areas, where the true prevalence may not reflect that of other geographic areas, Dr. Brown said at the meeting, sponsored by OB.GYN. NEWS, FAMILY PRACTICE NEWS, and Boston University.

Recent studies indicate that TMP-SMX resistance “may be leveling off” after peaking at about 25%, which is probably because of the reduced use of this treatment, she said. But as the use of TMP-SMX for UTIs has decreased, resistance to other antimicrobial agents has been increasing.

In 890 isolates from women with UTIs in the United States who were a part of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, the prevalence of TMP-SMX resistance was about 23%. Resistance to ampicillin was 38%, and resistance to levofloxacin was nearly 7%.

As the use of TMP-SMX has dropped, the use of fluoroquinolones has increased, Dr. Brown said, noting that rates of resistance to β-lactams such as ampicillin have been high for some time.

In the NAUTICA study, resistance to nitrofurantoin was only 1.8%, which she said was “remarkable,” considering that it has been available for about 50 years. But that rate has probably remained so low because the agent has several mechanisms of action and is indicated only for cystitis, she noted.

There are several clinical implications of these resistance trends: In treatment studies of pyelonephritis, antimicrobial resistance has clearly been shown to increase the risks of both clinical and microbiologic failure, she said. She cited a retrospective cohort study of women with acute uncomplicated cystitis, in which the risk of clinical failure was 45.4%, and a prospective study in Israel of empiric TMP-SMX in an area where the prevalence of resistance was high, in which the risk of clinical failure was 46%.

Identifying risk factors for resistance can help guide antibiotic choice, she said, referring to the difficulty facing clinicians, who usually do not have access to resistance trends and who likely will be given an overestimate of resistance if they call their local microbiology lab.

Results of retrospective case-control studies have identified potential risk factors for infection with a uropathogen resistant to TMP-SMX. Two risk factors found in every such study include recent antibiotic use and recent hospitalization, she said. Recent travel to underdeveloped countries has been identified as an independent risk factor in several studies.

The standard treatment of uncomplicated cystitis is 3 days of double-strength formulations of TMP-SMX twice a day. Avoid empiric treatment with TMP-SMX in patients who have recently been hospitalized or have taken antibiotics in the previous 3 months, she said.

Alternative treatments for those with risk factors for resistance are a 7-day course of nitrofurantoin or a 3-day course of a fluoroquinolone. The major drawback of the former is that a full-week course is necessary.

As for the fluoroquinolones, ciprofloxacin is available in generic formulations, so the drug is less expensive. The Food and Drug Administration has approved gatifloxacin as a single-dose treatment for uncomplicated cystitis. One fluoroquinolone that should not be used for UTI is moxifloxacin, which is indicated for respiratory infections, because treatment results in low levels of the drug in the urinary tract.

A single dose of fosfomycin is another alternative, but this is considered a second-line treatment because the efficacy is not that high and it is expensive. One benefit, however, is that resistance to this agent appears to be low, Dr. Brown said.

Short-course treatment is not appropriate for complicated cystitis, which should be treated with a 7-day course of therapy, she said. Avoid empiric TMP-SMX treatment in patients who have recently been treated with antibiotics or have recently been hospitalized, as you would for patients with uncomplicated cystitis. Culture all patients, and adjust treatment based on susceptibility data, she said.

As many as 25% of women with acute cystitis can develop frequent, recurrent UTIs, which are reinfections, not relapses. (Fewer than 5% of these women have a correctable structural or functional abnormality of the urinary tract.)

WASHINGTON — The prevalence of urinary tract infections in women resistant to standard treatment has been increasing, but there are indications that the increase has begun to level off, Patricia D. Brown, M.D., said at an update on sexually transmitted infections.

Emerging uropathogenic Escherichia coli antimicrobial resistance—particularly to the front-line, first choice treatment of urinary tract infections (UTIs), trimethoprim-sulfamethoxazole (TMP-SMX)—has been documented worldwide. However, much of the data are based on passive surveillance, which can overestimate prevalence, because women with acute, uncomplicated UTIs often do not have cultures performed, so these cases are not reported, said Dr. Brown of Wayne State University, Detroit.

Women who do have a culture have complicated disease and fail treatment, leading to overestimates of true prevalence, she added. Still, passive surveillance can provide information on trends.

In the United States, active surveillance has been conducted in specific geographic areas, where the true prevalence may not reflect that of other geographic areas, Dr. Brown said at the meeting, sponsored by OB.GYN. NEWS, FAMILY PRACTICE NEWS, and Boston University.

Recent studies indicate that TMP-SMX resistance “may be leveling off” after peaking at about 25%, which is probably because of the reduced use of this treatment, she said. But as the use of TMP-SMX for UTIs has decreased, resistance to other antimicrobial agents has been increasing.

In 890 isolates from women with UTIs in the United States who were a part of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, the prevalence of TMP-SMX resistance was about 23%. Resistance to ampicillin was 38%, and resistance to levofloxacin was nearly 7%.

As the use of TMP-SMX has dropped, the use of fluoroquinolones has increased, Dr. Brown said, noting that rates of resistance to β-lactams such as ampicillin have been high for some time.

In the NAUTICA study, resistance to nitrofurantoin was only 1.8%, which she said was “remarkable,” considering that it has been available for about 50 years. But that rate has probably remained so low because the agent has several mechanisms of action and is indicated only for cystitis, she noted.

There are several clinical implications of these resistance trends: In treatment studies of pyelonephritis, antimicrobial resistance has clearly been shown to increase the risks of both clinical and microbiologic failure, she said. She cited a retrospective cohort study of women with acute uncomplicated cystitis, in which the risk of clinical failure was 45.4%, and a prospective study in Israel of empiric TMP-SMX in an area where the prevalence of resistance was high, in which the risk of clinical failure was 46%.

Identifying risk factors for resistance can help guide antibiotic choice, she said, referring to the difficulty facing clinicians, who usually do not have access to resistance trends and who likely will be given an overestimate of resistance if they call their local microbiology lab.

Results of retrospective case-control studies have identified potential risk factors for infection with a uropathogen resistant to TMP-SMX. Two risk factors found in every such study include recent antibiotic use and recent hospitalization, she said. Recent travel to underdeveloped countries has been identified as an independent risk factor in several studies.

The standard treatment of uncomplicated cystitis is 3 days of double-strength formulations of TMP-SMX twice a day. Avoid empiric treatment with TMP-SMX in patients who have recently been hospitalized or have taken antibiotics in the previous 3 months, she said.

Alternative treatments for those with risk factors for resistance are a 7-day course of nitrofurantoin or a 3-day course of a fluoroquinolone. The major drawback of the former is that a full-week course is necessary.

As for the fluoroquinolones, ciprofloxacin is available in generic formulations, so the drug is less expensive. The Food and Drug Administration has approved gatifloxacin as a single-dose treatment for uncomplicated cystitis. One fluoroquinolone that should not be used for UTI is moxifloxacin, which is indicated for respiratory infections, because treatment results in low levels of the drug in the urinary tract.

A single dose of fosfomycin is another alternative, but this is considered a second-line treatment because the efficacy is not that high and it is expensive. One benefit, however, is that resistance to this agent appears to be low, Dr. Brown said.

Short-course treatment is not appropriate for complicated cystitis, which should be treated with a 7-day course of therapy, she said. Avoid empiric TMP-SMX treatment in patients who have recently been treated with antibiotics or have recently been hospitalized, as you would for patients with uncomplicated cystitis. Culture all patients, and adjust treatment based on susceptibility data, she said.

As many as 25% of women with acute cystitis can develop frequent, recurrent UTIs, which are reinfections, not relapses. (Fewer than 5% of these women have a correctable structural or functional abnormality of the urinary tract.)

BETHESDA, MD. — The use of hormonal contraception is among the factors associated with increased viral shedding among women with genital herpes simplex virus type-2 infections, Sharon L. Hillier, Ph.D., said at a conference on vulvovaginal diseases.

Women who have recently been infected with HSV-2 and those with bacterial vaginosis (BV) have also been found to have greater viral shedding, said Dr. Hillier, director, reproductive infectious disease research, Magee-Womens Hospital, Pittsburgh. Shedding decreases over time after the primary episode.

Other women at risk for increased shedding include younger, pregnant, or the immunocompromised, and especially those who are HIV infected, she added.

The data on whether hormonal contraceptives are associated with increased shedding in this population have been mixed, she said, citing one study finding an association and two others, which found no such association.

But a study published in May that followed 330 HSV-2 seropositive women at 4-month intervals for 1 year, for a total of 956 visits, found a twofold increased risk of shedding among hormonal contraceptive users. At each visit, vaginal swab specimens were collected and tested for BV, yeast, group B streptococcus, and HSV-2 DNA, according to Thomas L. Cherpes, M.D., and associates at the University of Pittsburgh (Clin. Infect. Dis. 2005;40:1422–8).

A total of 95% of the women did not know they had herpes, noted Dr. Hillier, one of the study's authors and professor of obstetrics, gynecology, and reproductive sciences and of molecular genetics and biochemistry at the university.

Like other investigators, they found shedding increased threefold in those who were infected in the previous 4 months. That indicates once a woman has seroconverted, she is likely to infect her partner in the months following seroconversion.

The risk of shedding was 2.3 times greater among those with BV. Noting that women with BV have been found to have proinflammatory changes in the cytokine milieu, which normalize with treatment, Dr. Hillier said that “the hypothesis is that the altered flora that occur in women with BV actually cause this proinflammatory state in which herpes is more likely to reactivate.” She and her associates are beginning a study to examine the impact of BV treatment on HSV-2 viral shedding.

A surprising finding was that heavy colonization with group B streptococci (GBS) increased the shedding risk by twofold, “for reasons we're still trying to figure out,” Dr. Hillier said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

The increased risks of shedding associated with recent infection, BV, GBS colonization, and hormonal contraception were all statistically significant.

Like BV, hormonal contraception is another potentially modifiable risk factor for shedding, although she said she would not recommend that anyone stop taking hormonal contraceptive.

Women with BV are also more susceptible to acquiring HSV-2, Dr. Hillier said. There is biologic plausibility for this link, since the loss of the acidic environment produced by the lactobacillus (normal vaginal flora) in women with BV may create a more permissive environment for HSV-2, she said. Moreover, hydrogen peroxide-producing lactobacilli have antiviral activity, which may serve as a first line of defense against viral infection.

BETHESDA, MD. — The use of hormonal contraception is among the factors associated with increased viral shedding among women with genital herpes simplex virus type-2 infections, Sharon L. Hillier, Ph.D., said at a conference on vulvovaginal diseases.

Women who have recently been infected with HSV-2 and those with bacterial vaginosis (BV) have also been found to have greater viral shedding, said Dr. Hillier, director, reproductive infectious disease research, Magee-Womens Hospital, Pittsburgh. Shedding decreases over time after the primary episode.

Other women at risk for increased shedding include younger, pregnant, or the immunocompromised, and especially those who are HIV infected, she added.

The data on whether hormonal contraceptives are associated with increased shedding in this population have been mixed, she said, citing one study finding an association and two others, which found no such association.

But a study published in May that followed 330 HSV-2 seropositive women at 4-month intervals for 1 year, for a total of 956 visits, found a twofold increased risk of shedding among hormonal contraceptive users. At each visit, vaginal swab specimens were collected and tested for BV, yeast, group B streptococcus, and HSV-2 DNA, according to Thomas L. Cherpes, M.D., and associates at the University of Pittsburgh (Clin. Infect. Dis. 2005;40:1422–8).

A total of 95% of the women did not know they had herpes, noted Dr. Hillier, one of the study's authors and professor of obstetrics, gynecology, and reproductive sciences and of molecular genetics and biochemistry at the university.

Like other investigators, they found shedding increased threefold in those who were infected in the previous 4 months. That indicates once a woman has seroconverted, she is likely to infect her partner in the months following seroconversion.

The risk of shedding was 2.3 times greater among those with BV. Noting that women with BV have been found to have proinflammatory changes in the cytokine milieu, which normalize with treatment, Dr. Hillier said that “the hypothesis is that the altered flora that occur in women with BV actually cause this proinflammatory state in which herpes is more likely to reactivate.” She and her associates are beginning a study to examine the impact of BV treatment on HSV-2 viral shedding.

A surprising finding was that heavy colonization with group B streptococci (GBS) increased the shedding risk by twofold, “for reasons we're still trying to figure out,” Dr. Hillier said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

The increased risks of shedding associated with recent infection, BV, GBS colonization, and hormonal contraception were all statistically significant.

Like BV, hormonal contraception is another potentially modifiable risk factor for shedding, although she said she would not recommend that anyone stop taking hormonal contraceptive.

Women with BV are also more susceptible to acquiring HSV-2, Dr. Hillier said. There is biologic plausibility for this link, since the loss of the acidic environment produced by the lactobacillus (normal vaginal flora) in women with BV may create a more permissive environment for HSV-2, she said. Moreover, hydrogen peroxide-producing lactobacilli have antiviral activity, which may serve as a first line of defense against viral infection.

BETHESDA, MD. — The use of hormonal contraception is among the factors associated with increased viral shedding among women with genital herpes simplex virus type-2 infections, Sharon L. Hillier, Ph.D., said at a conference on vulvovaginal diseases.

Women who have recently been infected with HSV-2 and those with bacterial vaginosis (BV) have also been found to have greater viral shedding, said Dr. Hillier, director, reproductive infectious disease research, Magee-Womens Hospital, Pittsburgh. Shedding decreases over time after the primary episode.

Other women at risk for increased shedding include younger, pregnant, or the immunocompromised, and especially those who are HIV infected, she added.

The data on whether hormonal contraceptives are associated with increased shedding in this population have been mixed, she said, citing one study finding an association and two others, which found no such association.

But a study published in May that followed 330 HSV-2 seropositive women at 4-month intervals for 1 year, for a total of 956 visits, found a twofold increased risk of shedding among hormonal contraceptive users. At each visit, vaginal swab specimens were collected and tested for BV, yeast, group B streptococcus, and HSV-2 DNA, according to Thomas L. Cherpes, M.D., and associates at the University of Pittsburgh (Clin. Infect. Dis. 2005;40:1422–8).

A total of 95% of the women did not know they had herpes, noted Dr. Hillier, one of the study's authors and professor of obstetrics, gynecology, and reproductive sciences and of molecular genetics and biochemistry at the university.

Like other investigators, they found shedding increased threefold in those who were infected in the previous 4 months. That indicates once a woman has seroconverted, she is likely to infect her partner in the months following seroconversion.

The risk of shedding was 2.3 times greater among those with BV. Noting that women with BV have been found to have proinflammatory changes in the cytokine milieu, which normalize with treatment, Dr. Hillier said that “the hypothesis is that the altered flora that occur in women with BV actually cause this proinflammatory state in which herpes is more likely to reactivate.” She and her associates are beginning a study to examine the impact of BV treatment on HSV-2 viral shedding.

A surprising finding was that heavy colonization with group B streptococci (GBS) increased the shedding risk by twofold, “for reasons we're still trying to figure out,” Dr. Hillier said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

The increased risks of shedding associated with recent infection, BV, GBS colonization, and hormonal contraception were all statistically significant.

Like BV, hormonal contraception is another potentially modifiable risk factor for shedding, although she said she would not recommend that anyone stop taking hormonal contraceptive.

Women with BV are also more susceptible to acquiring HSV-2, Dr. Hillier said. There is biologic plausibility for this link, since the loss of the acidic environment produced by the lactobacillus (normal vaginal flora) in women with BV may create a more permissive environment for HSV-2, she said. Moreover, hydrogen peroxide-producing lactobacilli have antiviral activity, which may serve as a first line of defense against viral infection.

ROCKVILLE, MD. — The Food and Drug Administration has approved two major changes to the schedule for agranulocytosis monitoring in people on clozapine, an atypical antipsychotic sometimes used off label for management of dementia: the addition of absolute neutrophil count tests to regular monitoring and a reduction in the frequency of testing after 1 year of satisfactory white blood cell counts and absolute neutrophil counts.

The revised monitoring guidelines are as follows: Before starting treatment, patients must have a baseline white blood cell (WBC) count and an absolute neutrophil count (ANC). This should be followed by a WBC and ANC test every week for the first 6 months.

After 6 months, if WBC counts and ANCs have been acceptable (defined as a WBC greater than or equal to 3,500/mm

After 12 months of treatment, if WBC counts and ANCs have remained at acceptable levels during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.

The previous schedule neither included ANC testing nor allowed for further reductions in the frequency of testing after 1 year, with patients continuing to be tested every 2 weeks indefinitely.

Gregory Dubitsky, M.D., of the FDA's division of neuropharmacologic drug products, Rockville, said in an interview that the reduction in the frequency of monitoring after 1 year was based on considerations of data from the Clozaril National Registry and experience in the United Kingdom and Australia.

The decision to add ANC testing was based on the United Kingdom's experience, which suggested that moderate leukopenia might be detected earlier if ANC was used as an independent measure of hematologic function, as opposed to the total WBC count alone, he added.

An FDA analysis of the registry data found that people with moderate leukopenia appeared to be at a “considerably higher” risk of agranulocytosis, Dr. Dubitsky noted. On the basis of this finding, the label says that the benefits of continuing clozapine in such patients should be carefully balanced against this risk when deciding whether to continue treatment with the drug, he said. This information was not on the label previously. On the label, agranulocytosis is defined as an ANC below 500/mm

Other changes to the label include the frequency of monitoring recommended for patients who interrupt a course of clozapine treatment, and ANC criteria for various stages of leukopenia, Dr. Dubitsky said.

Further explanations of the revised monitoring schedule and other changes are included on the new label, which was posted on the FDA's MedWatch Web site last month.

Novartis, manufacturer of Clozaril, the trade formulation, is planning to send out a “Dear Health Care Provider” letter explaining the changes in the monitoring schedule as well as several other unrelated changes on the label. The letter is currently being reviewed by the FDA, according to Novartis. There are now several generic formulations of clozapine, which will also be required to make the same changes to their product labels.

The approval of clozapine in 1989 for the management of treatment-resistant schizophrenia was tied to the “no blood, no drug” requirement that the drug be made available through a special distribution system that required weekly WBC counts before the next week's supply of clozapine was provided to the patient.

All the WBC data have been entered into the Clozaril National Registry and have been used to make decisions on monitoring frequency.

At recent FDA advisory panel meetings on safety issues associated with various drugs, such as Vioxx and the other COX-2 inhibitors and the acne drug isotretinoin, the clozapine “no blood, no drug” policy was raised as an example of a risk management program that makes it possible to keep a drug on the market for patients who can benefit from it, while successfully managing the drug's potential serious risks.

The monitoring schedule has been changed once before: In 1998, the schedule was changed to allow a reduction in testing WBC counts to every 2 weeks after 6 months, in patients whose WBC counts were maintained at acceptable levels during the first 6 months of weekly testing.

The revised Clozaril label is available on the FDA's Web site at: www.fda.gov/medwatch/SAFETY/2005/may05.htm#Clozaril

ROCKVILLE, MD. — The Food and Drug Administration has approved two major changes to the schedule for agranulocytosis monitoring in people on clozapine, an atypical antipsychotic sometimes used off label for management of dementia: the addition of absolute neutrophil count tests to regular monitoring and a reduction in the frequency of testing after 1 year of satisfactory white blood cell counts and absolute neutrophil counts.

The revised monitoring guidelines are as follows: Before starting treatment, patients must have a baseline white blood cell (WBC) count and an absolute neutrophil count (ANC). This should be followed by a WBC and ANC test every week for the first 6 months.

After 6 months, if WBC counts and ANCs have been acceptable (defined as a WBC greater than or equal to 3,500/mm

After 12 months of treatment, if WBC counts and ANCs have remained at acceptable levels during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.

The previous schedule neither included ANC testing nor allowed for further reductions in the frequency of testing after 1 year, with patients continuing to be tested every 2 weeks indefinitely.

Gregory Dubitsky, M.D., of the FDA's division of neuropharmacologic drug products, Rockville, said in an interview that the reduction in the frequency of monitoring after 1 year was based on considerations of data from the Clozaril National Registry and experience in the United Kingdom and Australia.

The decision to add ANC testing was based on the United Kingdom's experience, which suggested that moderate leukopenia might be detected earlier if ANC was used as an independent measure of hematologic function, as opposed to the total WBC count alone, he added.

An FDA analysis of the registry data found that people with moderate leukopenia appeared to be at a “considerably higher” risk of agranulocytosis, Dr. Dubitsky noted. On the basis of this finding, the label says that the benefits of continuing clozapine in such patients should be carefully balanced against this risk when deciding whether to continue treatment with the drug, he said. This information was not on the label previously. On the label, agranulocytosis is defined as an ANC below 500/mm

Other changes to the label include the frequency of monitoring recommended for patients who interrupt a course of clozapine treatment, and ANC criteria for various stages of leukopenia, Dr. Dubitsky said.

Further explanations of the revised monitoring schedule and other changes are included on the new label, which was posted on the FDA's MedWatch Web site last month.

Novartis, manufacturer of Clozaril, the trade formulation, is planning to send out a “Dear Health Care Provider” letter explaining the changes in the monitoring schedule as well as several other unrelated changes on the label. The letter is currently being reviewed by the FDA, according to Novartis. There are now several generic formulations of clozapine, which will also be required to make the same changes to their product labels.

The approval of clozapine in 1989 for the management of treatment-resistant schizophrenia was tied to the “no blood, no drug” requirement that the drug be made available through a special distribution system that required weekly WBC counts before the next week's supply of clozapine was provided to the patient.

All the WBC data have been entered into the Clozaril National Registry and have been used to make decisions on monitoring frequency.

At recent FDA advisory panel meetings on safety issues associated with various drugs, such as Vioxx and the other COX-2 inhibitors and the acne drug isotretinoin, the clozapine “no blood, no drug” policy was raised as an example of a risk management program that makes it possible to keep a drug on the market for patients who can benefit from it, while successfully managing the drug's potential serious risks.

The monitoring schedule has been changed once before: In 1998, the schedule was changed to allow a reduction in testing WBC counts to every 2 weeks after 6 months, in patients whose WBC counts were maintained at acceptable levels during the first 6 months of weekly testing.

The revised Clozaril label is available on the FDA's Web site at: www.fda.gov/medwatch/SAFETY/2005/may05.htm#Clozaril

ROCKVILLE, MD. — The Food and Drug Administration has approved two major changes to the schedule for agranulocytosis monitoring in people on clozapine, an atypical antipsychotic sometimes used off label for management of dementia: the addition of absolute neutrophil count tests to regular monitoring and a reduction in the frequency of testing after 1 year of satisfactory white blood cell counts and absolute neutrophil counts.

The revised monitoring guidelines are as follows: Before starting treatment, patients must have a baseline white blood cell (WBC) count and an absolute neutrophil count (ANC). This should be followed by a WBC and ANC test every week for the first 6 months.

After 6 months, if WBC counts and ANCs have been acceptable (defined as a WBC greater than or equal to 3,500/mm

After 12 months of treatment, if WBC counts and ANCs have remained at acceptable levels during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.

The previous schedule neither included ANC testing nor allowed for further reductions in the frequency of testing after 1 year, with patients continuing to be tested every 2 weeks indefinitely.

Gregory Dubitsky, M.D., of the FDA's division of neuropharmacologic drug products, Rockville, said in an interview that the reduction in the frequency of monitoring after 1 year was based on considerations of data from the Clozaril National Registry and experience in the United Kingdom and Australia.

The decision to add ANC testing was based on the United Kingdom's experience, which suggested that moderate leukopenia might be detected earlier if ANC was used as an independent measure of hematologic function, as opposed to the total WBC count alone, he added.

An FDA analysis of the registry data found that people with moderate leukopenia appeared to be at a “considerably higher” risk of agranulocytosis, Dr. Dubitsky noted. On the basis of this finding, the label says that the benefits of continuing clozapine in such patients should be carefully balanced against this risk when deciding whether to continue treatment with the drug, he said. This information was not on the label previously. On the label, agranulocytosis is defined as an ANC below 500/mm

Other changes to the label include the frequency of monitoring recommended for patients who interrupt a course of clozapine treatment, and ANC criteria for various stages of leukopenia, Dr. Dubitsky said.

Further explanations of the revised monitoring schedule and other changes are included on the new label, which was posted on the FDA's MedWatch Web site last month.

Novartis, manufacturer of Clozaril, the trade formulation, is planning to send out a “Dear Health Care Provider” letter explaining the changes in the monitoring schedule as well as several other unrelated changes on the label. The letter is currently being reviewed by the FDA, according to Novartis. There are now several generic formulations of clozapine, which will also be required to make the same changes to their product labels.

The approval of clozapine in 1989 for the management of treatment-resistant schizophrenia was tied to the “no blood, no drug” requirement that the drug be made available through a special distribution system that required weekly WBC counts before the next week's supply of clozapine was provided to the patient.

All the WBC data have been entered into the Clozaril National Registry and have been used to make decisions on monitoring frequency.

At recent FDA advisory panel meetings on safety issues associated with various drugs, such as Vioxx and the other COX-2 inhibitors and the acne drug isotretinoin, the clozapine “no blood, no drug” policy was raised as an example of a risk management program that makes it possible to keep a drug on the market for patients who can benefit from it, while successfully managing the drug's potential serious risks.

The monitoring schedule has been changed once before: In 1998, the schedule was changed to allow a reduction in testing WBC counts to every 2 weeks after 6 months, in patients whose WBC counts were maintained at acceptable levels during the first 6 months of weekly testing.

The revised Clozaril label is available on the FDA's Web site at: www.fda.gov/medwatch/SAFETY/2005/may05.htm#Clozaril

Reports of comas and other serious injuries in people with implanted neurologic stimulators incurred during MRI procedures have spurred the Food and Drug Administration to issue a reminder about these risks.

The agency has received “several” reports of coma, permanent neurologic impairment, and other serious injuries in patients who had deep brain stimulators and vagus nerve stimulators in place when they underwent MRI. “Similar injuries could be caused by any type of implanted neurologic stimulator,” such as spinal cord, peripheral nerve, and neuromuscular stimulators, according to the warning, issued by the FDA's Center for Devices and Radiological Health.

These injuries probably result when the electrodes at the end of the lead wires heat up, injuring the surrounding tissue, the statement said.

The FDA is recommending that physicians who implant or monitor neurologic stimulators explain to patients about MRI procedures, and stress that they must ask their monitoring physician, before having any MRI, whether it can be performed safely.

The notification includes a list of recommendations for radiologists and health care professionals who use MRI equipment. They include consulting with the referring physician and either reviewing the label or contacting the manufacturer of the specific model of implanted neurologic stimulator to learn the types and/or strengths of MRI equipment tested for the interaction with the device.

The notification also advises that patients be carefully screened for implanted devices before MRI procedures are performed, even if the device has been turned off, and should be asked about devices that have been removed, since some leads or portions of leads can remain in the body after removal and “may act as an antenna and become heated” during the MRI exam.

Reports of comas and other serious injuries in people with implanted neurologic stimulators incurred during MRI procedures have spurred the Food and Drug Administration to issue a reminder about these risks.

The agency has received “several” reports of coma, permanent neurologic impairment, and other serious injuries in patients who had deep brain stimulators and vagus nerve stimulators in place when they underwent MRI. “Similar injuries could be caused by any type of implanted neurologic stimulator,” such as spinal cord, peripheral nerve, and neuromuscular stimulators, according to the warning, issued by the FDA's Center for Devices and Radiological Health.

These injuries probably result when the electrodes at the end of the lead wires heat up, injuring the surrounding tissue, the statement said.

The FDA is recommending that physicians who implant or monitor neurologic stimulators explain to patients about MRI procedures, and stress that they must ask their monitoring physician, before having any MRI, whether it can be performed safely.

The notification includes a list of recommendations for radiologists and health care professionals who use MRI equipment. They include consulting with the referring physician and either reviewing the label or contacting the manufacturer of the specific model of implanted neurologic stimulator to learn the types and/or strengths of MRI equipment tested for the interaction with the device.

The notification also advises that patients be carefully screened for implanted devices before MRI procedures are performed, even if the device has been turned off, and should be asked about devices that have been removed, since some leads or portions of leads can remain in the body after removal and “may act as an antenna and become heated” during the MRI exam.

Reports of comas and other serious injuries in people with implanted neurologic stimulators incurred during MRI procedures have spurred the Food and Drug Administration to issue a reminder about these risks.

The agency has received “several” reports of coma, permanent neurologic impairment, and other serious injuries in patients who had deep brain stimulators and vagus nerve stimulators in place when they underwent MRI. “Similar injuries could be caused by any type of implanted neurologic stimulator,” such as spinal cord, peripheral nerve, and neuromuscular stimulators, according to the warning, issued by the FDA's Center for Devices and Radiological Health.

These injuries probably result when the electrodes at the end of the lead wires heat up, injuring the surrounding tissue, the statement said.

The FDA is recommending that physicians who implant or monitor neurologic stimulators explain to patients about MRI procedures, and stress that they must ask their monitoring physician, before having any MRI, whether it can be performed safely.

The notification includes a list of recommendations for radiologists and health care professionals who use MRI equipment. They include consulting with the referring physician and either reviewing the label or contacting the manufacturer of the specific model of implanted neurologic stimulator to learn the types and/or strengths of MRI equipment tested for the interaction with the device.

The notification also advises that patients be carefully screened for implanted devices before MRI procedures are performed, even if the device has been turned off, and should be asked about devices that have been removed, since some leads or portions of leads can remain in the body after removal and “may act as an antenna and become heated” during the MRI exam.

BETHESDA, MD. — An older age, a history of cervical intraepithelial neoplasia, and the presence of multifocal lesions in the upper third of the vagina are among the features associated with vaginal intraepithelial neoplasia, Thomas C. Wright Jr. said at a conference on vulvovaginal diseases.

Vaginal intraepithelial neoplasia (VAIN) is not common, accounting for only 0.4% of intraepithelial lesions of the lower genital tract, according to Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Women at higher risk include those with vulvar intraepithelial neoplasia (VIN), cigarette smokers, and those who have had radiation therapy. A woman who has had radiation therapy for endometrial cancer and presents with an abnormal Pap smear exemplifies one clinical scenario in which the index of suspicion for VAIN should be high, he noted.

Another typical VAIN case is a postmenopausal patient who has been treated for cervical intraepithelial neoplasia (CIN), even 10 years earlier, often with a hysterectomy, and has been considered cured. She then unexpectedly has a high-grade squamous lesion on cytology, with no lesion on the vagina that is visible to the naked eye.

Some of these risk factors were associated with VAIN in a 2001 study of 121 women with biopsy-confirmed VAIN, which found that 41% smoked, 39% had a history of human papilloma virus (HPV), 22% had undergone surgery for CIN, and 23% had undergone a total abdominal hysterectomy. The mean age of the patients was 35 years, and the majority had VAIN-1, a diagnosis Dr. Wright said he is “very leery” about classifying “as true VAIN lesions.”

Most of the patients he sees with VAIN are in their 40s to late 60s. VAIN is rare among women in their 20s and 30s, but when it does occur among younger women, there usually is a history of immunosuppression or CIN, Dr. Wright said.

The sensitivity of cytology in diagnosing VAIN remains uncertain. Most VAIN patients are postmenopausal, raising the question of whether a patient has high-grade VAIN or “severe atrophy, which is causing the cytology to mimic high-grade VAIN,” he said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

On cytology, squamous intraepithelial neoplasia and VAIN “look exactly the same,” he added. And on histopathology, VAIN looks “exactly the same” as CIN, VIN, or anal intraepithelial neoplasia.

He advised caution about the diagnosis of VAIN-1. “A lot of us are trying not to make low-grade diagnoses of VIN or VAIN,” and instead, “classify the majority of these lesions as flat condylomas, because the natural history of these low-grade lesions is not really well characterized.”

It is unclear whether a flat, low-grade-appearing lesion in a 60-year-old has any premalignant potential, he added. Low-grade VAIN has many features of a flat condyloma, compared with VAIN-3, which is more clearly a high-grade lesion.

As for the location of VAIN lesions, most are found in the upper third of the vagina, usually contiguous with CIN, if a cervix is present. Most cases are multifocal, often with lesions found in the “dog-ears of the vault after hysterectomy,” which makes colposcopy very difficult. Colposcopy is required to diagnose VAIN, but is difficult, especially in postmenopausal women who have had a hysterectomy, because it is necessary to look inside the folds and “dog-ears,” he said.

VIN may be present as well, so the vulva needs to be examined, he said, adding that “a fair number of patients” will have VIN, CIN, and VAIN at the same time.

On colposcopy, VAIN “frequently appears as slightly raised, acetowhite lesions,” which can be subtle, especially in postmenopausal patients with low estrogen levels, he said.

In the vagina, with high-grade lesions, vascular patterns such as mosaicism in the vagina usually are not present as they are with cervical lesions. These lesions usually are not acetowhite and are identified only after the application of Lugol's solution.

On colposcopy, conditions that can mimic VAIN are congenital transformation zones that extend into the vagina and leukoplakia, which can appear on the vagina, not just the cervix, he said.

Vaginal ulcers or trauma and granulation tissue also can look like VAIN lesions on colposcopy. Inflammation caused by trichomonas, candida, atrophic vaginitis, or radiation atrophy can obscure VAIN lesions, he added.

Treatments for VAIN include excisional biopsy in the office, intravaginal 5-fluorouracil, laser ablation or electrofulguration, and partial vaginectomy. Cryosurgery is not used very much now, he added. VAIN-1 usually is not treated aggressively, but followed, except in women suspected of having a higher-grade lesion, such as those who have had a hysterectomy for CIN 2 or 3 or cancer, or a conization for CIN 2 or 3, Dr. Wright said.

BETHESDA, MD. — An older age, a history of cervical intraepithelial neoplasia, and the presence of multifocal lesions in the upper third of the vagina are among the features associated with vaginal intraepithelial neoplasia, Thomas C. Wright Jr. said at a conference on vulvovaginal diseases.

Vaginal intraepithelial neoplasia (VAIN) is not common, accounting for only 0.4% of intraepithelial lesions of the lower genital tract, according to Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Women at higher risk include those with vulvar intraepithelial neoplasia (VIN), cigarette smokers, and those who have had radiation therapy. A woman who has had radiation therapy for endometrial cancer and presents with an abnormal Pap smear exemplifies one clinical scenario in which the index of suspicion for VAIN should be high, he noted.

Another typical VAIN case is a postmenopausal patient who has been treated for cervical intraepithelial neoplasia (CIN), even 10 years earlier, often with a hysterectomy, and has been considered cured. She then unexpectedly has a high-grade squamous lesion on cytology, with no lesion on the vagina that is visible to the naked eye.

Some of these risk factors were associated with VAIN in a 2001 study of 121 women with biopsy-confirmed VAIN, which found that 41% smoked, 39% had a history of human papilloma virus (HPV), 22% had undergone surgery for CIN, and 23% had undergone a total abdominal hysterectomy. The mean age of the patients was 35 years, and the majority had VAIN-1, a diagnosis Dr. Wright said he is “very leery” about classifying “as true VAIN lesions.”

Most of the patients he sees with VAIN are in their 40s to late 60s. VAIN is rare among women in their 20s and 30s, but when it does occur among younger women, there usually is a history of immunosuppression or CIN, Dr. Wright said.

The sensitivity of cytology in diagnosing VAIN remains uncertain. Most VAIN patients are postmenopausal, raising the question of whether a patient has high-grade VAIN or “severe atrophy, which is causing the cytology to mimic high-grade VAIN,” he said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

On cytology, squamous intraepithelial neoplasia and VAIN “look exactly the same,” he added. And on histopathology, VAIN looks “exactly the same” as CIN, VIN, or anal intraepithelial neoplasia.

He advised caution about the diagnosis of VAIN-1. “A lot of us are trying not to make low-grade diagnoses of VIN or VAIN,” and instead, “classify the majority of these lesions as flat condylomas, because the natural history of these low-grade lesions is not really well characterized.”

It is unclear whether a flat, low-grade-appearing lesion in a 60-year-old has any premalignant potential, he added. Low-grade VAIN has many features of a flat condyloma, compared with VAIN-3, which is more clearly a high-grade lesion.

As for the location of VAIN lesions, most are found in the upper third of the vagina, usually contiguous with CIN, if a cervix is present. Most cases are multifocal, often with lesions found in the “dog-ears of the vault after hysterectomy,” which makes colposcopy very difficult. Colposcopy is required to diagnose VAIN, but is difficult, especially in postmenopausal women who have had a hysterectomy, because it is necessary to look inside the folds and “dog-ears,” he said.

VIN may be present as well, so the vulva needs to be examined, he said, adding that “a fair number of patients” will have VIN, CIN, and VAIN at the same time.

On colposcopy, VAIN “frequently appears as slightly raised, acetowhite lesions,” which can be subtle, especially in postmenopausal patients with low estrogen levels, he said.

In the vagina, with high-grade lesions, vascular patterns such as mosaicism in the vagina usually are not present as they are with cervical lesions. These lesions usually are not acetowhite and are identified only after the application of Lugol's solution.

On colposcopy, conditions that can mimic VAIN are congenital transformation zones that extend into the vagina and leukoplakia, which can appear on the vagina, not just the cervix, he said.

Vaginal ulcers or trauma and granulation tissue also can look like VAIN lesions on colposcopy. Inflammation caused by trichomonas, candida, atrophic vaginitis, or radiation atrophy can obscure VAIN lesions, he added.

Treatments for VAIN include excisional biopsy in the office, intravaginal 5-fluorouracil, laser ablation or electrofulguration, and partial vaginectomy. Cryosurgery is not used very much now, he added. VAIN-1 usually is not treated aggressively, but followed, except in women suspected of having a higher-grade lesion, such as those who have had a hysterectomy for CIN 2 or 3 or cancer, or a conization for CIN 2 or 3, Dr. Wright said.

BETHESDA, MD. — An older age, a history of cervical intraepithelial neoplasia, and the presence of multifocal lesions in the upper third of the vagina are among the features associated with vaginal intraepithelial neoplasia, Thomas C. Wright Jr. said at a conference on vulvovaginal diseases.

Vaginal intraepithelial neoplasia (VAIN) is not common, accounting for only 0.4% of intraepithelial lesions of the lower genital tract, according to Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Women at higher risk include those with vulvar intraepithelial neoplasia (VIN), cigarette smokers, and those who have had radiation therapy. A woman who has had radiation therapy for endometrial cancer and presents with an abnormal Pap smear exemplifies one clinical scenario in which the index of suspicion for VAIN should be high, he noted.

Another typical VAIN case is a postmenopausal patient who has been treated for cervical intraepithelial neoplasia (CIN), even 10 years earlier, often with a hysterectomy, and has been considered cured. She then unexpectedly has a high-grade squamous lesion on cytology, with no lesion on the vagina that is visible to the naked eye.

Some of these risk factors were associated with VAIN in a 2001 study of 121 women with biopsy-confirmed VAIN, which found that 41% smoked, 39% had a history of human papilloma virus (HPV), 22% had undergone surgery for CIN, and 23% had undergone a total abdominal hysterectomy. The mean age of the patients was 35 years, and the majority had VAIN-1, a diagnosis Dr. Wright said he is “very leery” about classifying “as true VAIN lesions.”

Most of the patients he sees with VAIN are in their 40s to late 60s. VAIN is rare among women in their 20s and 30s, but when it does occur among younger women, there usually is a history of immunosuppression or CIN, Dr. Wright said.

The sensitivity of cytology in diagnosing VAIN remains uncertain. Most VAIN patients are postmenopausal, raising the question of whether a patient has high-grade VAIN or “severe atrophy, which is causing the cytology to mimic high-grade VAIN,” he said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

On cytology, squamous intraepithelial neoplasia and VAIN “look exactly the same,” he added. And on histopathology, VAIN looks “exactly the same” as CIN, VIN, or anal intraepithelial neoplasia.

He advised caution about the diagnosis of VAIN-1. “A lot of us are trying not to make low-grade diagnoses of VIN or VAIN,” and instead, “classify the majority of these lesions as flat condylomas, because the natural history of these low-grade lesions is not really well characterized.”

It is unclear whether a flat, low-grade-appearing lesion in a 60-year-old has any premalignant potential, he added. Low-grade VAIN has many features of a flat condyloma, compared with VAIN-3, which is more clearly a high-grade lesion.

As for the location of VAIN lesions, most are found in the upper third of the vagina, usually contiguous with CIN, if a cervix is present. Most cases are multifocal, often with lesions found in the “dog-ears of the vault after hysterectomy,” which makes colposcopy very difficult. Colposcopy is required to diagnose VAIN, but is difficult, especially in postmenopausal women who have had a hysterectomy, because it is necessary to look inside the folds and “dog-ears,” he said.

VIN may be present as well, so the vulva needs to be examined, he said, adding that “a fair number of patients” will have VIN, CIN, and VAIN at the same time.

On colposcopy, VAIN “frequently appears as slightly raised, acetowhite lesions,” which can be subtle, especially in postmenopausal patients with low estrogen levels, he said.

In the vagina, with high-grade lesions, vascular patterns such as mosaicism in the vagina usually are not present as they are with cervical lesions. These lesions usually are not acetowhite and are identified only after the application of Lugol's solution.

On colposcopy, conditions that can mimic VAIN are congenital transformation zones that extend into the vagina and leukoplakia, which can appear on the vagina, not just the cervix, he said.

Vaginal ulcers or trauma and granulation tissue also can look like VAIN lesions on colposcopy. Inflammation caused by trichomonas, candida, atrophic vaginitis, or radiation atrophy can obscure VAIN lesions, he added.

Treatments for VAIN include excisional biopsy in the office, intravaginal 5-fluorouracil, laser ablation or electrofulguration, and partial vaginectomy. Cryosurgery is not used very much now, he added. VAIN-1 usually is not treated aggressively, but followed, except in women suspected of having a higher-grade lesion, such as those who have had a hysterectomy for CIN 2 or 3 or cancer, or a conization for CIN 2 or 3, Dr. Wright said.

BETHESDA, MD. — Most experts now believe that desquamative inflammatory vaginitis is not a diagnosis of one condition, but may represent a range of blistering disorders, such as lichen planus, mucous membrane pemphigoid, and pemphigus vulgaris, Hope K. Haefner, M.D., said at a conference on vulvovaginal diseases.

With descriptions in the medical literature dating to the 1950s, the signs and symptoms of desquamative inflammatory vaginitis (DIV) include dyspareunia and exudative, chronic vaginitis, with yellow-watery, purulent discharge that is occasionally blood-tinged, said Dr. Haefner, director of the University of Michigan Center for Vulvar Diseases, Ann Arbor.

Patients with DIV also may have a spotted rash on the vagina and cervix, massive vaginal cell exfoliation, and an increased vaginal pH, she said.

Previous terms used to describe this condition include exudative or membranous vaginitis, and hydrorrhea vaginalis.

DIV can occur at any age, and although it has been considered rare, it is being seen more frequently than in the past.

“Although we don't know what it is … we don't think it is an infectious process,” Dr. Haefner said, noting that in studies describing DIV in the 1950s and 1960s infectious organisms were detected in association with DIV but have since been ruled out as a cause.

Other forms of vulvovaginitis caused by trichomonas and other infections can be confused with DIV, as can noninfectious causes of erosive vulvovaginitis, such as lichen planus and graft-versus-host disease, she said. Other noninfectious causes of erosive vulvovaginitis include collagen vascular diseases and a local toxic effect of a drug. The cause also may be idiopathic.

Distinguishing DIV from atrophy can be difficult, since lab findings are similar to those found with atrophic vaginitis, with a nonspecific histology and parabasal cells and many polymorphonuclear leukocytes (PMNs) on cytology. Atrophic vaginitis has serosanguineous or watery discharge similar to that seen with DIV, as well as an elevated vaginal pH, with a thin vagina and red petechiae, Dr. Haefner said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Atrophic vaginitis and erosive lichen planus are among the noninfectious conditions that are high on Dr. Haefner's list of differential diagnoses in a patient she suspects may have DIV. Lower on the list are other noninfectious causes of these symptoms, including lichen sclerosus, lupus erythematosus, cicatricial pemphigoid, Stevens-Johnson syndrome, graft-versus-host disease, pemphigus of the mouth and skin, and a local drug reaction such as contact dermatitis.

Like other experts in this area, Dr. Haefner believes that DIV can be an expression of erosive lichen planus, which can have the same wet smear, pH, cytology, and biopsy results. However, not all DIV is lichen planus, she pointed out.

Vulvovaginal symptoms of erosive lichen planus include burning; pruritus; dyspareunia that can be mild to severe, preventing coitus at times; bleeding spontaneously after coitus; and vaginal discharge, she said, noting that erosions are very painful. The difference with lichen planus is that it often is associated with erosive changes in the mouth, with a white reticulated border, adhesions, and atrophy, probably related to T-cell autoimmunity.

“When you see patients with DIV, think about looking in the mouth,” she advised.

In lichen planus, erosions may be found in the conjunctivae, external ear canal, esophagus, and anus.

In some cases, histology can help in diagnosing lichen planus, but in Dr. Haefner's experience, this has not been very helpful because lab and cytologic changes are nonspecific and may be similar to those found with atrophic vaginitis.

In diagnosing patients with DIV, she recommended considering what is happening with the whole patient, and whether the condition is acute or chronic and focal or diffuse. Also consider whether it involves the vestibule and/or the vagina and whether the patient has a local estradiol deficiency, oral mucosal or ocular disease, or any iatrogenic topical etiology.

As for the use of dilators, Dr. Haefner said that for patients with chronic lichen planus, prophylactic dilation is important, because those patients often present with “shut” vaginas. However, prophylactic dilation is not necessary and would be considered overtreatment if used for all patients with DIV.

To distinguish whether a patient has DIV or lichen planus, consider performing a biopsy and immunofluorescent studies to rule in or out some of the conditions in the differential diagnosis.

Because DIV is not a single disease, no one treatment will be effective in all cases. Treatment with 2% clindamycin cream for 2 weeks is a first-line therapy for most patients. Although DIV is not considered an infection, clindamycin is still useful because it has an anti-inflammatory effect.

Those who need a second course of treatment may respond to treatment with hydrocortisone at a dose of 100 mg/g in a clindamycin 2% emollient cream base. A 5-g applicator should be inserted every other day for a total of 14 doses. This treatment regimen is expensive, however, and is not recommended for a first episode, said Dr. Haefner, who stated that she has no relevant financial relationships with any commercial interest relative to the subject of this presentation.

BETHESDA, MD. — Most experts now believe that desquamative inflammatory vaginitis is not a diagnosis of one condition, but may represent a range of blistering disorders, such as lichen planus, mucous membrane pemphigoid, and pemphigus vulgaris, Hope K. Haefner, M.D., said at a conference on vulvovaginal diseases.

With descriptions in the medical literature dating to the 1950s, the signs and symptoms of desquamative inflammatory vaginitis (DIV) include dyspareunia and exudative, chronic vaginitis, with yellow-watery, purulent discharge that is occasionally blood-tinged, said Dr. Haefner, director of the University of Michigan Center for Vulvar Diseases, Ann Arbor.

Patients with DIV also may have a spotted rash on the vagina and cervix, massive vaginal cell exfoliation, and an increased vaginal pH, she said.

Previous terms used to describe this condition include exudative or membranous vaginitis, and hydrorrhea vaginalis.

DIV can occur at any age, and although it has been considered rare, it is being seen more frequently than in the past.

“Although we don't know what it is … we don't think it is an infectious process,” Dr. Haefner said, noting that in studies describing DIV in the 1950s and 1960s infectious organisms were detected in association with DIV but have since been ruled out as a cause.

Other forms of vulvovaginitis caused by trichomonas and other infections can be confused with DIV, as can noninfectious causes of erosive vulvovaginitis, such as lichen planus and graft-versus-host disease, she said. Other noninfectious causes of erosive vulvovaginitis include collagen vascular diseases and a local toxic effect of a drug. The cause also may be idiopathic.

Distinguishing DIV from atrophy can be difficult, since lab findings are similar to those found with atrophic vaginitis, with a nonspecific histology and parabasal cells and many polymorphonuclear leukocytes (PMNs) on cytology. Atrophic vaginitis has serosanguineous or watery discharge similar to that seen with DIV, as well as an elevated vaginal pH, with a thin vagina and red petechiae, Dr. Haefner said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Atrophic vaginitis and erosive lichen planus are among the noninfectious conditions that are high on Dr. Haefner's list of differential diagnoses in a patient she suspects may have DIV. Lower on the list are other noninfectious causes of these symptoms, including lichen sclerosus, lupus erythematosus, cicatricial pemphigoid, Stevens-Johnson syndrome, graft-versus-host disease, pemphigus of the mouth and skin, and a local drug reaction such as contact dermatitis.

Like other experts in this area, Dr. Haefner believes that DIV can be an expression of erosive lichen planus, which can have the same wet smear, pH, cytology, and biopsy results. However, not all DIV is lichen planus, she pointed out.

Vulvovaginal symptoms of erosive lichen planus include burning; pruritus; dyspareunia that can be mild to severe, preventing coitus at times; bleeding spontaneously after coitus; and vaginal discharge, she said, noting that erosions are very painful. The difference with lichen planus is that it often is associated with erosive changes in the mouth, with a white reticulated border, adhesions, and atrophy, probably related to T-cell autoimmunity.

“When you see patients with DIV, think about looking in the mouth,” she advised.

In lichen planus, erosions may be found in the conjunctivae, external ear canal, esophagus, and anus.

In some cases, histology can help in diagnosing lichen planus, but in Dr. Haefner's experience, this has not been very helpful because lab and cytologic changes are nonspecific and may be similar to those found with atrophic vaginitis.

In diagnosing patients with DIV, she recommended considering what is happening with the whole patient, and whether the condition is acute or chronic and focal or diffuse. Also consider whether it involves the vestibule and/or the vagina and whether the patient has a local estradiol deficiency, oral mucosal or ocular disease, or any iatrogenic topical etiology.

As for the use of dilators, Dr. Haefner said that for patients with chronic lichen planus, prophylactic dilation is important, because those patients often present with “shut” vaginas. However, prophylactic dilation is not necessary and would be considered overtreatment if used for all patients with DIV.

To distinguish whether a patient has DIV or lichen planus, consider performing a biopsy and immunofluorescent studies to rule in or out some of the conditions in the differential diagnosis.

Because DIV is not a single disease, no one treatment will be effective in all cases. Treatment with 2% clindamycin cream for 2 weeks is a first-line therapy for most patients. Although DIV is not considered an infection, clindamycin is still useful because it has an anti-inflammatory effect.

Those who need a second course of treatment may respond to treatment with hydrocortisone at a dose of 100 mg/g in a clindamycin 2% emollient cream base. A 5-g applicator should be inserted every other day for a total of 14 doses. This treatment regimen is expensive, however, and is not recommended for a first episode, said Dr. Haefner, who stated that she has no relevant financial relationships with any commercial interest relative to the subject of this presentation.

BETHESDA, MD. — Most experts now believe that desquamative inflammatory vaginitis is not a diagnosis of one condition, but may represent a range of blistering disorders, such as lichen planus, mucous membrane pemphigoid, and pemphigus vulgaris, Hope K. Haefner, M.D., said at a conference on vulvovaginal diseases.

With descriptions in the medical literature dating to the 1950s, the signs and symptoms of desquamative inflammatory vaginitis (DIV) include dyspareunia and exudative, chronic vaginitis, with yellow-watery, purulent discharge that is occasionally blood-tinged, said Dr. Haefner, director of the University of Michigan Center for Vulvar Diseases, Ann Arbor.

Patients with DIV also may have a spotted rash on the vagina and cervix, massive vaginal cell exfoliation, and an increased vaginal pH, she said.

Previous terms used to describe this condition include exudative or membranous vaginitis, and hydrorrhea vaginalis.

DIV can occur at any age, and although it has been considered rare, it is being seen more frequently than in the past.

“Although we don't know what it is … we don't think it is an infectious process,” Dr. Haefner said, noting that in studies describing DIV in the 1950s and 1960s infectious organisms were detected in association with DIV but have since been ruled out as a cause.

Other forms of vulvovaginitis caused by trichomonas and other infections can be confused with DIV, as can noninfectious causes of erosive vulvovaginitis, such as lichen planus and graft-versus-host disease, she said. Other noninfectious causes of erosive vulvovaginitis include collagen vascular diseases and a local toxic effect of a drug. The cause also may be idiopathic.

Distinguishing DIV from atrophy can be difficult, since lab findings are similar to those found with atrophic vaginitis, with a nonspecific histology and parabasal cells and many polymorphonuclear leukocytes (PMNs) on cytology. Atrophic vaginitis has serosanguineous or watery discharge similar to that seen with DIV, as well as an elevated vaginal pH, with a thin vagina and red petechiae, Dr. Haefner said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Atrophic vaginitis and erosive lichen planus are among the noninfectious conditions that are high on Dr. Haefner's list of differential diagnoses in a patient she suspects may have DIV. Lower on the list are other noninfectious causes of these symptoms, including lichen sclerosus, lupus erythematosus, cicatricial pemphigoid, Stevens-Johnson syndrome, graft-versus-host disease, pemphigus of the mouth and skin, and a local drug reaction such as contact dermatitis.

Like other experts in this area, Dr. Haefner believes that DIV can be an expression of erosive lichen planus, which can have the same wet smear, pH, cytology, and biopsy results. However, not all DIV is lichen planus, she pointed out.

Vulvovaginal symptoms of erosive lichen planus include burning; pruritus; dyspareunia that can be mild to severe, preventing coitus at times; bleeding spontaneously after coitus; and vaginal discharge, she said, noting that erosions are very painful. The difference with lichen planus is that it often is associated with erosive changes in the mouth, with a white reticulated border, adhesions, and atrophy, probably related to T-cell autoimmunity.

“When you see patients with DIV, think about looking in the mouth,” she advised.

In lichen planus, erosions may be found in the conjunctivae, external ear canal, esophagus, and anus.

In some cases, histology can help in diagnosing lichen planus, but in Dr. Haefner's experience, this has not been very helpful because lab and cytologic changes are nonspecific and may be similar to those found with atrophic vaginitis.

In diagnosing patients with DIV, she recommended considering what is happening with the whole patient, and whether the condition is acute or chronic and focal or diffuse. Also consider whether it involves the vestibule and/or the vagina and whether the patient has a local estradiol deficiency, oral mucosal or ocular disease, or any iatrogenic topical etiology.

As for the use of dilators, Dr. Haefner said that for patients with chronic lichen planus, prophylactic dilation is important, because those patients often present with “shut” vaginas. However, prophylactic dilation is not necessary and would be considered overtreatment if used for all patients with DIV.

To distinguish whether a patient has DIV or lichen planus, consider performing a biopsy and immunofluorescent studies to rule in or out some of the conditions in the differential diagnosis.

Because DIV is not a single disease, no one treatment will be effective in all cases. Treatment with 2% clindamycin cream for 2 weeks is a first-line therapy for most patients. Although DIV is not considered an infection, clindamycin is still useful because it has an anti-inflammatory effect.

Those who need a second course of treatment may respond to treatment with hydrocortisone at a dose of 100 mg/g in a clindamycin 2% emollient cream base. A 5-g applicator should be inserted every other day for a total of 14 doses. This treatment regimen is expensive, however, and is not recommended for a first episode, said Dr. Haefner, who stated that she has no relevant financial relationships with any commercial interest relative to the subject of this presentation.

ROCKVILLE, MD. – At a meeting last month, members of the Food and Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee agreed that the risk of tardive dyskinesia associated with the metoclopramide component of a fixed-dose combination pill outweighed the product's benefits for treating migraines.

All 12 panel members found that there was not enough evidence to assume that the intermittent chronic use of the product, which combines metoclopramide with naproxen, did not cause tardive dyskinesia (TD) and that it was not possible to determine a maximum number of monthly doses that could be recommended to avoid the risk of TD.

TD is a well-known side effect of metoclopramide, a neuroleptic dopamine receptor antagonist, although the incidence is unclear, said Eric Bastings, M.D., clinical team leader in the FDA's division of neurology products, Rockville. Although no cases were reported in trials of the fixed-dose combination of 16 mg of metoclopramide with 500 mg of naproxen, called MT 100, the database was too small to detect rare events, he told the panel.

In May 2004, the FDA sent the company a “not approvable” letter, stating that the company had not established that MT 100 was effective for acute treatment of migraine or that the metoclopramide component contributed to the effectiveness, and that there was no evidence to support the company's argument that intermittent long-term use for migraines would not be associated with TD.

The advisory panel meeting was held to discuss the TD risk associated with the addition of metoclopramide, which is approved in the United States for short-term treatment of gastroesophageal reflux disease and diabetic gastroparesis. The label warns about the risk of TD, which increases with the duration of treatment but may occur after relatively brief periods of treatment at low doses.

The day after the meeting, Pozen Inc., a Chapel Hill, N.C.-based pharmaceutical company, announced in a statement that it would no longer pursue approval of the combination product in the United States, “based on a thoughtful review of the outcome” of the meeting. Contributing to the decision was the company's plan to file an application for approval of another product to treat acute migraines, a combination formulation of sumatriptan and naproxen.

Several days later, the company announced that it had submitted the new drug application to the FDA for the sumatriptan-naproxen combination.

In two phase III trials of over 2,000 patients with moderate or severe migraine, the sustained pain response at 24 hours associated with one dose of MT 100 was 4% and 6% above the level achieved with naproxen alone (36% and 32% among MT 100 users vs. 30% and 28% on naproxen alone), which the FDA said was not significant. There were no significant differences in the 2-hour pain response.

Although there were no TD cases reported in trials, the company estimated that the annual incidence of TD at a daily metoclopramide dose of 30 mg-40 mg for 72 days a year would be up to 0.038%. All but 1 of the 12 panelists agreed this was not a reasonable estimate; most said that the incidence was simply unknown and several others said they believed the risk was higher.

Metoclopramide enhances the absorption of naproxen and counteracts gastric stasis associated with migraines, with antinausea and antiemetic effects, according to Pozen.

ROCKVILLE, MD. – At a meeting last month, members of the Food and Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee agreed that the risk of tardive dyskinesia associated with the metoclopramide component of a fixed-dose combination pill outweighed the product's benefits for treating migraines.

All 12 panel members found that there was not enough evidence to assume that the intermittent chronic use of the product, which combines metoclopramide with naproxen, did not cause tardive dyskinesia (TD) and that it was not possible to determine a maximum number of monthly doses that could be recommended to avoid the risk of TD.

TD is a well-known side effect of metoclopramide, a neuroleptic dopamine receptor antagonist, although the incidence is unclear, said Eric Bastings, M.D., clinical team leader in the FDA's division of neurology products, Rockville. Although no cases were reported in trials of the fixed-dose combination of 16 mg of metoclopramide with 500 mg of naproxen, called MT 100, the database was too small to detect rare events, he told the panel.

In May 2004, the FDA sent the company a “not approvable” letter, stating that the company had not established that MT 100 was effective for acute treatment of migraine or that the metoclopramide component contributed to the effectiveness, and that there was no evidence to support the company's argument that intermittent long-term use for migraines would not be associated with TD.

The advisory panel meeting was held to discuss the TD risk associated with the addition of metoclopramide, which is approved in the United States for short-term treatment of gastroesophageal reflux disease and diabetic gastroparesis. The label warns about the risk of TD, which increases with the duration of treatment but may occur after relatively brief periods of treatment at low doses.

The day after the meeting, Pozen Inc., a Chapel Hill, N.C.-based pharmaceutical company, announced in a statement that it would no longer pursue approval of the combination product in the United States, “based on a thoughtful review of the outcome” of the meeting. Contributing to the decision was the company's plan to file an application for approval of another product to treat acute migraines, a combination formulation of sumatriptan and naproxen.

Several days later, the company announced that it had submitted the new drug application to the FDA for the sumatriptan-naproxen combination.

In two phase III trials of over 2,000 patients with moderate or severe migraine, the sustained pain response at 24 hours associated with one dose of MT 100 was 4% and 6% above the level achieved with naproxen alone (36% and 32% among MT 100 users vs. 30% and 28% on naproxen alone), which the FDA said was not significant. There were no significant differences in the 2-hour pain response.

Although there were no TD cases reported in trials, the company estimated that the annual incidence of TD at a daily metoclopramide dose of 30 mg-40 mg for 72 days a year would be up to 0.038%. All but 1 of the 12 panelists agreed this was not a reasonable estimate; most said that the incidence was simply unknown and several others said they believed the risk was higher.

Metoclopramide enhances the absorption of naproxen and counteracts gastric stasis associated with migraines, with antinausea and antiemetic effects, according to Pozen.

ROCKVILLE, MD. – At a meeting last month, members of the Food and Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee agreed that the risk of tardive dyskinesia associated with the metoclopramide component of a fixed-dose combination pill outweighed the product's benefits for treating migraines.

All 12 panel members found that there was not enough evidence to assume that the intermittent chronic use of the product, which combines metoclopramide with naproxen, did not cause tardive dyskinesia (TD) and that it was not possible to determine a maximum number of monthly doses that could be recommended to avoid the risk of TD.

TD is a well-known side effect of metoclopramide, a neuroleptic dopamine receptor antagonist, although the incidence is unclear, said Eric Bastings, M.D., clinical team leader in the FDA's division of neurology products, Rockville. Although no cases were reported in trials of the fixed-dose combination of 16 mg of metoclopramide with 500 mg of naproxen, called MT 100, the database was too small to detect rare events, he told the panel.

In May 2004, the FDA sent the company a “not approvable” letter, stating that the company had not established that MT 100 was effective for acute treatment of migraine or that the metoclopramide component contributed to the effectiveness, and that there was no evidence to support the company's argument that intermittent long-term use for migraines would not be associated with TD.

The advisory panel meeting was held to discuss the TD risk associated with the addition of metoclopramide, which is approved in the United States for short-term treatment of gastroesophageal reflux disease and diabetic gastroparesis. The label warns about the risk of TD, which increases with the duration of treatment but may occur after relatively brief periods of treatment at low doses.

The day after the meeting, Pozen Inc., a Chapel Hill, N.C.-based pharmaceutical company, announced in a statement that it would no longer pursue approval of the combination product in the United States, “based on a thoughtful review of the outcome” of the meeting. Contributing to the decision was the company's plan to file an application for approval of another product to treat acute migraines, a combination formulation of sumatriptan and naproxen.

Several days later, the company announced that it had submitted the new drug application to the FDA for the sumatriptan-naproxen combination.

In two phase III trials of over 2,000 patients with moderate or severe migraine, the sustained pain response at 24 hours associated with one dose of MT 100 was 4% and 6% above the level achieved with naproxen alone (36% and 32% among MT 100 users vs. 30% and 28% on naproxen alone), which the FDA said was not significant. There were no significant differences in the 2-hour pain response.

Although there were no TD cases reported in trials, the company estimated that the annual incidence of TD at a daily metoclopramide dose of 30 mg-40 mg for 72 days a year would be up to 0.038%. All but 1 of the 12 panelists agreed this was not a reasonable estimate; most said that the incidence was simply unknown and several others said they believed the risk was higher.

Metoclopramide enhances the absorption of naproxen and counteracts gastric stasis associated with migraines, with antinausea and antiemetic effects, according to Pozen.

The Food and Drug Administration has approved an insomnia drug with a unique mechanism of action and several features unique among hypnotics approved for insomnia: It is not a controlled substance and does not produce some CNS side effects associated with other hypnotics approved for insomnia, according to one of the drug's investigators.

The drug, ramelteon, a melatonin receptor agonist, was approved in July for treating insomnia characterized by difficulty with sleep onset. Ramelteon binds to melatonin MT₁ and MT₂ receptors, two of the three known melatonin receptors. It is believed to be effective in potentiating sleep, since the receptors “acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle,” according to the drug's label.

Ramelteon, which will be marketed as Rozerem by Takeda Pharmaceuticals Inc., will not be available until late September, the company said in a statement. In two studies of patients with chronic insomnia–one in people aged 18–64 and another in those aged 65 and older–those taking ramelteon fell asleep faster and slept longer than those on placebo. The recommended dosage is 8 mg taken within 30 minutes of going to bed; it should not be taken with or immediately after a high-fat meal.

In an interview with this newspaper, Gary Richardson, M.D., senior research scientist at the Sleep Research Center at Henry Ford Hospital, Detroit, said ramelteon does not produce the CNS sedation, memory impairment, or imbalance that are side effects of the other hypnotic drugs approved for insomnia, the benzodiazepines and the newer nonbenzodiazepines–a particular advantage in elderly patients. Because the action of the drugs is specific to the M₁ and M₂ receptors, which are located only in the suprachiasmatic nuclei (SCN), the activity of the drug is specific.

There are precautions and potential drug interactions to consider, however: Ramelteon should not be used in people with severe hepatic impairment and should be used cautiously in those with moderate hepatic impairment. CYP1A2 is the major isoenzyme involved in metabolizing ramelteon, so it cannot be taken with fluvoxamine, a strong CYP1A2 inhibitor, and should be administered with caution with drugs that are weaker CYP1A2 inhibitors, according to the drug's label. Other drugs on a list of drugs that may have effects on ramelteon metabolism include rifampin, a strong CYP enzyme inducer. Cautious use with strong CYP3A4 inhibitors, such as ketoconazole, and strong CYP2C9 inhibitors, such as fluconazole, are among the other recommendations.

Another consideration is that increases in serum prolactin have been documented in some women and men on ramelteon, with no clinical effects. But the label advises that prolactin and testosterone levels should be considered in patients with unexplained amenorrhea, galactorrhea, reduced libido, or problems with fertility. Dr. Richardson, an investigator in trials and a consultant to Takeda, said that although the increases in prolactin levels in women were self-limited and below what an endocrinologist would consider pathological, this finding should be kept in mind, particularly because some women may have unrecognized mild to moderate hyperprolactinemia at baseline and may be more susceptible to this potential effect.

Melatonin, taken as a supplement, has never been shown to be effective as a hypnotic taken at bedtime to promote sleep. This may be related to a metabolite of melatonin, which increases with increasing doses and prevents it from being effective, he said. Ramelteon is not scheduled as a controlled substance. In a study evaluating its abuse potential in 14 people with a history of sedative/hypnotic abuse or anxiolytic abuse, no differences were found between a placebo and increasing doses of ramelteon.

The Food and Drug Administration has approved an insomnia drug with a unique mechanism of action and several features unique among hypnotics approved for insomnia: It is not a controlled substance and does not produce some CNS side effects associated with other hypnotics approved for insomnia, according to one of the drug's investigators.

The drug, ramelteon, a melatonin receptor agonist, was approved in July for treating insomnia characterized by difficulty with sleep onset. Ramelteon binds to melatonin MT₁ and MT₂ receptors, two of the three known melatonin receptors. It is believed to be effective in potentiating sleep, since the receptors “acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle,” according to the drug's label.

Ramelteon, which will be marketed as Rozerem by Takeda Pharmaceuticals Inc., will not be available until late September, the company said in a statement. In two studies of patients with chronic insomnia–one in people aged 18–64 and another in those aged 65 and older–those taking ramelteon fell asleep faster and slept longer than those on placebo. The recommended dosage is 8 mg taken within 30 minutes of going to bed; it should not be taken with or immediately after a high-fat meal.

In an interview with this newspaper, Gary Richardson, M.D., senior research scientist at the Sleep Research Center at Henry Ford Hospital, Detroit, said ramelteon does not produce the CNS sedation, memory impairment, or imbalance that are side effects of the other hypnotic drugs approved for insomnia, the benzodiazepines and the newer nonbenzodiazepines–a particular advantage in elderly patients. Because the action of the drugs is specific to the M₁ and M₂ receptors, which are located only in the suprachiasmatic nuclei (SCN), the activity of the drug is specific.

There are precautions and potential drug interactions to consider, however: Ramelteon should not be used in people with severe hepatic impairment and should be used cautiously in those with moderate hepatic impairment. CYP1A2 is the major isoenzyme involved in metabolizing ramelteon, so it cannot be taken with fluvoxamine, a strong CYP1A2 inhibitor, and should be administered with caution with drugs that are weaker CYP1A2 inhibitors, according to the drug's label. Other drugs on a list of drugs that may have effects on ramelteon metabolism include rifampin, a strong CYP enzyme inducer. Cautious use with strong CYP3A4 inhibitors, such as ketoconazole, and strong CYP2C9 inhibitors, such as fluconazole, are among the other recommendations.

Another consideration is that increases in serum prolactin have been documented in some women and men on ramelteon, with no clinical effects. But the label advises that prolactin and testosterone levels should be considered in patients with unexplained amenorrhea, galactorrhea, reduced libido, or problems with fertility. Dr. Richardson, an investigator in trials and a consultant to Takeda, said that although the increases in prolactin levels in women were self-limited and below what an endocrinologist would consider pathological, this finding should be kept in mind, particularly because some women may have unrecognized mild to moderate hyperprolactinemia at baseline and may be more susceptible to this potential effect.

Melatonin, taken as a supplement, has never been shown to be effective as a hypnotic taken at bedtime to promote sleep. This may be related to a metabolite of melatonin, which increases with increasing doses and prevents it from being effective, he said. Ramelteon is not scheduled as a controlled substance. In a study evaluating its abuse potential in 14 people with a history of sedative/hypnotic abuse or anxiolytic abuse, no differences were found between a placebo and increasing doses of ramelteon.

The Food and Drug Administration has approved an insomnia drug with a unique mechanism of action and several features unique among hypnotics approved for insomnia: It is not a controlled substance and does not produce some CNS side effects associated with other hypnotics approved for insomnia, according to one of the drug's investigators.

The drug, ramelteon, a melatonin receptor agonist, was approved in July for treating insomnia characterized by difficulty with sleep onset. Ramelteon binds to melatonin MT₁ and MT₂ receptors, two of the three known melatonin receptors. It is believed to be effective in potentiating sleep, since the receptors “acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle,” according to the drug's label.

Ramelteon, which will be marketed as Rozerem by Takeda Pharmaceuticals Inc., will not be available until late September, the company said in a statement. In two studies of patients with chronic insomnia–one in people aged 18–64 and another in those aged 65 and older–those taking ramelteon fell asleep faster and slept longer than those on placebo. The recommended dosage is 8 mg taken within 30 minutes of going to bed; it should not be taken with or immediately after a high-fat meal.

In an interview with this newspaper, Gary Richardson, M.D., senior research scientist at the Sleep Research Center at Henry Ford Hospital, Detroit, said ramelteon does not produce the CNS sedation, memory impairment, or imbalance that are side effects of the other hypnotic drugs approved for insomnia, the benzodiazepines and the newer nonbenzodiazepines–a particular advantage in elderly patients. Because the action of the drugs is specific to the M₁ and M₂ receptors, which are located only in the suprachiasmatic nuclei (SCN), the activity of the drug is specific.

There are precautions and potential drug interactions to consider, however: Ramelteon should not be used in people with severe hepatic impairment and should be used cautiously in those with moderate hepatic impairment. CYP1A2 is the major isoenzyme involved in metabolizing ramelteon, so it cannot be taken with fluvoxamine, a strong CYP1A2 inhibitor, and should be administered with caution with drugs that are weaker CYP1A2 inhibitors, according to the drug's label. Other drugs on a list of drugs that may have effects on ramelteon metabolism include rifampin, a strong CYP enzyme inducer. Cautious use with strong CYP3A4 inhibitors, such as ketoconazole, and strong CYP2C9 inhibitors, such as fluconazole, are among the other recommendations.

Another consideration is that increases in serum prolactin have been documented in some women and men on ramelteon, with no clinical effects. But the label advises that prolactin and testosterone levels should be considered in patients with unexplained amenorrhea, galactorrhea, reduced libido, or problems with fertility. Dr. Richardson, an investigator in trials and a consultant to Takeda, said that although the increases in prolactin levels in women were self-limited and below what an endocrinologist would consider pathological, this finding should be kept in mind, particularly because some women may have unrecognized mild to moderate hyperprolactinemia at baseline and may be more susceptible to this potential effect.

Melatonin, taken as a supplement, has never been shown to be effective as a hypnotic taken at bedtime to promote sleep. This may be related to a metabolite of melatonin, which increases with increasing doses and prevents it from being effective, he said. Ramelteon is not scheduled as a controlled substance. In a study evaluating its abuse potential in 14 people with a history of sedative/hypnotic abuse or anxiolytic abuse, no differences were found between a placebo and increasing doses of ramelteon.

ROCKVILLE, MD. — No new safety concerns were raised by a review of adverse events reported during a recent 1-year period in adolescents taking a combination oral contraceptive, according to Jean Wendy Temeck, M.D., of the Food and Drug Administration's division of pediatric drug development.

The FDA's review of adverse events reported for Ortho Tri-Cyclen and Ortho Tri-Cyclen Lo, which contain norgestimate and ethinyl estradiol, was conducted between December 2003 and January 2005, the year after the FDA granted marketing exclusivity to the drug. Exclusivity is granted to a drug when companies perform pediatric studies of the product in exchange for a 6-month extension on the patent for the drugs.

In this case, the drug manufacturer, Ortho-McNeil Pharmaceutical Inc., which is based in Raritan, N.J., conducted a placebo-controlled study to determine whether the oral contraceptive improved bone density in adolescent girls who had been diagnosed with anorexia nervosa. The study showed no differences from placebo in increases in hip and lumbar-spine bone mineral density following 1 year of treatment.

Dr. Temek reported the findings at a meeting of the FDA's Pediatric Advisory Committee. The Best Pharmaceuticals for Children Act requires that the FDA's Office of Pediatric Therapeutics review postmarketing adverse event reports made to the FDA's MedWatch adverse event reporting system during the year after a drug receives exclusivity. These reports are then referred to the Pediatric Advisory Committee for a review.

The uses of Ortho Tri-Cyclen for female patients at 16 years of age and younger include dysfunctional uterine bleeding and acne, she said. During the postexclusivity period (Dec. 18, 2003, through Jan. 18, 2005) there were 14 unduplicated pediatric adverse event reports associated with Ortho Tri-Cyclen, including 11 serious reports and no deaths.

The 14 reports included 12 cases in adolescent girls and 2 cases involving infants that had been exposed in utero. Adverse events that were reported more than once were headaches and metrorrhagia, events that are listed in the label of Ortho Tri-Cyclen, and convulsions, an adverse event that is not in the label.

There were four hospitalizations, which included the two in utero exposures. The other two hospitalizations were in a 16-year-old patient with benign intracranial hypertension, an increase in cerebrospinal fluid pressure, and a visual field defect; and in a 14-year-old patient who had cerebral thrombosis and headache. These two patients also were using isotretinoin.

A third patient who was also on isotretinoin, as well as prednisone, was reported to have depression, dizziness, and headache, which are unlabeled events for the oral contraceptive; other symptoms included decreased interest, insomnia, and panic attack.

The labels for isotretinoin and prednisone include the possible risk of increased intracranial pressure, depression, insomnia, emotional instability, dizziness, and headache, Dr. Temeck noted.

Of the two infants who were exposed in utero, one was in a breech presentation and born prematurely, and the baby's mother also had taken penicillin, betamethasone, and alprazolam while pregnant. The second exposed infant was reported to have cerebral artery occlusion, convulsion, apnea, and developmental delay.

There were three adolescents who did report visual adverse events, which are not mentioned in the Ortho Tri-Cyclen product label: a 14-year-old patient also on oxcarbazepine who was reported to have papilledema and cluster headache; a 16-year old patient also on doxycycline and tretinoin, who experienced scotoma, blurred vision, headache and influenza-like illness; and a 16-year old patient also on isotretinoin and prednisone, who had a visual-field defect, in addition to benign intracranial hypertension and increased cerebrospinal fluid pressure. (The label for Ortho Tri-Cyclen does contain a warning of retinal thrombosis.)

The other two serious adverse events that were reported were in one 14-year-old who developed hypertension and another 14-year-old who has dysarthria and hypoesthesia—two events that are not included on the label. Convulsions also were reported in a 15-year-old who had a history of intermittent seizures.

Despite the fact that there were reports of some serious adverse events during this period, “no pattern of new safety concerns” was identified, Dr. Temeck said. Based on the presentation, the advisory panel agreed with the FDA that monitoring of adverse events for these oral contraceptives could be switched to regular monitoring.

Health care professionals and consumers can report any drug- or device-related adverse events to MedWatch by calling 800-332-1088, sending a fax to 800-332-0178, writing to MedWatch, Food and Drug Administration, 5600 Fishers Ln., Rockville, MD 20857-9787; or visiting www.fda.gov/medwatch

ROCKVILLE, MD. — No new safety concerns were raised by a review of adverse events reported during a recent 1-year period in adolescents taking a combination oral contraceptive, according to Jean Wendy Temeck, M.D., of the Food and Drug Administration's division of pediatric drug development.

The FDA's review of adverse events reported for Ortho Tri-Cyclen and Ortho Tri-Cyclen Lo, which contain norgestimate and ethinyl estradiol, was conducted between December 2003 and January 2005, the year after the FDA granted marketing exclusivity to the drug. Exclusivity is granted to a drug when companies perform pediatric studies of the product in exchange for a 6-month extension on the patent for the drugs.

In this case, the drug manufacturer, Ortho-McNeil Pharmaceutical Inc., which is based in Raritan, N.J., conducted a placebo-controlled study to determine whether the oral contraceptive improved bone density in adolescent girls who had been diagnosed with anorexia nervosa. The study showed no differences from placebo in increases in hip and lumbar-spine bone mineral density following 1 year of treatment.

Dr. Temek reported the findings at a meeting of the FDA's Pediatric Advisory Committee. The Best Pharmaceuticals for Children Act requires that the FDA's Office of Pediatric Therapeutics review postmarketing adverse event reports made to the FDA's MedWatch adverse event reporting system during the year after a drug receives exclusivity. These reports are then referred to the Pediatric Advisory Committee for a review.

The uses of Ortho Tri-Cyclen for female patients at 16 years of age and younger include dysfunctional uterine bleeding and acne, she said. During the postexclusivity period (Dec. 18, 2003, through Jan. 18, 2005) there were 14 unduplicated pediatric adverse event reports associated with Ortho Tri-Cyclen, including 11 serious reports and no deaths.

The 14 reports included 12 cases in adolescent girls and 2 cases involving infants that had been exposed in utero. Adverse events that were reported more than once were headaches and metrorrhagia, events that are listed in the label of Ortho Tri-Cyclen, and convulsions, an adverse event that is not in the label.

There were four hospitalizations, which included the two in utero exposures. The other two hospitalizations were in a 16-year-old patient with benign intracranial hypertension, an increase in cerebrospinal fluid pressure, and a visual field defect; and in a 14-year-old patient who had cerebral thrombosis and headache. These two patients also were using isotretinoin.

A third patient who was also on isotretinoin, as well as prednisone, was reported to have depression, dizziness, and headache, which are unlabeled events for the oral contraceptive; other symptoms included decreased interest, insomnia, and panic attack.

The labels for isotretinoin and prednisone include the possible risk of increased intracranial pressure, depression, insomnia, emotional instability, dizziness, and headache, Dr. Temeck noted.

Of the two infants who were exposed in utero, one was in a breech presentation and born prematurely, and the baby's mother also had taken penicillin, betamethasone, and alprazolam while pregnant. The second exposed infant was reported to have cerebral artery occlusion, convulsion, apnea, and developmental delay.

There were three adolescents who did report visual adverse events, which are not mentioned in the Ortho Tri-Cyclen product label: a 14-year-old patient also on oxcarbazepine who was reported to have papilledema and cluster headache; a 16-year old patient also on doxycycline and tretinoin, who experienced scotoma, blurred vision, headache and influenza-like illness; and a 16-year old patient also on isotretinoin and prednisone, who had a visual-field defect, in addition to benign intracranial hypertension and increased cerebrospinal fluid pressure. (The label for Ortho Tri-Cyclen does contain a warning of retinal thrombosis.)

The other two serious adverse events that were reported were in one 14-year-old who developed hypertension and another 14-year-old who has dysarthria and hypoesthesia—two events that are not included on the label. Convulsions also were reported in a 15-year-old who had a history of intermittent seizures.

Despite the fact that there were reports of some serious adverse events during this period, “no pattern of new safety concerns” was identified, Dr. Temeck said. Based on the presentation, the advisory panel agreed with the FDA that monitoring of adverse events for these oral contraceptives could be switched to regular monitoring.

Health care professionals and consumers can report any drug- or device-related adverse events to MedWatch by calling 800-332-1088, sending a fax to 800-332-0178, writing to MedWatch, Food and Drug Administration, 5600 Fishers Ln., Rockville, MD 20857-9787; or visiting www.fda.gov/medwatch

ROCKVILLE, MD. — No new safety concerns were raised by a review of adverse events reported during a recent 1-year period in adolescents taking a combination oral contraceptive, according to Jean Wendy Temeck, M.D., of the Food and Drug Administration's division of pediatric drug development.

The FDA's review of adverse events reported for Ortho Tri-Cyclen and Ortho Tri-Cyclen Lo, which contain norgestimate and ethinyl estradiol, was conducted between December 2003 and January 2005, the year after the FDA granted marketing exclusivity to the drug. Exclusivity is granted to a drug when companies perform pediatric studies of the product in exchange for a 6-month extension on the patent for the drugs.

In this case, the drug manufacturer, Ortho-McNeil Pharmaceutical Inc., which is based in Raritan, N.J., conducted a placebo-controlled study to determine whether the oral contraceptive improved bone density in adolescent girls who had been diagnosed with anorexia nervosa. The study showed no differences from placebo in increases in hip and lumbar-spine bone mineral density following 1 year of treatment.

Dr. Temek reported the findings at a meeting of the FDA's Pediatric Advisory Committee. The Best Pharmaceuticals for Children Act requires that the FDA's Office of Pediatric Therapeutics review postmarketing adverse event reports made to the FDA's MedWatch adverse event reporting system during the year after a drug receives exclusivity. These reports are then referred to the Pediatric Advisory Committee for a review.

The uses of Ortho Tri-Cyclen for female patients at 16 years of age and younger include dysfunctional uterine bleeding and acne, she said. During the postexclusivity period (Dec. 18, 2003, through Jan. 18, 2005) there were 14 unduplicated pediatric adverse event reports associated with Ortho Tri-Cyclen, including 11 serious reports and no deaths.

The 14 reports included 12 cases in adolescent girls and 2 cases involving infants that had been exposed in utero. Adverse events that were reported more than once were headaches and metrorrhagia, events that are listed in the label of Ortho Tri-Cyclen, and convulsions, an adverse event that is not in the label.

There were four hospitalizations, which included the two in utero exposures. The other two hospitalizations were in a 16-year-old patient with benign intracranial hypertension, an increase in cerebrospinal fluid pressure, and a visual field defect; and in a 14-year-old patient who had cerebral thrombosis and headache. These two patients also were using isotretinoin.

A third patient who was also on isotretinoin, as well as prednisone, was reported to have depression, dizziness, and headache, which are unlabeled events for the oral contraceptive; other symptoms included decreased interest, insomnia, and panic attack.

The labels for isotretinoin and prednisone include the possible risk of increased intracranial pressure, depression, insomnia, emotional instability, dizziness, and headache, Dr. Temeck noted.

Of the two infants who were exposed in utero, one was in a breech presentation and born prematurely, and the baby's mother also had taken penicillin, betamethasone, and alprazolam while pregnant. The second exposed infant was reported to have cerebral artery occlusion, convulsion, apnea, and developmental delay.

There were three adolescents who did report visual adverse events, which are not mentioned in the Ortho Tri-Cyclen product label: a 14-year-old patient also on oxcarbazepine who was reported to have papilledema and cluster headache; a 16-year old patient also on doxycycline and tretinoin, who experienced scotoma, blurred vision, headache and influenza-like illness; and a 16-year old patient also on isotretinoin and prednisone, who had a visual-field defect, in addition to benign intracranial hypertension and increased cerebrospinal fluid pressure. (The label for Ortho Tri-Cyclen does contain a warning of retinal thrombosis.)

The other two serious adverse events that were reported were in one 14-year-old who developed hypertension and another 14-year-old who has dysarthria and hypoesthesia—two events that are not included on the label. Convulsions also were reported in a 15-year-old who had a history of intermittent seizures.

Despite the fact that there were reports of some serious adverse events during this period, “no pattern of new safety concerns” was identified, Dr. Temeck said. Based on the presentation, the advisory panel agreed with the FDA that monitoring of adverse events for these oral contraceptives could be switched to regular monitoring.

Health care professionals and consumers can report any drug- or device-related adverse events to MedWatch by calling 800-332-1088, sending a fax to 800-332-0178, writing to MedWatch, Food and Drug Administration, 5600 Fishers Ln., Rockville, MD 20857-9787; or visiting www.fda.gov/medwatch