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FDA issues safety update on metal-on-metal hips
Follow-up of patients who have received a metal-on-metal hip implant should include periodic physical examinations and imaging tests, and in some cases, measurements of metal ion levels in the blood, according to the Food and Drug Administration update on the safety these devices.
The update, released in January, states that these devices – made up of a metal ball, stem, and socket – "have unique risks in addition to the general risks of all hip implants," and include soft tissue damage caused by the release of tiny metal particles from the metal surfaces sliding against each other over time. This soft tissue damage can be associated pain, loosening of the implant, and may require revision surgery.
The release of metal ions (which may include cobalt and/or chromium) into the bloodstream may cause a systemic reaction, but at this time, "the FDA does not have enough scientific data to specify the concentration of metal ions in a patient’s body or blood necessary to produce adverse systemic effects," the statement said, adding that this reaction "seems to be specific to individual patients, with different patients having different reactions to the metal wear particles."
The recommendations in the safety update are largely directed at orthopedic surgeons, who are advised to follow-up with patients who are asymptomatic metal-on-metal hip implant recipients with a physical exam and routine x-rays every 1 to 2 years, paying close attention to the signs and symptoms that these implants may cause. Patients who are symptomatic should be followed at least every 6 months.
But since people who have these implants and are experiencing systemic symptoms are more likely to see their primary care physician or rheumatologist, it is "important for all health care providers to be aware of metal ion adverse events that may occur in metal-on-metal hip implant patients," the FDA statement said.
These adverse events, which the statement says are based on case reports, "may include" a general hypersensitivity reaction (skin rash), cardiomyopathy, neurologic changes (including sensory changes such as auditory or visual impairment), renal function impairment, and thyroid dysfunction (including neck discomfort, fatigue, weight gain, or feeling cold).
Other recommendations include consideration of metal ion testing in patients with symptoms or physical signs that the device may not be functioning properly.
The safety update and recommendations are based on the agency’s evaluation of the published literature, and recommendations made at a June 2012 Orthopaedic and Rehabilitation Devices Advisory Panel meeting.
The metal-on-metal hip resurfacing systems became popular in younger active patients who had healthier bone and were thought to last longer, but their use has declined in reaction to increased revision rates and reports of adverse events, and has resulted in FDA recalls of some devices. The orthopedic surgeons on that panel indicated that they rarely or never used these implants anymore.
In December 2012, the American Academy of Orthopaedic Surgeons, the American Association of Hip and Knee Surgeons, and the Hip Society issued a statement on these devices, which said that recent reports from national joint registries have reported that the failure rates of total hip replacement surgery using metal-on-metal implants are two- to threefold higher than "contemporary" total hip replacement surgery using non–metal-on-metal devices. More than 10,000 metal-on-metal implants have been implanted worldwide since 1996, the statement said.
To view the FDA safety statement, click here. Adverse events associated with metal-on-metal hip implants should be reported to the FDA’s MedWatch program online or at 800-332-1088.
Follow-up of patients who have received a metal-on-metal hip implant should include periodic physical examinations and imaging tests, and in some cases, measurements of metal ion levels in the blood, according to the Food and Drug Administration update on the safety these devices.
The update, released in January, states that these devices – made up of a metal ball, stem, and socket – "have unique risks in addition to the general risks of all hip implants," and include soft tissue damage caused by the release of tiny metal particles from the metal surfaces sliding against each other over time. This soft tissue damage can be associated pain, loosening of the implant, and may require revision surgery.
The release of metal ions (which may include cobalt and/or chromium) into the bloodstream may cause a systemic reaction, but at this time, "the FDA does not have enough scientific data to specify the concentration of metal ions in a patient’s body or blood necessary to produce adverse systemic effects," the statement said, adding that this reaction "seems to be specific to individual patients, with different patients having different reactions to the metal wear particles."
The recommendations in the safety update are largely directed at orthopedic surgeons, who are advised to follow-up with patients who are asymptomatic metal-on-metal hip implant recipients with a physical exam and routine x-rays every 1 to 2 years, paying close attention to the signs and symptoms that these implants may cause. Patients who are symptomatic should be followed at least every 6 months.
But since people who have these implants and are experiencing systemic symptoms are more likely to see their primary care physician or rheumatologist, it is "important for all health care providers to be aware of metal ion adverse events that may occur in metal-on-metal hip implant patients," the FDA statement said.
These adverse events, which the statement says are based on case reports, "may include" a general hypersensitivity reaction (skin rash), cardiomyopathy, neurologic changes (including sensory changes such as auditory or visual impairment), renal function impairment, and thyroid dysfunction (including neck discomfort, fatigue, weight gain, or feeling cold).
Other recommendations include consideration of metal ion testing in patients with symptoms or physical signs that the device may not be functioning properly.
The safety update and recommendations are based on the agency’s evaluation of the published literature, and recommendations made at a June 2012 Orthopaedic and Rehabilitation Devices Advisory Panel meeting.
The metal-on-metal hip resurfacing systems became popular in younger active patients who had healthier bone and were thought to last longer, but their use has declined in reaction to increased revision rates and reports of adverse events, and has resulted in FDA recalls of some devices. The orthopedic surgeons on that panel indicated that they rarely or never used these implants anymore.
In December 2012, the American Academy of Orthopaedic Surgeons, the American Association of Hip and Knee Surgeons, and the Hip Society issued a statement on these devices, which said that recent reports from national joint registries have reported that the failure rates of total hip replacement surgery using metal-on-metal implants are two- to threefold higher than "contemporary" total hip replacement surgery using non–metal-on-metal devices. More than 10,000 metal-on-metal implants have been implanted worldwide since 1996, the statement said.
To view the FDA safety statement, click here. Adverse events associated with metal-on-metal hip implants should be reported to the FDA’s MedWatch program online or at 800-332-1088.
Follow-up of patients who have received a metal-on-metal hip implant should include periodic physical examinations and imaging tests, and in some cases, measurements of metal ion levels in the blood, according to the Food and Drug Administration update on the safety these devices.
The update, released in January, states that these devices – made up of a metal ball, stem, and socket – "have unique risks in addition to the general risks of all hip implants," and include soft tissue damage caused by the release of tiny metal particles from the metal surfaces sliding against each other over time. This soft tissue damage can be associated pain, loosening of the implant, and may require revision surgery.
The release of metal ions (which may include cobalt and/or chromium) into the bloodstream may cause a systemic reaction, but at this time, "the FDA does not have enough scientific data to specify the concentration of metal ions in a patient’s body or blood necessary to produce adverse systemic effects," the statement said, adding that this reaction "seems to be specific to individual patients, with different patients having different reactions to the metal wear particles."
The recommendations in the safety update are largely directed at orthopedic surgeons, who are advised to follow-up with patients who are asymptomatic metal-on-metal hip implant recipients with a physical exam and routine x-rays every 1 to 2 years, paying close attention to the signs and symptoms that these implants may cause. Patients who are symptomatic should be followed at least every 6 months.
But since people who have these implants and are experiencing systemic symptoms are more likely to see their primary care physician or rheumatologist, it is "important for all health care providers to be aware of metal ion adverse events that may occur in metal-on-metal hip implant patients," the FDA statement said.
These adverse events, which the statement says are based on case reports, "may include" a general hypersensitivity reaction (skin rash), cardiomyopathy, neurologic changes (including sensory changes such as auditory or visual impairment), renal function impairment, and thyroid dysfunction (including neck discomfort, fatigue, weight gain, or feeling cold).
Other recommendations include consideration of metal ion testing in patients with symptoms or physical signs that the device may not be functioning properly.
The safety update and recommendations are based on the agency’s evaluation of the published literature, and recommendations made at a June 2012 Orthopaedic and Rehabilitation Devices Advisory Panel meeting.
The metal-on-metal hip resurfacing systems became popular in younger active patients who had healthier bone and were thought to last longer, but their use has declined in reaction to increased revision rates and reports of adverse events, and has resulted in FDA recalls of some devices. The orthopedic surgeons on that panel indicated that they rarely or never used these implants anymore.
In December 2012, the American Academy of Orthopaedic Surgeons, the American Association of Hip and Knee Surgeons, and the Hip Society issued a statement on these devices, which said that recent reports from national joint registries have reported that the failure rates of total hip replacement surgery using metal-on-metal implants are two- to threefold higher than "contemporary" total hip replacement surgery using non–metal-on-metal devices. More than 10,000 metal-on-metal implants have been implanted worldwide since 1996, the statement said.
To view the FDA safety statement, click here. Adverse events associated with metal-on-metal hip implants should be reported to the FDA’s MedWatch program online or at 800-332-1088.
FDA panel votes against inhaled mannitol for cystic fibrosis
SILVER SPRING, MD. – Uncertainty over safety and efficacy data, particularly in children, moved a Food and Drug Administration advisory panel to unanimously recommend against approval of a dry powder formulation of mannitol for treating cystic fibrosis.
At a Jan. 30 meeting, the Pulmonary-Allergy Drugs Advisory Committee voted 14 to 0 against FDA approval of the product for the management of cystic fibrosis in patients aged 6 years and older, the indication under review. The proposed dose is 400 mg twice a day, administered via a breath-actuated dry powder inhaler over about 5 minutes, using ten 40-mg capsules for the total dose.
Mannitol "hydrates the lung surface, leading to improved airway clearance," according to the Australian manufacturer, Pharmaxis. Dry powder mannitol (DPM) is approved for people aged 6 years and older in Australia and for adults in the European Union.
"I wish I could have voted yes, because I think there is a place for a drug like this, but I think that further studies are necessary," said one of the panelists, Dr. Mary Cataletto, a pediatric pulmonologist and professor of clinical pediatrics at the State University of New York at Stony Brook. Like several other panelists, Dr. Jeffrey Wagener, professor of pediatrics at the University of Colorado, Aurora, said he may have voted in favor of approval if the indication had been limited to adults. "But there was no evidence DPM was effective in children, and "we need more information, more study, in children, particularly long term, looking at exacerbations and other outcomes besides FEV1 [forced expiratory volume in 1 second]," he added.
Pharmaxis presented the results of two phase III studies that enrolled 600 patients aged 6 years and older with cystic fibrosis (mean age about 20-23 years) with a baseline FEV1 of 30% or greater and less than 90% predicted. The trials compared treatment with 400 mg of DPM twice a day to treatment with 50 mg of DPM twice a day (controls). Patients continued other CF treatments, except for hypertonic saline, which, like mannitol, is considered an airway hydrator, and started treatment after passing a mannitol tolerance test.
In one of the studies, conducted outside the United States, the primary endpoint, the average change from baseline in FEV1 over 26 weeks, was significantly greater among those on treatment compared with controls (118 mL vs. 35 mL). But this study had a large amount of missing data because of patients dropping out, an issue raised by the FDA reviewers. In the second study, conducted in the United States, Canada, Argentina, and several European countries, the dropout rate was lower, but improvements in FEV1 from baseline at 26 weeks were only numerically, not significantly, greater among those on treatment compared with controls (107 mL vs. 52 mL).
The safety issue that elicited the most concern among panelists and was the main focus of the safety discussion was the higher rate of hemoptysis associated with treatment, particularly among those under age 18. In the two studies, the rate of hemoptysis (reported as an adverse event, not associated with an exacerbation), was almost 11% in adults on DPM, compared with about 8% of controls. But in those aged 6-17 years, the rate was almost 8% among those on DPM, compared with almost 2% among controls, according to the company, which agreed that hemoptysis in the pediatric age group was a safety signal that needed to be evaluated further.
Other adverse events appeared to be related to tolerability of the treatment, and more patients on DPM stopped treatment because of adverse events (11% vs. 6%), for reasons that included cough and hemoptysis.
FDA reviewers raised statistical issues regarding the data, including the impact missing data had on the primary endpoint in the two studies, particularly in the non-U.S. study, and questioned whether the results provided an accurate estimate of the treatment’s effects.
Several panelists described the efficacy data as "underwhelming," but the panel generally agreed there was some evidence the drug was probably effective in a subset of patients, who have not yet been identified. They also referred to public testimony from several adults with CF who described the benefits of DPM, particularly on their ability to cough up mucus after a treatment, as anecdotal evidence that the drug was effective in some patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding. If approved, Pharmaxis plans to market DPM as Bronchitol. The company markets the Aridol bronchial hyperresponsiveness test that contains 635 mg of inhaled mannitol. A statement released by Pharmaxis after the panel meeting said that the company would continue to work with the FDA to bring the product to the United States.
The FDA’s deadline for making the decision on approval is in March.
FDA panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
SILVER SPRING, MD. – Uncertainty over safety and efficacy data, particularly in children, moved a Food and Drug Administration advisory panel to unanimously recommend against approval of a dry powder formulation of mannitol for treating cystic fibrosis.
At a Jan. 30 meeting, the Pulmonary-Allergy Drugs Advisory Committee voted 14 to 0 against FDA approval of the product for the management of cystic fibrosis in patients aged 6 years and older, the indication under review. The proposed dose is 400 mg twice a day, administered via a breath-actuated dry powder inhaler over about 5 minutes, using ten 40-mg capsules for the total dose.
Mannitol "hydrates the lung surface, leading to improved airway clearance," according to the Australian manufacturer, Pharmaxis. Dry powder mannitol (DPM) is approved for people aged 6 years and older in Australia and for adults in the European Union.
"I wish I could have voted yes, because I think there is a place for a drug like this, but I think that further studies are necessary," said one of the panelists, Dr. Mary Cataletto, a pediatric pulmonologist and professor of clinical pediatrics at the State University of New York at Stony Brook. Like several other panelists, Dr. Jeffrey Wagener, professor of pediatrics at the University of Colorado, Aurora, said he may have voted in favor of approval if the indication had been limited to adults. "But there was no evidence DPM was effective in children, and "we need more information, more study, in children, particularly long term, looking at exacerbations and other outcomes besides FEV1 [forced expiratory volume in 1 second]," he added.
Pharmaxis presented the results of two phase III studies that enrolled 600 patients aged 6 years and older with cystic fibrosis (mean age about 20-23 years) with a baseline FEV1 of 30% or greater and less than 90% predicted. The trials compared treatment with 400 mg of DPM twice a day to treatment with 50 mg of DPM twice a day (controls). Patients continued other CF treatments, except for hypertonic saline, which, like mannitol, is considered an airway hydrator, and started treatment after passing a mannitol tolerance test.
In one of the studies, conducted outside the United States, the primary endpoint, the average change from baseline in FEV1 over 26 weeks, was significantly greater among those on treatment compared with controls (118 mL vs. 35 mL). But this study had a large amount of missing data because of patients dropping out, an issue raised by the FDA reviewers. In the second study, conducted in the United States, Canada, Argentina, and several European countries, the dropout rate was lower, but improvements in FEV1 from baseline at 26 weeks were only numerically, not significantly, greater among those on treatment compared with controls (107 mL vs. 52 mL).
The safety issue that elicited the most concern among panelists and was the main focus of the safety discussion was the higher rate of hemoptysis associated with treatment, particularly among those under age 18. In the two studies, the rate of hemoptysis (reported as an adverse event, not associated with an exacerbation), was almost 11% in adults on DPM, compared with about 8% of controls. But in those aged 6-17 years, the rate was almost 8% among those on DPM, compared with almost 2% among controls, according to the company, which agreed that hemoptysis in the pediatric age group was a safety signal that needed to be evaluated further.
Other adverse events appeared to be related to tolerability of the treatment, and more patients on DPM stopped treatment because of adverse events (11% vs. 6%), for reasons that included cough and hemoptysis.
FDA reviewers raised statistical issues regarding the data, including the impact missing data had on the primary endpoint in the two studies, particularly in the non-U.S. study, and questioned whether the results provided an accurate estimate of the treatment’s effects.
Several panelists described the efficacy data as "underwhelming," but the panel generally agreed there was some evidence the drug was probably effective in a subset of patients, who have not yet been identified. They also referred to public testimony from several adults with CF who described the benefits of DPM, particularly on their ability to cough up mucus after a treatment, as anecdotal evidence that the drug was effective in some patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding. If approved, Pharmaxis plans to market DPM as Bronchitol. The company markets the Aridol bronchial hyperresponsiveness test that contains 635 mg of inhaled mannitol. A statement released by Pharmaxis after the panel meeting said that the company would continue to work with the FDA to bring the product to the United States.
The FDA’s deadline for making the decision on approval is in March.
FDA panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
SILVER SPRING, MD. – Uncertainty over safety and efficacy data, particularly in children, moved a Food and Drug Administration advisory panel to unanimously recommend against approval of a dry powder formulation of mannitol for treating cystic fibrosis.
At a Jan. 30 meeting, the Pulmonary-Allergy Drugs Advisory Committee voted 14 to 0 against FDA approval of the product for the management of cystic fibrosis in patients aged 6 years and older, the indication under review. The proposed dose is 400 mg twice a day, administered via a breath-actuated dry powder inhaler over about 5 minutes, using ten 40-mg capsules for the total dose.
Mannitol "hydrates the lung surface, leading to improved airway clearance," according to the Australian manufacturer, Pharmaxis. Dry powder mannitol (DPM) is approved for people aged 6 years and older in Australia and for adults in the European Union.
"I wish I could have voted yes, because I think there is a place for a drug like this, but I think that further studies are necessary," said one of the panelists, Dr. Mary Cataletto, a pediatric pulmonologist and professor of clinical pediatrics at the State University of New York at Stony Brook. Like several other panelists, Dr. Jeffrey Wagener, professor of pediatrics at the University of Colorado, Aurora, said he may have voted in favor of approval if the indication had been limited to adults. "But there was no evidence DPM was effective in children, and "we need more information, more study, in children, particularly long term, looking at exacerbations and other outcomes besides FEV1 [forced expiratory volume in 1 second]," he added.
Pharmaxis presented the results of two phase III studies that enrolled 600 patients aged 6 years and older with cystic fibrosis (mean age about 20-23 years) with a baseline FEV1 of 30% or greater and less than 90% predicted. The trials compared treatment with 400 mg of DPM twice a day to treatment with 50 mg of DPM twice a day (controls). Patients continued other CF treatments, except for hypertonic saline, which, like mannitol, is considered an airway hydrator, and started treatment after passing a mannitol tolerance test.
In one of the studies, conducted outside the United States, the primary endpoint, the average change from baseline in FEV1 over 26 weeks, was significantly greater among those on treatment compared with controls (118 mL vs. 35 mL). But this study had a large amount of missing data because of patients dropping out, an issue raised by the FDA reviewers. In the second study, conducted in the United States, Canada, Argentina, and several European countries, the dropout rate was lower, but improvements in FEV1 from baseline at 26 weeks were only numerically, not significantly, greater among those on treatment compared with controls (107 mL vs. 52 mL).
The safety issue that elicited the most concern among panelists and was the main focus of the safety discussion was the higher rate of hemoptysis associated with treatment, particularly among those under age 18. In the two studies, the rate of hemoptysis (reported as an adverse event, not associated with an exacerbation), was almost 11% in adults on DPM, compared with about 8% of controls. But in those aged 6-17 years, the rate was almost 8% among those on DPM, compared with almost 2% among controls, according to the company, which agreed that hemoptysis in the pediatric age group was a safety signal that needed to be evaluated further.
Other adverse events appeared to be related to tolerability of the treatment, and more patients on DPM stopped treatment because of adverse events (11% vs. 6%), for reasons that included cough and hemoptysis.
FDA reviewers raised statistical issues regarding the data, including the impact missing data had on the primary endpoint in the two studies, particularly in the non-U.S. study, and questioned whether the results provided an accurate estimate of the treatment’s effects.
Several panelists described the efficacy data as "underwhelming," but the panel generally agreed there was some evidence the drug was probably effective in a subset of patients, who have not yet been identified. They also referred to public testimony from several adults with CF who described the benefits of DPM, particularly on their ability to cough up mucus after a treatment, as anecdotal evidence that the drug was effective in some patients.
The FDA usually follows the recommendations of its advisory panels, which are not binding. If approved, Pharmaxis plans to market DPM as Bronchitol. The company markets the Aridol bronchial hyperresponsiveness test that contains 635 mg of inhaled mannitol. A statement released by Pharmaxis after the panel meeting said that the company would continue to work with the FDA to bring the product to the United States.
The FDA’s deadline for making the decision on approval is in March.
FDA panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
AT A MEETING OF THE FDA'S PULMONARY-ALLERGY DRUGS ADVISORY COMMITTEE
Study identifies predictors of cognitive impairment in schizophrenia
A model using three patient characteristics was a significant predictor of general neurocognitive impairment in patients 3 years after their first episode of a nonaffective psychosis was diagnosed, in a study conducted in Spain.
Of the different clinical, neuropsychological, premorbid, and sociodemographic variables, three – premorbid IQ, baseline performances on verbal memory, and motor dexterity tasks – were the only statistically significant predictors of global neurocognitive function in the patients at the 3-year follow-up, reported Dr. Rosa Ayesa-Arriola, of the department of psychiatry at Marqués de Valdecilla University Hospital, Santander, Spain, and her associates. (Prog. Neuropsychopharmacol. Biol. Psychiatry 2013;43:23-8).
The model using these three variables was almost 80% accurate in predicting neurocognitive functioning overall, correctly classifying 75% of the patients who did not have neurocognitive impairment and 83.6% of those who had impairment at 3 years, they said. These results indicate that a lower premorbid IQ and worse performances on verbal memory and motor dexterity tasks "robustly predicted" general neurocognitive impairment, and that it might be possible to correctly identify long-term neurocognitive impairment "by detecting baseline deficits in verbal memory, fine motor skills, and low IQ," they wrote.
The study is the first to compare neurocognitive outcomes in patients with a first episode of psychosis "within the context of a multifactorial model," they noted.
The study evaluated data on about 150 patients, aged 15-60 years, who were treated as outpatients and inpatients at the hospital for their first episode of psychosis (most had schizophrenia) and were randomly assigned to antipsychotic treatments. (The patients are part of a large epidemiologic and longitudinal intervention program of patients with first-episode psychosis.) The data collected included neurocognitive assessments at baseline, and at the 3-year follow-up and information on premorbid and sociodemographic variables for patients were collected from patients, relatives, and medical records.
Although more studies are needed to replicate and evaluate the effectiveness of the model, they concluded, since people with "schizophrenia have cognitive deficits that impair [fundamental] aspects of their daily lives, the suggested predictive model could be an important step in approving a drug for a cognitive improvement indication or to alter the way that schizophrenia is currently treated."
The authors cited the large homogenous sample and the 3-year longitudinal design as strengths of the study but acknowledged several limitations. For instance, some patients were not included in the 3-year analysis because neuropsychological evaluations were incomplete, and other factors could influence results, such as medication adherence or hospitalizations during the 3-year period. Dr. Ayesha-Arriola had no conflicts of interest.
neuropsychological, premorbid, sociodemographic variables, premorbid IQ, verbal memory, motor dexterity, Dr. Rosa Ayesa-Arriola,
A model using three patient characteristics was a significant predictor of general neurocognitive impairment in patients 3 years after their first episode of a nonaffective psychosis was diagnosed, in a study conducted in Spain.
Of the different clinical, neuropsychological, premorbid, and sociodemographic variables, three – premorbid IQ, baseline performances on verbal memory, and motor dexterity tasks – were the only statistically significant predictors of global neurocognitive function in the patients at the 3-year follow-up, reported Dr. Rosa Ayesa-Arriola, of the department of psychiatry at Marqués de Valdecilla University Hospital, Santander, Spain, and her associates. (Prog. Neuropsychopharmacol. Biol. Psychiatry 2013;43:23-8).
The model using these three variables was almost 80% accurate in predicting neurocognitive functioning overall, correctly classifying 75% of the patients who did not have neurocognitive impairment and 83.6% of those who had impairment at 3 years, they said. These results indicate that a lower premorbid IQ and worse performances on verbal memory and motor dexterity tasks "robustly predicted" general neurocognitive impairment, and that it might be possible to correctly identify long-term neurocognitive impairment "by detecting baseline deficits in verbal memory, fine motor skills, and low IQ," they wrote.
The study is the first to compare neurocognitive outcomes in patients with a first episode of psychosis "within the context of a multifactorial model," they noted.
The study evaluated data on about 150 patients, aged 15-60 years, who were treated as outpatients and inpatients at the hospital for their first episode of psychosis (most had schizophrenia) and were randomly assigned to antipsychotic treatments. (The patients are part of a large epidemiologic and longitudinal intervention program of patients with first-episode psychosis.) The data collected included neurocognitive assessments at baseline, and at the 3-year follow-up and information on premorbid and sociodemographic variables for patients were collected from patients, relatives, and medical records.
Although more studies are needed to replicate and evaluate the effectiveness of the model, they concluded, since people with "schizophrenia have cognitive deficits that impair [fundamental] aspects of their daily lives, the suggested predictive model could be an important step in approving a drug for a cognitive improvement indication or to alter the way that schizophrenia is currently treated."
The authors cited the large homogenous sample and the 3-year longitudinal design as strengths of the study but acknowledged several limitations. For instance, some patients were not included in the 3-year analysis because neuropsychological evaluations were incomplete, and other factors could influence results, such as medication adherence or hospitalizations during the 3-year period. Dr. Ayesha-Arriola had no conflicts of interest.
A model using three patient characteristics was a significant predictor of general neurocognitive impairment in patients 3 years after their first episode of a nonaffective psychosis was diagnosed, in a study conducted in Spain.
Of the different clinical, neuropsychological, premorbid, and sociodemographic variables, three – premorbid IQ, baseline performances on verbal memory, and motor dexterity tasks – were the only statistically significant predictors of global neurocognitive function in the patients at the 3-year follow-up, reported Dr. Rosa Ayesa-Arriola, of the department of psychiatry at Marqués de Valdecilla University Hospital, Santander, Spain, and her associates. (Prog. Neuropsychopharmacol. Biol. Psychiatry 2013;43:23-8).
The model using these three variables was almost 80% accurate in predicting neurocognitive functioning overall, correctly classifying 75% of the patients who did not have neurocognitive impairment and 83.6% of those who had impairment at 3 years, they said. These results indicate that a lower premorbid IQ and worse performances on verbal memory and motor dexterity tasks "robustly predicted" general neurocognitive impairment, and that it might be possible to correctly identify long-term neurocognitive impairment "by detecting baseline deficits in verbal memory, fine motor skills, and low IQ," they wrote.
The study is the first to compare neurocognitive outcomes in patients with a first episode of psychosis "within the context of a multifactorial model," they noted.
The study evaluated data on about 150 patients, aged 15-60 years, who were treated as outpatients and inpatients at the hospital for their first episode of psychosis (most had schizophrenia) and were randomly assigned to antipsychotic treatments. (The patients are part of a large epidemiologic and longitudinal intervention program of patients with first-episode psychosis.) The data collected included neurocognitive assessments at baseline, and at the 3-year follow-up and information on premorbid and sociodemographic variables for patients were collected from patients, relatives, and medical records.
Although more studies are needed to replicate and evaluate the effectiveness of the model, they concluded, since people with "schizophrenia have cognitive deficits that impair [fundamental] aspects of their daily lives, the suggested predictive model could be an important step in approving a drug for a cognitive improvement indication or to alter the way that schizophrenia is currently treated."
The authors cited the large homogenous sample and the 3-year longitudinal design as strengths of the study but acknowledged several limitations. For instance, some patients were not included in the 3-year analysis because neuropsychological evaluations were incomplete, and other factors could influence results, such as medication adherence or hospitalizations during the 3-year period. Dr. Ayesha-Arriola had no conflicts of interest.
neuropsychological, premorbid, sociodemographic variables, premorbid IQ, verbal memory, motor dexterity, Dr. Rosa Ayesa-Arriola,
neuropsychological, premorbid, sociodemographic variables, premorbid IQ, verbal memory, motor dexterity, Dr. Rosa Ayesa-Arriola,
FROM PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
Major Finding: A combination of three baseline patient characteristics were significantly predictive of neurocognitive function 3 years after the first episode of nonaffective psychosis, predicting almost 84% of patients with impaired function.
Data Source: A longitudinal study of 146 patients diagnosed with their first episode of non-affective psychosis, identified predictors of neurocognitive impairment in the patients 3 years later.
Disclosures: Dr. Ayesha-Arriola had no conflicts of interest.
Once-daily beta-agonist for COPD earns FDA panel support
SILVER SPRING, MD. – Olodaterol, an inhaled long-acting beta2-adrenergic agonist, is an effective bronchodilator and should be approved for the treatment of chronic obstructive pulmonary disease, based on clinical trials in more than 3,000 patients with moderate to very severe COPD, the majority of a Food and Drug Administration advisory panel agreed at a meeting on Jan. 29.
The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 15-1, with one abstention, to recommend approval of olodaterol for the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD including chronic bronchitis and/or emphysema – the indication proposed by the manufacturer, Boehringer Ingelheim. Olodaterol is formulated in an inhalation spray solution, administered once a day via a metered dose inhaler (the Respimat device), at a dose of 5 mcg (two actuations of 2.5 mcg each).
The panelists voting in favor of approval agreed that clinical trial results showed that the drug had a bronchodilator effect comparable to other established bronchodilators, in a real-world setting where patients were on background medications, and at a dosing regimen that was similar to other treatments.
In separate votes on safety and efficacy, the panel also voted 15-1, with 1 abstention, that the data provided "substantial evidence" that the drug was effective; and 15-1, with 1 abstention, that the safety profile was adequate for the proposed indication and was comparable to that of other LABAs. But the panel recommended postmarketing surveillance of safety, including malignancies, and safety in black patients, who made up less than 5% of the enrolled patients in the studies.
In the studies, there were more neoplasms among those treated with olodaterol, but the increase was not statistically significant and did not reach the level of a safety signal, according to the company. But several panelists said that they were struck by the four diagnoses of small-cell lung cancers in patients on the 10-mcg daily dose that was also tested in the studies. While this was not a reason to recommend against approval, they said that malignancies – lung cancers in particular – in treated patients should be closely monitored after approval.
In four pivotal studies presented by the company, treatment with olodaterol (5 mcg or 10 mcg a day) was compared with placebo in 3,104 patients with moderate to very severe COPD (mean age 65 years) who were also on background medications (a muscarinic antagonist in 47%, an anti-inflammatory in 52%, a muscarinic antagonist and an antinflammatory in 29%, and a muscarinic antagonist with an inhaled corticosteroid and a xanthine in 5%).
Compared with placebo, treatment with 5 mcg per day was associated with statistically significant improvements in the two primary endpoints – FEV1 AUC (0-3 hours) and trough FEV1 responses – at 12 weeks in the two studies conducted primarily in the United States, and at 24 weeks in the two studies conducted primarily in Europe. Improvements in lung function with the 5-mcg dose were comparable to the 10-mcg dose, which is not a proposed dose.
Death rates and serious adverse events were similar in patients treated with olodaterol and comparators, and COPD exacerbations were the most common cause of death.
Boehringer Ingelheim has also proposed that the labeling include a claim that treatment with olodaterol increased exercise tolerance, increased respiratory capacity, and reduced lung hyperinflation. If approved by the FDA, this would be the first exercise tolerance claim to be included in labeling of a COPD drug, but based on the comments of the panel, this is unlikely.
In the study, the benefits in exercise tolerance after 6 weeks of treatment were based on effects on exercise tolerance testing performed 2 hours after the morning dose, at the time of the drug’s peak effect, in about 308 patients. It was unclear whether the effects could be maintained if the test had been performed later, which is particularly important because the indication is for maintenance treatment, according to the FDA reviewers.
The panel was not asked to vote on the exercise claim but discussed whether the results were clinically meaningful. Several panelists said that the improvements in exercise tolerance were notable, but since improvements were measured in a laboratory setting 2 hours after patients received the daily dose of olodaterol, it would be useful to evaluate how these improvements affected an individual’s activities of daily living. It would also be useful to provide a measurement later in the day to see if the effects persist throughout a period of time the patient may be active.
If approved, olodaterol will be marketed as Striverdi Respimat. It has already been approved in more than 60 countries.
The LABAs currently approved by the FDA are salmeterol, formoterol, and indacaterol.
The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
SILVER SPRING, MD. – Olodaterol, an inhaled long-acting beta2-adrenergic agonist, is an effective bronchodilator and should be approved for the treatment of chronic obstructive pulmonary disease, based on clinical trials in more than 3,000 patients with moderate to very severe COPD, the majority of a Food and Drug Administration advisory panel agreed at a meeting on Jan. 29.
The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 15-1, with one abstention, to recommend approval of olodaterol for the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD including chronic bronchitis and/or emphysema – the indication proposed by the manufacturer, Boehringer Ingelheim. Olodaterol is formulated in an inhalation spray solution, administered once a day via a metered dose inhaler (the Respimat device), at a dose of 5 mcg (two actuations of 2.5 mcg each).
The panelists voting in favor of approval agreed that clinical trial results showed that the drug had a bronchodilator effect comparable to other established bronchodilators, in a real-world setting where patients were on background medications, and at a dosing regimen that was similar to other treatments.
In separate votes on safety and efficacy, the panel also voted 15-1, with 1 abstention, that the data provided "substantial evidence" that the drug was effective; and 15-1, with 1 abstention, that the safety profile was adequate for the proposed indication and was comparable to that of other LABAs. But the panel recommended postmarketing surveillance of safety, including malignancies, and safety in black patients, who made up less than 5% of the enrolled patients in the studies.
In the studies, there were more neoplasms among those treated with olodaterol, but the increase was not statistically significant and did not reach the level of a safety signal, according to the company. But several panelists said that they were struck by the four diagnoses of small-cell lung cancers in patients on the 10-mcg daily dose that was also tested in the studies. While this was not a reason to recommend against approval, they said that malignancies – lung cancers in particular – in treated patients should be closely monitored after approval.
In four pivotal studies presented by the company, treatment with olodaterol (5 mcg or 10 mcg a day) was compared with placebo in 3,104 patients with moderate to very severe COPD (mean age 65 years) who were also on background medications (a muscarinic antagonist in 47%, an anti-inflammatory in 52%, a muscarinic antagonist and an antinflammatory in 29%, and a muscarinic antagonist with an inhaled corticosteroid and a xanthine in 5%).
Compared with placebo, treatment with 5 mcg per day was associated with statistically significant improvements in the two primary endpoints – FEV1 AUC (0-3 hours) and trough FEV1 responses – at 12 weeks in the two studies conducted primarily in the United States, and at 24 weeks in the two studies conducted primarily in Europe. Improvements in lung function with the 5-mcg dose were comparable to the 10-mcg dose, which is not a proposed dose.
Death rates and serious adverse events were similar in patients treated with olodaterol and comparators, and COPD exacerbations were the most common cause of death.
Boehringer Ingelheim has also proposed that the labeling include a claim that treatment with olodaterol increased exercise tolerance, increased respiratory capacity, and reduced lung hyperinflation. If approved by the FDA, this would be the first exercise tolerance claim to be included in labeling of a COPD drug, but based on the comments of the panel, this is unlikely.
In the study, the benefits in exercise tolerance after 6 weeks of treatment were based on effects on exercise tolerance testing performed 2 hours after the morning dose, at the time of the drug’s peak effect, in about 308 patients. It was unclear whether the effects could be maintained if the test had been performed later, which is particularly important because the indication is for maintenance treatment, according to the FDA reviewers.
The panel was not asked to vote on the exercise claim but discussed whether the results were clinically meaningful. Several panelists said that the improvements in exercise tolerance were notable, but since improvements were measured in a laboratory setting 2 hours after patients received the daily dose of olodaterol, it would be useful to evaluate how these improvements affected an individual’s activities of daily living. It would also be useful to provide a measurement later in the day to see if the effects persist throughout a period of time the patient may be active.
If approved, olodaterol will be marketed as Striverdi Respimat. It has already been approved in more than 60 countries.
The LABAs currently approved by the FDA are salmeterol, formoterol, and indacaterol.
The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
SILVER SPRING, MD. – Olodaterol, an inhaled long-acting beta2-adrenergic agonist, is an effective bronchodilator and should be approved for the treatment of chronic obstructive pulmonary disease, based on clinical trials in more than 3,000 patients with moderate to very severe COPD, the majority of a Food and Drug Administration advisory panel agreed at a meeting on Jan. 29.
The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 15-1, with one abstention, to recommend approval of olodaterol for the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD including chronic bronchitis and/or emphysema – the indication proposed by the manufacturer, Boehringer Ingelheim. Olodaterol is formulated in an inhalation spray solution, administered once a day via a metered dose inhaler (the Respimat device), at a dose of 5 mcg (two actuations of 2.5 mcg each).
The panelists voting in favor of approval agreed that clinical trial results showed that the drug had a bronchodilator effect comparable to other established bronchodilators, in a real-world setting where patients were on background medications, and at a dosing regimen that was similar to other treatments.
In separate votes on safety and efficacy, the panel also voted 15-1, with 1 abstention, that the data provided "substantial evidence" that the drug was effective; and 15-1, with 1 abstention, that the safety profile was adequate for the proposed indication and was comparable to that of other LABAs. But the panel recommended postmarketing surveillance of safety, including malignancies, and safety in black patients, who made up less than 5% of the enrolled patients in the studies.
In the studies, there were more neoplasms among those treated with olodaterol, but the increase was not statistically significant and did not reach the level of a safety signal, according to the company. But several panelists said that they were struck by the four diagnoses of small-cell lung cancers in patients on the 10-mcg daily dose that was also tested in the studies. While this was not a reason to recommend against approval, they said that malignancies – lung cancers in particular – in treated patients should be closely monitored after approval.
In four pivotal studies presented by the company, treatment with olodaterol (5 mcg or 10 mcg a day) was compared with placebo in 3,104 patients with moderate to very severe COPD (mean age 65 years) who were also on background medications (a muscarinic antagonist in 47%, an anti-inflammatory in 52%, a muscarinic antagonist and an antinflammatory in 29%, and a muscarinic antagonist with an inhaled corticosteroid and a xanthine in 5%).
Compared with placebo, treatment with 5 mcg per day was associated with statistically significant improvements in the two primary endpoints – FEV1 AUC (0-3 hours) and trough FEV1 responses – at 12 weeks in the two studies conducted primarily in the United States, and at 24 weeks in the two studies conducted primarily in Europe. Improvements in lung function with the 5-mcg dose were comparable to the 10-mcg dose, which is not a proposed dose.
Death rates and serious adverse events were similar in patients treated with olodaterol and comparators, and COPD exacerbations were the most common cause of death.
Boehringer Ingelheim has also proposed that the labeling include a claim that treatment with olodaterol increased exercise tolerance, increased respiratory capacity, and reduced lung hyperinflation. If approved by the FDA, this would be the first exercise tolerance claim to be included in labeling of a COPD drug, but based on the comments of the panel, this is unlikely.
In the study, the benefits in exercise tolerance after 6 weeks of treatment were based on effects on exercise tolerance testing performed 2 hours after the morning dose, at the time of the drug’s peak effect, in about 308 patients. It was unclear whether the effects could be maintained if the test had been performed later, which is particularly important because the indication is for maintenance treatment, according to the FDA reviewers.
The panel was not asked to vote on the exercise claim but discussed whether the results were clinically meaningful. Several panelists said that the improvements in exercise tolerance were notable, but since improvements were measured in a laboratory setting 2 hours after patients received the daily dose of olodaterol, it would be useful to evaluate how these improvements affected an individual’s activities of daily living. It would also be useful to provide a measurement later in the day to see if the effects persist throughout a period of time the patient may be active.
If approved, olodaterol will be marketed as Striverdi Respimat. It has already been approved in more than 60 countries.
The LABAs currently approved by the FDA are salmeterol, formoterol, and indacaterol.
The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
AT A MEETING OF THE FDA'S PULMONARY-ALLERGY DRUGS ADVISORY COMMITTEE
FDA panel backs more restricted hydrocodone prescribing
SILVER SPRING, MD. – Vicodin, Norco, and other hydrocodone combination products should be reclassified as schedule II drugs, because stricter controls on prescribing are needed to address the current epidemic of abuse, misuse, and diversion of these products in the United States, the majority of a Food and Drug Administration advisory panel has recommended.
At the end of a 2-day meeting on Jan. 25, the FDA’s Drug Safety and Risk Management Advisory Committee voted 19 to 10 that these products should be rescheduled from schedule III under the Controlled Substances Act (CSA), to schedule II. Schedule III allows written or oral prescribing, and five refills within 6 months, while schedule II drugs require handwritten prescriptions and other restrictions. The meeting was held in response to a request from the U.S. Drug Enforcement Administration that these products be rescheduled because of evidence they are overprescribed, diverted, and abused.
Panelists said that based on the epidemiologic and pharmacologic data presented during the meeting – which they acknowledged had limitations and was somewhat confusing – the abuse potential and pharmacology of hydrocodone combination products were similar to those of oxycodone and other schedule II drugs.
Those voting in favor of rescheduling said that it would result in a net public health benefit by making these drugs less available for abuse and reducing the amount that ends up in medication cabinets and on the street. And they acknowledged that there is little concrete evidence that tighter regulation would reduce the widespread abuse, misuse, and diversion of these products. In addition, rescheduling is likely to have some negative consequences, panelists noted.
"While I don’t think reclassification is some panacea for the opiate use problem in this country, I think it’s an important step in getting physicians to rethink prescribing practices and to look at other approaches in pain management," said Mary Ellen Olbrisch, Ph.D., professor of psychiatry and surgery, Virginia Commonwealth University, Richmond. She added that other measures would be necessary to ensure access to patients with appropriate needs for these drugs, such as legislation in states allowing nonphysician providers to prescribe schedule II drugs.
"For me, the most persuasive argument was that rescheduling is a signal to the public [and] to the medical profession about the abuse potential, and it [corrects] the misperception that hydrocodone combination products are a safer option than class II [agents] when it comes to long-term risk of abuse," added Elaine Morrato, Dr.P.H., of the department of health systems, management and policy, Colorado School of Public Health, Aurora.
Dr. Peter Kaboli, of the department of internal medicine at the University of Iowa, and a hospitalist at the Iowa City Veterans Affairs Medical Center, said that when considering the CSA’s list of factors used to determine scheduling of drugs with abuse potential, "it seemed pretty clear to me that the preponderance of the evidence supported rescheduling." Those factors include the drug’s actual or relative potential for abuse; scientific evidence of its pharmacologic effect; history and current pattern of abuse; and the scope, duration, and significance of abuse.
"We are witnessing the unintended consequences of poorly controlled opioid prescribing now," with people dying and developing hyperalgesia, dependence, and addiction, said Dr. Lewis Nelson, professor of emergency medicine at New York University. While there will be unintended consequences of stricter regulation, these products have become an alternative to heroin, and rescheduling will likely reduce the supply on the street and have a net benefit, he said.
But panelists voting against rescheduling said there was no evidence that rescheduling would have an impact on abuse and diversion, and would likely result in an increase in the use of heroin and other illicit drugs, and problems with other schedule III drugs. They were also concerned about the negative consequences of rescheduling on the treatment of pain, with the increased burden and reduced access to effective pain medications for patients in pain, particularly those in rural areas or those who have difficulty getting to a doctor for a prescription renewal.
Voting no, Dr. John Mendelson, senior scientist in the Addiction and Pharmacology Research Laboratory at St. Luke’s Hospital, San Francisco, said, "The net result will be increased prescribing of other [schedule II] drugs, which may have greater abuse liability and actually fuel rather than reduce an epidemic in progress." Another likely outcome is an increase in illicit opiate use and the abrupt withdrawal of medication for some patients who need it, he added, referring to public testimony at the meeting about people whose suicides were directly related to abrupt withdrawal from a hydrocodone product.
Winifred A. Landis, R.Ph., a pharmacist in Lafayette, Ind., said that the recommendation for rescheduling was "a knee jerk reaction" and that when prescribed and used appropriately, hydrocodone combination products should remain as schedule III drugs. "Those who are addiction-seeking will find other medications that are available, whether it’s clonazepam, alprazolam, or hydrocodone, and at the same time we’re going to reduce access for those who really need the medication for pain."
Almost all (99%) of hydrocodone used in the world is in the United States, where hydrocodone combination products are the most widely prescribed products: In 2011, there were about 131 million prescriptions for the combination hydrocodone analgesic products, for 47 million people, compared with 34.6 million for oxycodone combination drugs prescribed for 15.1 million patients, according to national prescription data cited by the FDA. About 40% of the hydrocodone combination analgesics are prescribed by primary care practitioners.
Because of indiscriminate prescribing, rogue pain clinics, leftovers in medication cabinets, and other sources, "there’s so much hydrocodone on the street it’s getting into the wrong hands," Joseph Rannazzisi, the deputy assistant administrator in the Drug Enforcement Administration’s office of diversion control, said at the meeting. He described these drugs as a gateway drug to harder drugs for teenagers, who tend to combine it with benzodiazepines and muscle relaxants.
The FDA’s analysis of the national data indicates that hydrocodone products are widely abused. High school students are more likely to abuse hydrocodone products than oxycodone products, because there are so many more hydrocodone prescriptions and wider availability of leftover drugs in homes. However, hydrocodone combination products have lower abuse ratios than oxycodone combination products, according to the FDA reviewers, who acknowledged that calculating accurate abuse ratios is complicated
Panelists strongly recommended close study of the impact of the scheduling change on prescribing practices, abuse, and diversion. There should be a transition period in the rescheduling process so patients with appropriate needs for the drug and prescribers can adjust to the tighter regulations and avoid losing access to the drug abruptly.
Currently, there are 81 products that contain up to 10 mg of hydrocodone per dosage unit with acetaminophen or ibuprofen, and 12 cough suppressant products that contain up to 10 mg of hydrocodone per dosage unit, with chlorpheniramine, homatropine, or pseudoephedrine, according to the FDA. Hydrocodone alone is a schedule II drug, but there is no single-ingredient hydrocodone product available. In December another FDA advisory panel voted against approval of an extended-release, single-ingredient hydrocodone formulation, largely because of what they considered an enormous potential for abuse once it became available.
Parents and other family members of people who had committed suicide or died of overdoses related to hydrocodone products also testified at the meeting, including several who had testified a month earlier at the meeting on the extended-release hydrocodone product, calling for tighter controls on the drug.
Dr. Olbrisch, Dr. Morrato, Dr. Kaboli, Dr. Nelson, Dr. Mendelson, and Ms. Landis are committee members. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. While a panelist may be given a waiver, none were granted at this meeting.
SILVER SPRING, MD. – Vicodin, Norco, and other hydrocodone combination products should be reclassified as schedule II drugs, because stricter controls on prescribing are needed to address the current epidemic of abuse, misuse, and diversion of these products in the United States, the majority of a Food and Drug Administration advisory panel has recommended.
At the end of a 2-day meeting on Jan. 25, the FDA’s Drug Safety and Risk Management Advisory Committee voted 19 to 10 that these products should be rescheduled from schedule III under the Controlled Substances Act (CSA), to schedule II. Schedule III allows written or oral prescribing, and five refills within 6 months, while schedule II drugs require handwritten prescriptions and other restrictions. The meeting was held in response to a request from the U.S. Drug Enforcement Administration that these products be rescheduled because of evidence they are overprescribed, diverted, and abused.
Panelists said that based on the epidemiologic and pharmacologic data presented during the meeting – which they acknowledged had limitations and was somewhat confusing – the abuse potential and pharmacology of hydrocodone combination products were similar to those of oxycodone and other schedule II drugs.
Those voting in favor of rescheduling said that it would result in a net public health benefit by making these drugs less available for abuse and reducing the amount that ends up in medication cabinets and on the street. And they acknowledged that there is little concrete evidence that tighter regulation would reduce the widespread abuse, misuse, and diversion of these products. In addition, rescheduling is likely to have some negative consequences, panelists noted.
"While I don’t think reclassification is some panacea for the opiate use problem in this country, I think it’s an important step in getting physicians to rethink prescribing practices and to look at other approaches in pain management," said Mary Ellen Olbrisch, Ph.D., professor of psychiatry and surgery, Virginia Commonwealth University, Richmond. She added that other measures would be necessary to ensure access to patients with appropriate needs for these drugs, such as legislation in states allowing nonphysician providers to prescribe schedule II drugs.
"For me, the most persuasive argument was that rescheduling is a signal to the public [and] to the medical profession about the abuse potential, and it [corrects] the misperception that hydrocodone combination products are a safer option than class II [agents] when it comes to long-term risk of abuse," added Elaine Morrato, Dr.P.H., of the department of health systems, management and policy, Colorado School of Public Health, Aurora.
Dr. Peter Kaboli, of the department of internal medicine at the University of Iowa, and a hospitalist at the Iowa City Veterans Affairs Medical Center, said that when considering the CSA’s list of factors used to determine scheduling of drugs with abuse potential, "it seemed pretty clear to me that the preponderance of the evidence supported rescheduling." Those factors include the drug’s actual or relative potential for abuse; scientific evidence of its pharmacologic effect; history and current pattern of abuse; and the scope, duration, and significance of abuse.
"We are witnessing the unintended consequences of poorly controlled opioid prescribing now," with people dying and developing hyperalgesia, dependence, and addiction, said Dr. Lewis Nelson, professor of emergency medicine at New York University. While there will be unintended consequences of stricter regulation, these products have become an alternative to heroin, and rescheduling will likely reduce the supply on the street and have a net benefit, he said.
But panelists voting against rescheduling said there was no evidence that rescheduling would have an impact on abuse and diversion, and would likely result in an increase in the use of heroin and other illicit drugs, and problems with other schedule III drugs. They were also concerned about the negative consequences of rescheduling on the treatment of pain, with the increased burden and reduced access to effective pain medications for patients in pain, particularly those in rural areas or those who have difficulty getting to a doctor for a prescription renewal.
Voting no, Dr. John Mendelson, senior scientist in the Addiction and Pharmacology Research Laboratory at St. Luke’s Hospital, San Francisco, said, "The net result will be increased prescribing of other [schedule II] drugs, which may have greater abuse liability and actually fuel rather than reduce an epidemic in progress." Another likely outcome is an increase in illicit opiate use and the abrupt withdrawal of medication for some patients who need it, he added, referring to public testimony at the meeting about people whose suicides were directly related to abrupt withdrawal from a hydrocodone product.
Winifred A. Landis, R.Ph., a pharmacist in Lafayette, Ind., said that the recommendation for rescheduling was "a knee jerk reaction" and that when prescribed and used appropriately, hydrocodone combination products should remain as schedule III drugs. "Those who are addiction-seeking will find other medications that are available, whether it’s clonazepam, alprazolam, or hydrocodone, and at the same time we’re going to reduce access for those who really need the medication for pain."
Almost all (99%) of hydrocodone used in the world is in the United States, where hydrocodone combination products are the most widely prescribed products: In 2011, there were about 131 million prescriptions for the combination hydrocodone analgesic products, for 47 million people, compared with 34.6 million for oxycodone combination drugs prescribed for 15.1 million patients, according to national prescription data cited by the FDA. About 40% of the hydrocodone combination analgesics are prescribed by primary care practitioners.
Because of indiscriminate prescribing, rogue pain clinics, leftovers in medication cabinets, and other sources, "there’s so much hydrocodone on the street it’s getting into the wrong hands," Joseph Rannazzisi, the deputy assistant administrator in the Drug Enforcement Administration’s office of diversion control, said at the meeting. He described these drugs as a gateway drug to harder drugs for teenagers, who tend to combine it with benzodiazepines and muscle relaxants.
The FDA’s analysis of the national data indicates that hydrocodone products are widely abused. High school students are more likely to abuse hydrocodone products than oxycodone products, because there are so many more hydrocodone prescriptions and wider availability of leftover drugs in homes. However, hydrocodone combination products have lower abuse ratios than oxycodone combination products, according to the FDA reviewers, who acknowledged that calculating accurate abuse ratios is complicated
Panelists strongly recommended close study of the impact of the scheduling change on prescribing practices, abuse, and diversion. There should be a transition period in the rescheduling process so patients with appropriate needs for the drug and prescribers can adjust to the tighter regulations and avoid losing access to the drug abruptly.
Currently, there are 81 products that contain up to 10 mg of hydrocodone per dosage unit with acetaminophen or ibuprofen, and 12 cough suppressant products that contain up to 10 mg of hydrocodone per dosage unit, with chlorpheniramine, homatropine, or pseudoephedrine, according to the FDA. Hydrocodone alone is a schedule II drug, but there is no single-ingredient hydrocodone product available. In December another FDA advisory panel voted against approval of an extended-release, single-ingredient hydrocodone formulation, largely because of what they considered an enormous potential for abuse once it became available.
Parents and other family members of people who had committed suicide or died of overdoses related to hydrocodone products also testified at the meeting, including several who had testified a month earlier at the meeting on the extended-release hydrocodone product, calling for tighter controls on the drug.
Dr. Olbrisch, Dr. Morrato, Dr. Kaboli, Dr. Nelson, Dr. Mendelson, and Ms. Landis are committee members. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. While a panelist may be given a waiver, none were granted at this meeting.
SILVER SPRING, MD. – Vicodin, Norco, and other hydrocodone combination products should be reclassified as schedule II drugs, because stricter controls on prescribing are needed to address the current epidemic of abuse, misuse, and diversion of these products in the United States, the majority of a Food and Drug Administration advisory panel has recommended.
At the end of a 2-day meeting on Jan. 25, the FDA’s Drug Safety and Risk Management Advisory Committee voted 19 to 10 that these products should be rescheduled from schedule III under the Controlled Substances Act (CSA), to schedule II. Schedule III allows written or oral prescribing, and five refills within 6 months, while schedule II drugs require handwritten prescriptions and other restrictions. The meeting was held in response to a request from the U.S. Drug Enforcement Administration that these products be rescheduled because of evidence they are overprescribed, diverted, and abused.
Panelists said that based on the epidemiologic and pharmacologic data presented during the meeting – which they acknowledged had limitations and was somewhat confusing – the abuse potential and pharmacology of hydrocodone combination products were similar to those of oxycodone and other schedule II drugs.
Those voting in favor of rescheduling said that it would result in a net public health benefit by making these drugs less available for abuse and reducing the amount that ends up in medication cabinets and on the street. And they acknowledged that there is little concrete evidence that tighter regulation would reduce the widespread abuse, misuse, and diversion of these products. In addition, rescheduling is likely to have some negative consequences, panelists noted.
"While I don’t think reclassification is some panacea for the opiate use problem in this country, I think it’s an important step in getting physicians to rethink prescribing practices and to look at other approaches in pain management," said Mary Ellen Olbrisch, Ph.D., professor of psychiatry and surgery, Virginia Commonwealth University, Richmond. She added that other measures would be necessary to ensure access to patients with appropriate needs for these drugs, such as legislation in states allowing nonphysician providers to prescribe schedule II drugs.
"For me, the most persuasive argument was that rescheduling is a signal to the public [and] to the medical profession about the abuse potential, and it [corrects] the misperception that hydrocodone combination products are a safer option than class II [agents] when it comes to long-term risk of abuse," added Elaine Morrato, Dr.P.H., of the department of health systems, management and policy, Colorado School of Public Health, Aurora.
Dr. Peter Kaboli, of the department of internal medicine at the University of Iowa, and a hospitalist at the Iowa City Veterans Affairs Medical Center, said that when considering the CSA’s list of factors used to determine scheduling of drugs with abuse potential, "it seemed pretty clear to me that the preponderance of the evidence supported rescheduling." Those factors include the drug’s actual or relative potential for abuse; scientific evidence of its pharmacologic effect; history and current pattern of abuse; and the scope, duration, and significance of abuse.
"We are witnessing the unintended consequences of poorly controlled opioid prescribing now," with people dying and developing hyperalgesia, dependence, and addiction, said Dr. Lewis Nelson, professor of emergency medicine at New York University. While there will be unintended consequences of stricter regulation, these products have become an alternative to heroin, and rescheduling will likely reduce the supply on the street and have a net benefit, he said.
But panelists voting against rescheduling said there was no evidence that rescheduling would have an impact on abuse and diversion, and would likely result in an increase in the use of heroin and other illicit drugs, and problems with other schedule III drugs. They were also concerned about the negative consequences of rescheduling on the treatment of pain, with the increased burden and reduced access to effective pain medications for patients in pain, particularly those in rural areas or those who have difficulty getting to a doctor for a prescription renewal.
Voting no, Dr. John Mendelson, senior scientist in the Addiction and Pharmacology Research Laboratory at St. Luke’s Hospital, San Francisco, said, "The net result will be increased prescribing of other [schedule II] drugs, which may have greater abuse liability and actually fuel rather than reduce an epidemic in progress." Another likely outcome is an increase in illicit opiate use and the abrupt withdrawal of medication for some patients who need it, he added, referring to public testimony at the meeting about people whose suicides were directly related to abrupt withdrawal from a hydrocodone product.
Winifred A. Landis, R.Ph., a pharmacist in Lafayette, Ind., said that the recommendation for rescheduling was "a knee jerk reaction" and that when prescribed and used appropriately, hydrocodone combination products should remain as schedule III drugs. "Those who are addiction-seeking will find other medications that are available, whether it’s clonazepam, alprazolam, or hydrocodone, and at the same time we’re going to reduce access for those who really need the medication for pain."
Almost all (99%) of hydrocodone used in the world is in the United States, where hydrocodone combination products are the most widely prescribed products: In 2011, there were about 131 million prescriptions for the combination hydrocodone analgesic products, for 47 million people, compared with 34.6 million for oxycodone combination drugs prescribed for 15.1 million patients, according to national prescription data cited by the FDA. About 40% of the hydrocodone combination analgesics are prescribed by primary care practitioners.
Because of indiscriminate prescribing, rogue pain clinics, leftovers in medication cabinets, and other sources, "there’s so much hydrocodone on the street it’s getting into the wrong hands," Joseph Rannazzisi, the deputy assistant administrator in the Drug Enforcement Administration’s office of diversion control, said at the meeting. He described these drugs as a gateway drug to harder drugs for teenagers, who tend to combine it with benzodiazepines and muscle relaxants.
The FDA’s analysis of the national data indicates that hydrocodone products are widely abused. High school students are more likely to abuse hydrocodone products than oxycodone products, because there are so many more hydrocodone prescriptions and wider availability of leftover drugs in homes. However, hydrocodone combination products have lower abuse ratios than oxycodone combination products, according to the FDA reviewers, who acknowledged that calculating accurate abuse ratios is complicated
Panelists strongly recommended close study of the impact of the scheduling change on prescribing practices, abuse, and diversion. There should be a transition period in the rescheduling process so patients with appropriate needs for the drug and prescribers can adjust to the tighter regulations and avoid losing access to the drug abruptly.
Currently, there are 81 products that contain up to 10 mg of hydrocodone per dosage unit with acetaminophen or ibuprofen, and 12 cough suppressant products that contain up to 10 mg of hydrocodone per dosage unit, with chlorpheniramine, homatropine, or pseudoephedrine, according to the FDA. Hydrocodone alone is a schedule II drug, but there is no single-ingredient hydrocodone product available. In December another FDA advisory panel voted against approval of an extended-release, single-ingredient hydrocodone formulation, largely because of what they considered an enormous potential for abuse once it became available.
Parents and other family members of people who had committed suicide or died of overdoses related to hydrocodone products also testified at the meeting, including several who had testified a month earlier at the meeting on the extended-release hydrocodone product, calling for tighter controls on the drug.
Dr. Olbrisch, Dr. Morrato, Dr. Kaboli, Dr. Nelson, Dr. Mendelson, and Ms. Landis are committee members. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. While a panelist may be given a waiver, none were granted at this meeting.
AT A MEETING OF THE FDA'S DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE
Lab test for multiple gastroenteritis pathogens cleared for use
A test that can detect multiple causes of infectious gastroenteritis in one stool sample has been cleared for marketing by the Food and Drug Administration.
The xTAG Gastrointestinal Pathogen Panel (GPP), a multiplexed nucleic acid test, is the "first test that can simultaneously detect 11 common viral, bacterial, and parasitic causes of infectious gastroenteritis from a single patient sample," the agency said in a Jan. 14 statement announcing the approval.
The xTAG GPP tests for the bacteria Campylobacter, Clostridium difficile toxin A/B, Escherichia coli O157, enterotoxigenic E. coli (ETEC) LT/ST, Salmonella, Shigella, and Shiga-like toxin-producing E. coli (STEC) stx1/stx2; the viruses norovirus and rotavirus A; and the parasites Cryptosporidium and Giardia lamblia.
This test can help clinicians identify and treat the cause of gastroenteritis in patients more quickly, and "could also allow clinicians and public health professionals to more quickly identify and investigate the source of potential gastroenteritis outbreaks," Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health at the FDA’s Center for Devices and Radiological Health, said in the statement.
In studies conducted by the manufacturer, Luminex, results of the xTAG GPP were "comparable" with the results of individual tests for the 11 pathogens in stool samples from 1,407 patients with suspected infectious gastroenteritis, 313 samples from pediatric patients with suspected infectious gastroenteritis, and 203 samples from patients with confirmed cases of infectious gastroenteritis, according to the FDA. Because of the risk of false positives, "all positive results from the xTAG GPP need to be confirmed by additional testing," the agency’s announcement said.
The test, which is now available in the United States, can provide multiple results within 5 hours. It is the first and most comprehensive multiplexed product of its kind in the United States, according to a statement from Luminex.
The FDA cites data from the Centers for Disease Control and Prevention reporting that the number of deaths associated with gastroenteritis increased from nearly 7,000 to more than 17,000 per year between 1999 and 2007 in the United States. Two-thirds of the deaths were attributed to norovirus and C. difficile.
A test that can detect multiple causes of infectious gastroenteritis in one stool sample has been cleared for marketing by the Food and Drug Administration.
The xTAG Gastrointestinal Pathogen Panel (GPP), a multiplexed nucleic acid test, is the "first test that can simultaneously detect 11 common viral, bacterial, and parasitic causes of infectious gastroenteritis from a single patient sample," the agency said in a Jan. 14 statement announcing the approval.
The xTAG GPP tests for the bacteria Campylobacter, Clostridium difficile toxin A/B, Escherichia coli O157, enterotoxigenic E. coli (ETEC) LT/ST, Salmonella, Shigella, and Shiga-like toxin-producing E. coli (STEC) stx1/stx2; the viruses norovirus and rotavirus A; and the parasites Cryptosporidium and Giardia lamblia.
This test can help clinicians identify and treat the cause of gastroenteritis in patients more quickly, and "could also allow clinicians and public health professionals to more quickly identify and investigate the source of potential gastroenteritis outbreaks," Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health at the FDA’s Center for Devices and Radiological Health, said in the statement.
In studies conducted by the manufacturer, Luminex, results of the xTAG GPP were "comparable" with the results of individual tests for the 11 pathogens in stool samples from 1,407 patients with suspected infectious gastroenteritis, 313 samples from pediatric patients with suspected infectious gastroenteritis, and 203 samples from patients with confirmed cases of infectious gastroenteritis, according to the FDA. Because of the risk of false positives, "all positive results from the xTAG GPP need to be confirmed by additional testing," the agency’s announcement said.
The test, which is now available in the United States, can provide multiple results within 5 hours. It is the first and most comprehensive multiplexed product of its kind in the United States, according to a statement from Luminex.
The FDA cites data from the Centers for Disease Control and Prevention reporting that the number of deaths associated with gastroenteritis increased from nearly 7,000 to more than 17,000 per year between 1999 and 2007 in the United States. Two-thirds of the deaths were attributed to norovirus and C. difficile.
A test that can detect multiple causes of infectious gastroenteritis in one stool sample has been cleared for marketing by the Food and Drug Administration.
The xTAG Gastrointestinal Pathogen Panel (GPP), a multiplexed nucleic acid test, is the "first test that can simultaneously detect 11 common viral, bacterial, and parasitic causes of infectious gastroenteritis from a single patient sample," the agency said in a Jan. 14 statement announcing the approval.
The xTAG GPP tests for the bacteria Campylobacter, Clostridium difficile toxin A/B, Escherichia coli O157, enterotoxigenic E. coli (ETEC) LT/ST, Salmonella, Shigella, and Shiga-like toxin-producing E. coli (STEC) stx1/stx2; the viruses norovirus and rotavirus A; and the parasites Cryptosporidium and Giardia lamblia.
This test can help clinicians identify and treat the cause of gastroenteritis in patients more quickly, and "could also allow clinicians and public health professionals to more quickly identify and investigate the source of potential gastroenteritis outbreaks," Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health at the FDA’s Center for Devices and Radiological Health, said in the statement.
In studies conducted by the manufacturer, Luminex, results of the xTAG GPP were "comparable" with the results of individual tests for the 11 pathogens in stool samples from 1,407 patients with suspected infectious gastroenteritis, 313 samples from pediatric patients with suspected infectious gastroenteritis, and 203 samples from patients with confirmed cases of infectious gastroenteritis, according to the FDA. Because of the risk of false positives, "all positive results from the xTAG GPP need to be confirmed by additional testing," the agency’s announcement said.
The test, which is now available in the United States, can provide multiple results within 5 hours. It is the first and most comprehensive multiplexed product of its kind in the United States, according to a statement from Luminex.
The FDA cites data from the Centers for Disease Control and Prevention reporting that the number of deaths associated with gastroenteritis increased from nearly 7,000 to more than 17,000 per year between 1999 and 2007 in the United States. Two-thirds of the deaths were attributed to norovirus and C. difficile.
IOM issues report on vaccine schedule safety
The available data indicate that the immunization schedule for children through age 6 years is safe, according to a report released by the Institute of Medicine.
The report identifies areas that need more research, however, and makes recommendations about how to study safety issues if safety signals related to the vaccine schedule are identified. The report also concludes that more research is needed on the perception of vaccines and how to improve communications, recommending that the National Vaccine Program Office "systematically collect and assess evidence regarding public confidence in and concerns about the entire childhood immunization schedule, with the goal to improve communication with health care professionals, and between health care professionals and the public regarding the safety of the schedule."
The report, titled "The Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies," was released on Jan. 16. Unlike previous IOM vaccine-related reports, this report focuses on the safety of the childhood vaccination schedule overall, not the safety of individual vaccines.
The 13-member multidisciplinary committee was charged with reviewing the scientific data on health-related outcomes and safety issues associated with the vaccination schedule for children through age 6 years, which entailed public meetings to collect information, with participation from clinicians, federal and state agencies, international public health agencies, advocacy groups, vaccine manufacturers, and other stakeholders. The committee conducted an extensive literature review on vaccine-associated health outcomes and safety of the vaccine schedule, looking at issues that included the number of vaccines, frequency of administration, spacing between doses, cumulative doses, age of recipient, order of vaccine administration, as well as asthma, hypersensitivity, diabetes, and other autoimmune diseases, seizures and epilepsy, autism and other developmental disorders, and other outcomes.
"After our review, our committee found no evidence that the childhood immunization schedule is not safe," committee member Dr. Alfred Berg, professor in the department of family medicine, University of Washington, Seattle, said during a briefing held to announce the release of the report. "The evidence repeatedly points to the health benefits of the recommended schedule, including protecting children and the community from serious and life-threatening diseases."
The recommendations made to the national vaccine program office include standardizing definitions to use in future research, including defining outcomes and potentially susceptible populations. Dr. Berg added that, although there was no basis for concern about the safety of the current schedule, the committee recommended that stakeholder concerns about vaccine safety should be systematically assessed and used to help set priorities for future research when safety signals are detected.
The committee’s review "did not find reveal a base of evidence suggesting that the childhood immunization schedule is linked to autoimmune diseases, asthma, hypersensitivity, seizures or epilepsy, child developmental disorders, learning disorders or developmental disorders, or attention deficit or disruptive behavior disorders," the report concluded. However, although there was no evidence "to justify safety concerns," the report points out that "perceptions dictate parental support and actions," and that further study focused on understanding the perceptions of stakeholders and how their perceptions are formed "may help improve awareness and education efforts." With no epidemiologic or biological evidence to support safety concerns, the concerns alone "do not warrant the initiation of new high-cost randomized controlled trials," the committee concluded.
The report points out that the Vaccine Safety Datalink (VSD), a safety surveillance system, is currently the best tool for evaluating the vaccine safety, although it only tracks people in eight states and does not adequately represent low-income and minority populations. The committee is optimistic about the potential for other surveillance systems that are being developed in their ability to monitor vaccine safety, namely, two Food and Drug Administration programs that will enhance the collection of safety data on vaccines: the Sentinel Initiative program, and the new Post-Licensure Rapid Immunization Safety Monitoring program, which have potential to analyze vaccine exposures and adverse events "with a greater degree of statistical power," according to the report.
Committee member Dr. Elena Fuentes-Afflick, chief of pediatrics at San Francisco General Hospital, said that it is important to maintain and expand the monitoring system to identify rare complications or safety issues affecting particular subgroups. And if there is evidence suggestive of a safety issue, the report outlines research strategies and approaches that can be used to assess whether it is related to the individual vaccine or immunization schedule, she said. “It’s very difficult to do a study which would allow you to state how much of a difference is related to either an individual vaccine or to the vaccine schedule.” She noted that the report recommends against conducting a randomized controlled trial in this situation, because of feasibility, practical and ethical concerns related to a randomized trial that would compare vaccination to no vaccination.
As for the communication issue, pediatricians, public health officials, and other health care professionals “struggle” with how to communicate vaccine-related information “succinctly and in a way that is factual, understandable, and that invites conversation and dialogue,” said Dr. Fuentes-Afflick, who is also professor and vice-chair of pediatrics, and professor of epidemiology and biostatistics at the University of California, San Francisco.
With the recommendations made in this report, “we hope that in the future we will develop better tools and mechanisms to have that open communication around immunization issues,” she added.*
The IOM report was sponsored by the U.S. Department of Health and Human Services. The IOM consensus studies are conducted by committees carefully composed to ensure the requisite expertise and to avoid conflicts of interest.
*Update: This article was updated 1/18/2013.
The available data indicate that the immunization schedule for children through age 6 years is safe, according to a report released by the Institute of Medicine.
The report identifies areas that need more research, however, and makes recommendations about how to study safety issues if safety signals related to the vaccine schedule are identified. The report also concludes that more research is needed on the perception of vaccines and how to improve communications, recommending that the National Vaccine Program Office "systematically collect and assess evidence regarding public confidence in and concerns about the entire childhood immunization schedule, with the goal to improve communication with health care professionals, and between health care professionals and the public regarding the safety of the schedule."
The report, titled "The Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies," was released on Jan. 16. Unlike previous IOM vaccine-related reports, this report focuses on the safety of the childhood vaccination schedule overall, not the safety of individual vaccines.
The 13-member multidisciplinary committee was charged with reviewing the scientific data on health-related outcomes and safety issues associated with the vaccination schedule for children through age 6 years, which entailed public meetings to collect information, with participation from clinicians, federal and state agencies, international public health agencies, advocacy groups, vaccine manufacturers, and other stakeholders. The committee conducted an extensive literature review on vaccine-associated health outcomes and safety of the vaccine schedule, looking at issues that included the number of vaccines, frequency of administration, spacing between doses, cumulative doses, age of recipient, order of vaccine administration, as well as asthma, hypersensitivity, diabetes, and other autoimmune diseases, seizures and epilepsy, autism and other developmental disorders, and other outcomes.
"After our review, our committee found no evidence that the childhood immunization schedule is not safe," committee member Dr. Alfred Berg, professor in the department of family medicine, University of Washington, Seattle, said during a briefing held to announce the release of the report. "The evidence repeatedly points to the health benefits of the recommended schedule, including protecting children and the community from serious and life-threatening diseases."
The recommendations made to the national vaccine program office include standardizing definitions to use in future research, including defining outcomes and potentially susceptible populations. Dr. Berg added that, although there was no basis for concern about the safety of the current schedule, the committee recommended that stakeholder concerns about vaccine safety should be systematically assessed and used to help set priorities for future research when safety signals are detected.
The committee’s review "did not find reveal a base of evidence suggesting that the childhood immunization schedule is linked to autoimmune diseases, asthma, hypersensitivity, seizures or epilepsy, child developmental disorders, learning disorders or developmental disorders, or attention deficit or disruptive behavior disorders," the report concluded. However, although there was no evidence "to justify safety concerns," the report points out that "perceptions dictate parental support and actions," and that further study focused on understanding the perceptions of stakeholders and how their perceptions are formed "may help improve awareness and education efforts." With no epidemiologic or biological evidence to support safety concerns, the concerns alone "do not warrant the initiation of new high-cost randomized controlled trials," the committee concluded.
The report points out that the Vaccine Safety Datalink (VSD), a safety surveillance system, is currently the best tool for evaluating the vaccine safety, although it only tracks people in eight states and does not adequately represent low-income and minority populations. The committee is optimistic about the potential for other surveillance systems that are being developed in their ability to monitor vaccine safety, namely, two Food and Drug Administration programs that will enhance the collection of safety data on vaccines: the Sentinel Initiative program, and the new Post-Licensure Rapid Immunization Safety Monitoring program, which have potential to analyze vaccine exposures and adverse events "with a greater degree of statistical power," according to the report.
Committee member Dr. Elena Fuentes-Afflick, chief of pediatrics at San Francisco General Hospital, said that it is important to maintain and expand the monitoring system to identify rare complications or safety issues affecting particular subgroups. And if there is evidence suggestive of a safety issue, the report outlines research strategies and approaches that can be used to assess whether it is related to the individual vaccine or immunization schedule, she said. “It’s very difficult to do a study which would allow you to state how much of a difference is related to either an individual vaccine or to the vaccine schedule.” She noted that the report recommends against conducting a randomized controlled trial in this situation, because of feasibility, practical and ethical concerns related to a randomized trial that would compare vaccination to no vaccination.
As for the communication issue, pediatricians, public health officials, and other health care professionals “struggle” with how to communicate vaccine-related information “succinctly and in a way that is factual, understandable, and that invites conversation and dialogue,” said Dr. Fuentes-Afflick, who is also professor and vice-chair of pediatrics, and professor of epidemiology and biostatistics at the University of California, San Francisco.
With the recommendations made in this report, “we hope that in the future we will develop better tools and mechanisms to have that open communication around immunization issues,” she added.*
The IOM report was sponsored by the U.S. Department of Health and Human Services. The IOM consensus studies are conducted by committees carefully composed to ensure the requisite expertise and to avoid conflicts of interest.
*Update: This article was updated 1/18/2013.
The available data indicate that the immunization schedule for children through age 6 years is safe, according to a report released by the Institute of Medicine.
The report identifies areas that need more research, however, and makes recommendations about how to study safety issues if safety signals related to the vaccine schedule are identified. The report also concludes that more research is needed on the perception of vaccines and how to improve communications, recommending that the National Vaccine Program Office "systematically collect and assess evidence regarding public confidence in and concerns about the entire childhood immunization schedule, with the goal to improve communication with health care professionals, and between health care professionals and the public regarding the safety of the schedule."
The report, titled "The Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies," was released on Jan. 16. Unlike previous IOM vaccine-related reports, this report focuses on the safety of the childhood vaccination schedule overall, not the safety of individual vaccines.
The 13-member multidisciplinary committee was charged with reviewing the scientific data on health-related outcomes and safety issues associated with the vaccination schedule for children through age 6 years, which entailed public meetings to collect information, with participation from clinicians, federal and state agencies, international public health agencies, advocacy groups, vaccine manufacturers, and other stakeholders. The committee conducted an extensive literature review on vaccine-associated health outcomes and safety of the vaccine schedule, looking at issues that included the number of vaccines, frequency of administration, spacing between doses, cumulative doses, age of recipient, order of vaccine administration, as well as asthma, hypersensitivity, diabetes, and other autoimmune diseases, seizures and epilepsy, autism and other developmental disorders, and other outcomes.
"After our review, our committee found no evidence that the childhood immunization schedule is not safe," committee member Dr. Alfred Berg, professor in the department of family medicine, University of Washington, Seattle, said during a briefing held to announce the release of the report. "The evidence repeatedly points to the health benefits of the recommended schedule, including protecting children and the community from serious and life-threatening diseases."
The recommendations made to the national vaccine program office include standardizing definitions to use in future research, including defining outcomes and potentially susceptible populations. Dr. Berg added that, although there was no basis for concern about the safety of the current schedule, the committee recommended that stakeholder concerns about vaccine safety should be systematically assessed and used to help set priorities for future research when safety signals are detected.
The committee’s review "did not find reveal a base of evidence suggesting that the childhood immunization schedule is linked to autoimmune diseases, asthma, hypersensitivity, seizures or epilepsy, child developmental disorders, learning disorders or developmental disorders, or attention deficit or disruptive behavior disorders," the report concluded. However, although there was no evidence "to justify safety concerns," the report points out that "perceptions dictate parental support and actions," and that further study focused on understanding the perceptions of stakeholders and how their perceptions are formed "may help improve awareness and education efforts." With no epidemiologic or biological evidence to support safety concerns, the concerns alone "do not warrant the initiation of new high-cost randomized controlled trials," the committee concluded.
The report points out that the Vaccine Safety Datalink (VSD), a safety surveillance system, is currently the best tool for evaluating the vaccine safety, although it only tracks people in eight states and does not adequately represent low-income and minority populations. The committee is optimistic about the potential for other surveillance systems that are being developed in their ability to monitor vaccine safety, namely, two Food and Drug Administration programs that will enhance the collection of safety data on vaccines: the Sentinel Initiative program, and the new Post-Licensure Rapid Immunization Safety Monitoring program, which have potential to analyze vaccine exposures and adverse events "with a greater degree of statistical power," according to the report.
Committee member Dr. Elena Fuentes-Afflick, chief of pediatrics at San Francisco General Hospital, said that it is important to maintain and expand the monitoring system to identify rare complications or safety issues affecting particular subgroups. And if there is evidence suggestive of a safety issue, the report outlines research strategies and approaches that can be used to assess whether it is related to the individual vaccine or immunization schedule, she said. “It’s very difficult to do a study which would allow you to state how much of a difference is related to either an individual vaccine or to the vaccine schedule.” She noted that the report recommends against conducting a randomized controlled trial in this situation, because of feasibility, practical and ethical concerns related to a randomized trial that would compare vaccination to no vaccination.
As for the communication issue, pediatricians, public health officials, and other health care professionals “struggle” with how to communicate vaccine-related information “succinctly and in a way that is factual, understandable, and that invites conversation and dialogue,” said Dr. Fuentes-Afflick, who is also professor and vice-chair of pediatrics, and professor of epidemiology and biostatistics at the University of California, San Francisco.
With the recommendations made in this report, “we hope that in the future we will develop better tools and mechanisms to have that open communication around immunization issues,” she added.*
The IOM report was sponsored by the U.S. Department of Health and Human Services. The IOM consensus studies are conducted by committees carefully composed to ensure the requisite expertise and to avoid conflicts of interest.
*Update: This article was updated 1/18/2013.
FROM THE INSTITUTE OF MEDICINE
FDA panel backs approval of canagliflozin for type 2 diabetes
SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of canagliflozin for the treatment of type 2 diabetes with caveats, including precautions about its use in patients with moderately impaired renal function and recommendations to continue to evaluate cardiovascular safety after approval.
At a meeting on Jan. 10, FDA’s Endocrinologic and Metabolic Drugs Advisory voted 10-5 to recommend approval of the selective sodium glucose cotransporter 2 (SGLT2) inhibitor for treating type 2 diabetes, based on the available safety and efficacy data on canagliflozin, which blocks the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels.
The proposed indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, taken by mouth at a dose of 100 mg or 300 mg once a day, before the first meal of the day. If approved, the drug would be the first SGLT2 inhibitor to be approved by the FDA. Primarily expressed by the kidney, SGLT2 is responsible for the majority of renal glucose reabsorption.
The manufacturer, Janssen Pharmaceuticals, submitted the results of nine phase III international studies in almost 10,300 patients with type 2 diabetes, comparing the drug with placebo or active controls, as monotherapy and as add-on therapy to other antihyperglycemic drugs; and the interim results of a cardiovascular outcomes study, required by the FDA for all new type 2 diabetes drugs. In the outcomes study, there was an imbalance in the rate of major adverse cardiovascular events (mostly strokes), with more cases among the canagliflozin-treated patients in the first 30 days, but the risk dropped after 30 days to below the threshold – a hazard ratio of 1.8 – set by the FDA as an acceptable CV risk for a new type 2 diabetes treatment.
Panelists voting on both sides noted that the risk-benefit profile was less clear-cut in patients with impaired renal function, since canagliflozin was less effective and was associated with more adverse events as renal function decreased. Those voting in favor of approval said that, although they were uncertain about the imbalance in CV events during the first 30 days of treatment, they were reassured by the available data available so far. In another vote, 8 of the 15 panel members, including several who supported approval, said they still had concerns about whether the risk had been excluded for the drug and agreed that more data were needed.
Other safety issues that panelists said should be monitored after approval included the potential long-term effects of the dose dependent increase in LDL cholesterol associated with canagliflozin treatment, and the impact of treatment on bone density and fractures. In the studies, there were more fractures among patients treated with canagliflozin – mostly low trauma upper limb fracture, but the difference was not statistically significant.
The panel chair, Dr. Abraham Thomas, the head of the division of endocrinology, diabetes, bone, and mineral disorders at Henry Ford Hospital in Detroit, voted in favor of approval, citing the "definite benefits" of the drug, but added that he, like other panelists, still had concerns regarding safety. More data are needed to determine whether the increase in adverse cardiovascular outcomes –stroke in particular – is a real issue or "a red herring," he said. Once approved, long-term follow-up of safety issues such as the effects of treatment on cardiovascular risk and bone should be evaluated in long-term registry studies, since they can be difficult to identify in clinical trials, he added.
Voting against approval, Dr. William Knowler, chief of the diabetes epidemiology and clinical research section at the Phoenix branch of the National Institute of Diabetes and Digestive and Kidney Diseases, said that he would support approval of the drug as an add-on therapy but not as an initial treatment because there were no data comparing canagliflozin to metformin, the standard initial therapy recommended by American Diabetes Association/European Association for the Study of Diabetes treatment guidelines. "I think the drug would be acceptable as add-on therapy for some patients, but for a general indication including monotherapy, I cannot recommend it," he said.
Cardiologist William Hiatt, professor of medicine at the University of Colorado, Denver, said that he voted against approval because the cardiovascular risks had not been fully evaluated and that his residual concerns about safety could be resolved once the cardiovascular outcomes study was completed.
In the phase III studies, treatment with canagliflozin resulted in significant improvements in glycemic control, based on the primary endpoint, changes in hemoglobin A1c from baseline to the end of the study, with sustained responses over 52 weeks and a large proportion of patients achieving glycemic goals, according to Janssen. Treatment in patients with renal impairment was also associated with reductions in HbA1c, which were of less magnitude than the reductions seen in patients with normal kidney function. Other favorable effects associated with canagliflozin included decreased body weight and reductions in systolic blood pressure.
Adverse effects associated with canagliflozin included genital mycotic infections in both men and women. Urinary tract infections, urinary frequency or thirst, and other adverse events related to osmotic diuresis, and adverse events related to reductions in intravascular volume, such as postural hypotension, were also higher among those on canagliflozin. However, the discontinuation rate from adverse events was low, and the incidence of serious adverse events and deaths were similar among those on canagliflozin and controls. There was also a "modest" dose-dependent increase in bone resorption associated with the drug in studies, which the company said could be caused by weight loss. Renal adverse events were higher among those on canagliflozin, compared with placebo, and led to a higher discontinuation rate among those on 300 mg.
The cardiovascular outcome study CANVAS, is comparing the rate of a composite major adverse cardiovascular event (MACE) endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina) in about 4,300 patients at high risk of CV disease, with a 2:1 randomization. In the first 30 days of treatment, there were 13 events among those on canagliflozin (including six strokes, one of which was a fatal ischemic stroke), and one event in placebo patients in the first 30 days of treatment, an imbalance the company said reflected the month-to month variability and was not associated with adverse events related to volume depletion. The hazard ratio for MACE-plus events in the first 30 days of the cardiovascular outcomes study was 6.49, dropping to 0.89 after 30 days, and was 0.64 in other studies, according to the FDA.
Janssen is recommending a starting dose of 100 mg for patients on a loop diuretic, patients with moderate renal impairment (eGFR 30 to less than 60 mL/min per 1.73m2), or those who are aged 75 years and older, because these groups of patients were at higher risk of adverse reactions related to volume depletion in the studies. Because it would not be effective, canagliflozin would not be used in patients with severe renal impairment (eGFR less than 30 mL/min per 1.73m2), end stage renal disease, or in patients on dialysis.
Another SGLT2 inhibitor, dapagliflozin, was not approved by the FDA, presumably because of potential increases in the risk of bladder and breast cancers associated with the drug. If approved, Janssen plans to market canagliflozin as Invokana.* In December 2012, the company submitted an application for approval of a combined fixed dose formulation of canagliflozin with immediate-release metformin.
Canagliflozin, which is also under review for approval in the European Union, has not yet been approved anywhere. The FDA’s deadline for making a decision on approval is the end of March. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
*Correction, 1/15/13: An earlier version of this story misspelled Invokana.
SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of canagliflozin for the treatment of type 2 diabetes with caveats, including precautions about its use in patients with moderately impaired renal function and recommendations to continue to evaluate cardiovascular safety after approval.
At a meeting on Jan. 10, FDA’s Endocrinologic and Metabolic Drugs Advisory voted 10-5 to recommend approval of the selective sodium glucose cotransporter 2 (SGLT2) inhibitor for treating type 2 diabetes, based on the available safety and efficacy data on canagliflozin, which blocks the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels.
The proposed indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, taken by mouth at a dose of 100 mg or 300 mg once a day, before the first meal of the day. If approved, the drug would be the first SGLT2 inhibitor to be approved by the FDA. Primarily expressed by the kidney, SGLT2 is responsible for the majority of renal glucose reabsorption.
The manufacturer, Janssen Pharmaceuticals, submitted the results of nine phase III international studies in almost 10,300 patients with type 2 diabetes, comparing the drug with placebo or active controls, as monotherapy and as add-on therapy to other antihyperglycemic drugs; and the interim results of a cardiovascular outcomes study, required by the FDA for all new type 2 diabetes drugs. In the outcomes study, there was an imbalance in the rate of major adverse cardiovascular events (mostly strokes), with more cases among the canagliflozin-treated patients in the first 30 days, but the risk dropped after 30 days to below the threshold – a hazard ratio of 1.8 – set by the FDA as an acceptable CV risk for a new type 2 diabetes treatment.
Panelists voting on both sides noted that the risk-benefit profile was less clear-cut in patients with impaired renal function, since canagliflozin was less effective and was associated with more adverse events as renal function decreased. Those voting in favor of approval said that, although they were uncertain about the imbalance in CV events during the first 30 days of treatment, they were reassured by the available data available so far. In another vote, 8 of the 15 panel members, including several who supported approval, said they still had concerns about whether the risk had been excluded for the drug and agreed that more data were needed.
Other safety issues that panelists said should be monitored after approval included the potential long-term effects of the dose dependent increase in LDL cholesterol associated with canagliflozin treatment, and the impact of treatment on bone density and fractures. In the studies, there were more fractures among patients treated with canagliflozin – mostly low trauma upper limb fracture, but the difference was not statistically significant.
The panel chair, Dr. Abraham Thomas, the head of the division of endocrinology, diabetes, bone, and mineral disorders at Henry Ford Hospital in Detroit, voted in favor of approval, citing the "definite benefits" of the drug, but added that he, like other panelists, still had concerns regarding safety. More data are needed to determine whether the increase in adverse cardiovascular outcomes –stroke in particular – is a real issue or "a red herring," he said. Once approved, long-term follow-up of safety issues such as the effects of treatment on cardiovascular risk and bone should be evaluated in long-term registry studies, since they can be difficult to identify in clinical trials, he added.
Voting against approval, Dr. William Knowler, chief of the diabetes epidemiology and clinical research section at the Phoenix branch of the National Institute of Diabetes and Digestive and Kidney Diseases, said that he would support approval of the drug as an add-on therapy but not as an initial treatment because there were no data comparing canagliflozin to metformin, the standard initial therapy recommended by American Diabetes Association/European Association for the Study of Diabetes treatment guidelines. "I think the drug would be acceptable as add-on therapy for some patients, but for a general indication including monotherapy, I cannot recommend it," he said.
Cardiologist William Hiatt, professor of medicine at the University of Colorado, Denver, said that he voted against approval because the cardiovascular risks had not been fully evaluated and that his residual concerns about safety could be resolved once the cardiovascular outcomes study was completed.
In the phase III studies, treatment with canagliflozin resulted in significant improvements in glycemic control, based on the primary endpoint, changes in hemoglobin A1c from baseline to the end of the study, with sustained responses over 52 weeks and a large proportion of patients achieving glycemic goals, according to Janssen. Treatment in patients with renal impairment was also associated with reductions in HbA1c, which were of less magnitude than the reductions seen in patients with normal kidney function. Other favorable effects associated with canagliflozin included decreased body weight and reductions in systolic blood pressure.
Adverse effects associated with canagliflozin included genital mycotic infections in both men and women. Urinary tract infections, urinary frequency or thirst, and other adverse events related to osmotic diuresis, and adverse events related to reductions in intravascular volume, such as postural hypotension, were also higher among those on canagliflozin. However, the discontinuation rate from adverse events was low, and the incidence of serious adverse events and deaths were similar among those on canagliflozin and controls. There was also a "modest" dose-dependent increase in bone resorption associated with the drug in studies, which the company said could be caused by weight loss. Renal adverse events were higher among those on canagliflozin, compared with placebo, and led to a higher discontinuation rate among those on 300 mg.
The cardiovascular outcome study CANVAS, is comparing the rate of a composite major adverse cardiovascular event (MACE) endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina) in about 4,300 patients at high risk of CV disease, with a 2:1 randomization. In the first 30 days of treatment, there were 13 events among those on canagliflozin (including six strokes, one of which was a fatal ischemic stroke), and one event in placebo patients in the first 30 days of treatment, an imbalance the company said reflected the month-to month variability and was not associated with adverse events related to volume depletion. The hazard ratio for MACE-plus events in the first 30 days of the cardiovascular outcomes study was 6.49, dropping to 0.89 after 30 days, and was 0.64 in other studies, according to the FDA.
Janssen is recommending a starting dose of 100 mg for patients on a loop diuretic, patients with moderate renal impairment (eGFR 30 to less than 60 mL/min per 1.73m2), or those who are aged 75 years and older, because these groups of patients were at higher risk of adverse reactions related to volume depletion in the studies. Because it would not be effective, canagliflozin would not be used in patients with severe renal impairment (eGFR less than 30 mL/min per 1.73m2), end stage renal disease, or in patients on dialysis.
Another SGLT2 inhibitor, dapagliflozin, was not approved by the FDA, presumably because of potential increases in the risk of bladder and breast cancers associated with the drug. If approved, Janssen plans to market canagliflozin as Invokana.* In December 2012, the company submitted an application for approval of a combined fixed dose formulation of canagliflozin with immediate-release metformin.
Canagliflozin, which is also under review for approval in the European Union, has not yet been approved anywhere. The FDA’s deadline for making a decision on approval is the end of March. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
*Correction, 1/15/13: An earlier version of this story misspelled Invokana.
SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of canagliflozin for the treatment of type 2 diabetes with caveats, including precautions about its use in patients with moderately impaired renal function and recommendations to continue to evaluate cardiovascular safety after approval.
At a meeting on Jan. 10, FDA’s Endocrinologic and Metabolic Drugs Advisory voted 10-5 to recommend approval of the selective sodium glucose cotransporter 2 (SGLT2) inhibitor for treating type 2 diabetes, based on the available safety and efficacy data on canagliflozin, which blocks the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels.
The proposed indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, taken by mouth at a dose of 100 mg or 300 mg once a day, before the first meal of the day. If approved, the drug would be the first SGLT2 inhibitor to be approved by the FDA. Primarily expressed by the kidney, SGLT2 is responsible for the majority of renal glucose reabsorption.
The manufacturer, Janssen Pharmaceuticals, submitted the results of nine phase III international studies in almost 10,300 patients with type 2 diabetes, comparing the drug with placebo or active controls, as monotherapy and as add-on therapy to other antihyperglycemic drugs; and the interim results of a cardiovascular outcomes study, required by the FDA for all new type 2 diabetes drugs. In the outcomes study, there was an imbalance in the rate of major adverse cardiovascular events (mostly strokes), with more cases among the canagliflozin-treated patients in the first 30 days, but the risk dropped after 30 days to below the threshold – a hazard ratio of 1.8 – set by the FDA as an acceptable CV risk for a new type 2 diabetes treatment.
Panelists voting on both sides noted that the risk-benefit profile was less clear-cut in patients with impaired renal function, since canagliflozin was less effective and was associated with more adverse events as renal function decreased. Those voting in favor of approval said that, although they were uncertain about the imbalance in CV events during the first 30 days of treatment, they were reassured by the available data available so far. In another vote, 8 of the 15 panel members, including several who supported approval, said they still had concerns about whether the risk had been excluded for the drug and agreed that more data were needed.
Other safety issues that panelists said should be monitored after approval included the potential long-term effects of the dose dependent increase in LDL cholesterol associated with canagliflozin treatment, and the impact of treatment on bone density and fractures. In the studies, there were more fractures among patients treated with canagliflozin – mostly low trauma upper limb fracture, but the difference was not statistically significant.
The panel chair, Dr. Abraham Thomas, the head of the division of endocrinology, diabetes, bone, and mineral disorders at Henry Ford Hospital in Detroit, voted in favor of approval, citing the "definite benefits" of the drug, but added that he, like other panelists, still had concerns regarding safety. More data are needed to determine whether the increase in adverse cardiovascular outcomes –stroke in particular – is a real issue or "a red herring," he said. Once approved, long-term follow-up of safety issues such as the effects of treatment on cardiovascular risk and bone should be evaluated in long-term registry studies, since they can be difficult to identify in clinical trials, he added.
Voting against approval, Dr. William Knowler, chief of the diabetes epidemiology and clinical research section at the Phoenix branch of the National Institute of Diabetes and Digestive and Kidney Diseases, said that he would support approval of the drug as an add-on therapy but not as an initial treatment because there were no data comparing canagliflozin to metformin, the standard initial therapy recommended by American Diabetes Association/European Association for the Study of Diabetes treatment guidelines. "I think the drug would be acceptable as add-on therapy for some patients, but for a general indication including monotherapy, I cannot recommend it," he said.
Cardiologist William Hiatt, professor of medicine at the University of Colorado, Denver, said that he voted against approval because the cardiovascular risks had not been fully evaluated and that his residual concerns about safety could be resolved once the cardiovascular outcomes study was completed.
In the phase III studies, treatment with canagliflozin resulted in significant improvements in glycemic control, based on the primary endpoint, changes in hemoglobin A1c from baseline to the end of the study, with sustained responses over 52 weeks and a large proportion of patients achieving glycemic goals, according to Janssen. Treatment in patients with renal impairment was also associated with reductions in HbA1c, which were of less magnitude than the reductions seen in patients with normal kidney function. Other favorable effects associated with canagliflozin included decreased body weight and reductions in systolic blood pressure.
Adverse effects associated with canagliflozin included genital mycotic infections in both men and women. Urinary tract infections, urinary frequency or thirst, and other adverse events related to osmotic diuresis, and adverse events related to reductions in intravascular volume, such as postural hypotension, were also higher among those on canagliflozin. However, the discontinuation rate from adverse events was low, and the incidence of serious adverse events and deaths were similar among those on canagliflozin and controls. There was also a "modest" dose-dependent increase in bone resorption associated with the drug in studies, which the company said could be caused by weight loss. Renal adverse events were higher among those on canagliflozin, compared with placebo, and led to a higher discontinuation rate among those on 300 mg.
The cardiovascular outcome study CANVAS, is comparing the rate of a composite major adverse cardiovascular event (MACE) endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina) in about 4,300 patients at high risk of CV disease, with a 2:1 randomization. In the first 30 days of treatment, there were 13 events among those on canagliflozin (including six strokes, one of which was a fatal ischemic stroke), and one event in placebo patients in the first 30 days of treatment, an imbalance the company said reflected the month-to month variability and was not associated with adverse events related to volume depletion. The hazard ratio for MACE-plus events in the first 30 days of the cardiovascular outcomes study was 6.49, dropping to 0.89 after 30 days, and was 0.64 in other studies, according to the FDA.
Janssen is recommending a starting dose of 100 mg for patients on a loop diuretic, patients with moderate renal impairment (eGFR 30 to less than 60 mL/min per 1.73m2), or those who are aged 75 years and older, because these groups of patients were at higher risk of adverse reactions related to volume depletion in the studies. Because it would not be effective, canagliflozin would not be used in patients with severe renal impairment (eGFR less than 30 mL/min per 1.73m2), end stage renal disease, or in patients on dialysis.
Another SGLT2 inhibitor, dapagliflozin, was not approved by the FDA, presumably because of potential increases in the risk of bladder and breast cancers associated with the drug. If approved, Janssen plans to market canagliflozin as Invokana.* In December 2012, the company submitted an application for approval of a combined fixed dose formulation of canagliflozin with immediate-release metformin.
Canagliflozin, which is also under review for approval in the European Union, has not yet been approved anywhere. The FDA’s deadline for making a decision on approval is the end of March. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
*Correction, 1/15/13: An earlier version of this story misspelled Invokana.
FROM A MEETING OF THE FDA'S ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE
FDA proposal encourages development of abuse deterrent opioids
Encouraging manufacturers to develop opioid products that are formulated to deter abuse is one of the main goals of a new draft guidance released Jan. 9 by the Food and Drug Administration.
"Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling" provides information for companies interested in developing formulations of opioids with potential abuse deterrent properties, Dr. Douglas Throckmorton, deputy director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, said at a briefing.
The document explains the agency’s views on the types of studies that should be conducted to show that a product can deter abuse, how those studies will be evaluated by the agency, and what labeling claims would be allowed based on the results of the FDA’s evaluations of those data. The ability to add abuse deterrent claims to a product’s label is expected to encourage companies to develop these products, he said.
The technology of formulations that deter abuse and the clinical epidemiology and statistical methods used to evaluate the potential of such products for abuse deterrence is a relatively new area of research, and the FDA plans "to take a flexible approach" in evaluating these products as the science evolves, Dr. Throckmorton said.
During the briefing, he pointed out that the guidance is one of the components of the FDA’s effort to prevent prescription drug abuse and misuse, "while ensuring patients in pain continue to have access to these medicines." In 2009, almost 425,000 visits to emergency departments involving nonmedical or inappropriate use of opioids and an estimated 15,600 deaths in the United States were attributed to opioid products, he said.
This draft guidance fulfills mandates under the Food and Drug Administration Safety and Innovation Act and the Office of National Drug Control Policy’s Prescription Drug Abuse Prevention Plan.
The FDA statement announcing the guidance explains that abuse deterrent formulations "target the known or expected routes of abuse, such as crushing in order to snort or dissolving in order to inject, for the specific opioid drug substance in that formulation" and that the agency believes these formulations have "promise to help reduce prescription drug abuse."
Two opioid products with abuse deterrent formulations are currently available: Since 2010, OxyContin (controlled-release oxycodone) has been available in a formulation that prevents it from being chewed, crushed, or dissolved. A crush-resistant formulation of hydromorphone (Opana ER) was approved in September 2012. But the prescribing information for these products do not include claims regarding abuse deterrence properties.
The lack of abuse deterrent features was the main reason an FDA advisory panel recommended against approval of an extended-release, single-ingredient capsule formulation of hydrocodone at a meeting in December. Without such a feature, the product would quickly become widely abused once it was approved and marketed, some of the panelists predicted.
The FDA plans to hold a public meeting to discuss public feedback on the draft guidance.
During the briefing, Dr. Throckmorton said that the FDA had not yet decided what to do about generic formulations of opioids that have no abuse deterrent properties.
The guidance "is an important part of a larger effort by FDA aimed at preventing prescription drug abuse and misuse," and the agency is "extremely concerned about the inappropriate use of prescription opioids, which is a major public health challenge for our nation," FDA commissioner Dr. Margaret Hamburg said in the statement.
Comments and suggestions can be submitted to the FDA within 60 days of publication in the Federal Register, to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, Md., 20852 , with the docket number listed.
Encouraging manufacturers to develop opioid products that are formulated to deter abuse is one of the main goals of a new draft guidance released Jan. 9 by the Food and Drug Administration.
"Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling" provides information for companies interested in developing formulations of opioids with potential abuse deterrent properties, Dr. Douglas Throckmorton, deputy director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, said at a briefing.
The document explains the agency’s views on the types of studies that should be conducted to show that a product can deter abuse, how those studies will be evaluated by the agency, and what labeling claims would be allowed based on the results of the FDA’s evaluations of those data. The ability to add abuse deterrent claims to a product’s label is expected to encourage companies to develop these products, he said.
The technology of formulations that deter abuse and the clinical epidemiology and statistical methods used to evaluate the potential of such products for abuse deterrence is a relatively new area of research, and the FDA plans "to take a flexible approach" in evaluating these products as the science evolves, Dr. Throckmorton said.
During the briefing, he pointed out that the guidance is one of the components of the FDA’s effort to prevent prescription drug abuse and misuse, "while ensuring patients in pain continue to have access to these medicines." In 2009, almost 425,000 visits to emergency departments involving nonmedical or inappropriate use of opioids and an estimated 15,600 deaths in the United States were attributed to opioid products, he said.
This draft guidance fulfills mandates under the Food and Drug Administration Safety and Innovation Act and the Office of National Drug Control Policy’s Prescription Drug Abuse Prevention Plan.
The FDA statement announcing the guidance explains that abuse deterrent formulations "target the known or expected routes of abuse, such as crushing in order to snort or dissolving in order to inject, for the specific opioid drug substance in that formulation" and that the agency believes these formulations have "promise to help reduce prescription drug abuse."
Two opioid products with abuse deterrent formulations are currently available: Since 2010, OxyContin (controlled-release oxycodone) has been available in a formulation that prevents it from being chewed, crushed, or dissolved. A crush-resistant formulation of hydromorphone (Opana ER) was approved in September 2012. But the prescribing information for these products do not include claims regarding abuse deterrence properties.
The lack of abuse deterrent features was the main reason an FDA advisory panel recommended against approval of an extended-release, single-ingredient capsule formulation of hydrocodone at a meeting in December. Without such a feature, the product would quickly become widely abused once it was approved and marketed, some of the panelists predicted.
The FDA plans to hold a public meeting to discuss public feedback on the draft guidance.
During the briefing, Dr. Throckmorton said that the FDA had not yet decided what to do about generic formulations of opioids that have no abuse deterrent properties.
The guidance "is an important part of a larger effort by FDA aimed at preventing prescription drug abuse and misuse," and the agency is "extremely concerned about the inappropriate use of prescription opioids, which is a major public health challenge for our nation," FDA commissioner Dr. Margaret Hamburg said in the statement.
Comments and suggestions can be submitted to the FDA within 60 days of publication in the Federal Register, to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, Md., 20852 , with the docket number listed.
Encouraging manufacturers to develop opioid products that are formulated to deter abuse is one of the main goals of a new draft guidance released Jan. 9 by the Food and Drug Administration.
"Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling" provides information for companies interested in developing formulations of opioids with potential abuse deterrent properties, Dr. Douglas Throckmorton, deputy director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, said at a briefing.
The document explains the agency’s views on the types of studies that should be conducted to show that a product can deter abuse, how those studies will be evaluated by the agency, and what labeling claims would be allowed based on the results of the FDA’s evaluations of those data. The ability to add abuse deterrent claims to a product’s label is expected to encourage companies to develop these products, he said.
The technology of formulations that deter abuse and the clinical epidemiology and statistical methods used to evaluate the potential of such products for abuse deterrence is a relatively new area of research, and the FDA plans "to take a flexible approach" in evaluating these products as the science evolves, Dr. Throckmorton said.
During the briefing, he pointed out that the guidance is one of the components of the FDA’s effort to prevent prescription drug abuse and misuse, "while ensuring patients in pain continue to have access to these medicines." In 2009, almost 425,000 visits to emergency departments involving nonmedical or inappropriate use of opioids and an estimated 15,600 deaths in the United States were attributed to opioid products, he said.
This draft guidance fulfills mandates under the Food and Drug Administration Safety and Innovation Act and the Office of National Drug Control Policy’s Prescription Drug Abuse Prevention Plan.
The FDA statement announcing the guidance explains that abuse deterrent formulations "target the known or expected routes of abuse, such as crushing in order to snort or dissolving in order to inject, for the specific opioid drug substance in that formulation" and that the agency believes these formulations have "promise to help reduce prescription drug abuse."
Two opioid products with abuse deterrent formulations are currently available: Since 2010, OxyContin (controlled-release oxycodone) has been available in a formulation that prevents it from being chewed, crushed, or dissolved. A crush-resistant formulation of hydromorphone (Opana ER) was approved in September 2012. But the prescribing information for these products do not include claims regarding abuse deterrence properties.
The lack of abuse deterrent features was the main reason an FDA advisory panel recommended against approval of an extended-release, single-ingredient capsule formulation of hydrocodone at a meeting in December. Without such a feature, the product would quickly become widely abused once it was approved and marketed, some of the panelists predicted.
The FDA plans to hold a public meeting to discuss public feedback on the draft guidance.
During the briefing, Dr. Throckmorton said that the FDA had not yet decided what to do about generic formulations of opioids that have no abuse deterrent properties.
The guidance "is an important part of a larger effort by FDA aimed at preventing prescription drug abuse and misuse," and the agency is "extremely concerned about the inappropriate use of prescription opioids, which is a major public health challenge for our nation," FDA commissioner Dr. Margaret Hamburg said in the statement.
Comments and suggestions can be submitted to the FDA within 60 days of publication in the Federal Register, to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, Md., 20852 , with the docket number listed.
FDA approves apixaban for nonvalvular atrial fibrillation population
The approval of the factor Xa inhibitor apixaban provides another oral anticoagulant that is available to treat patients with atrial fibrillation.
Apixaban was approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in people with nonvalvular atrial fibrillation. It will be marketed as Eliquis, by Bristol-Myers Squibb and Pfizer.
The recommended dose is 5 mg twice daily; a lower dose, 2.5 mg twice daily, is recommended for people with at least two of the following features: age 80 years or older, body weight of 60 kg or less, or a serum creatinine of at least 1.5 mg/dL, according to the prescribing information. The lower dose is also recommended when administered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole and clarithromycin.
Rivaroxaban (Xarelto), a factor Xa inhibitor first approved in 2011, and dabigatran (Pradaxa), a direct thrombin inhibitor approved in 2010, are also indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Rivaroxaban is also approved for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reducing the risk of recurrence of DVT and of PE; and for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.
The FDA statement announcing the approval on Dec. 28 said that the safety and efficacy of apixaban was studied in a trial of more than 18,000 patients with nonvalvular atrial fibrillation, which determined that the rate of strokes among those treated with apixaban was lower than among those on warfarin.
In that study, the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 18,201 patients were treated with 5 mg or 2.5 mg of apixaban twice a day, or warfarin, targeted to an INR range of 2.0-3.0, for a median of 89 weeks. Apixaban was superior to warfarin in reducing the risk of ischemic or hemorrhagic stroke, and systemic embolism: 1.27%/year for those on apixaban vs. 1.60%/year among those on warfarin, a 21% reduced risk that was statistically significant.
Superiority over warfarin in ARISTOTLE was "primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin," and the rates of "purely ischemic strokes" were similar in patients on warfarin and those on apixaban, according to the prescribing information.
The rate of major bleeds was also significantly lower among those on apixaban (2.13% per year) than in those on warfarin (3.09% per year).
The FDA statement points out that apixaban should not be used to treat patients with prosthetic heart valves or with atrial fibrillation that is caused by a heart valve problem, who were not studied. In addition, "there is no agent that can reverse the anticoagulant effect" of apixaban, according to the FDA.
"The randomized clinical trial data for apixaban are quite strong and as doctors gain more familiarity with this medication, it will be a valuable alternative to warfarin for many patients with atrial fibrillation," Dr. Deepak Bhatt, professor of medicine, Harvard Medical School, Boston, and chief of cardiology at the Veterans Affairs Boston Healthcare System, said in an interview.
"Overall, it is good to have therapeutic choices but it is up to the physician community to optimize the use of these agents," said Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at Cedars-Sinai Medical Center, Los Angeles.
"With the approval of apixaban, the anticoagulant space has become somewhat crowded," he said in an interview, noting that in the absence of studies directly comparing these drugs, "physicians will have to figure out which patients are best treated with which agent." For now, he cautioned about manufacturers marketing the advantages of their individual agents. For example, rivaroxaban, approved for nonvalvular atrial fibrillation and for prevention and treatment of venous thromboembolism, has the broadest indication and with the once-daily recommended dosing, has a potential dose advantage, he noted. And while all agents reduce hemorrhagic stroke, "dabigatran at the 150-mg dose is the only agent that significantly reduces the risk of ischemic stroke compared with warfarin."
With the reduced stroke and bleeding risk, apixaban has "the most desirable benefit-risk balance ... and might be preferable in patients with mild to moderate renal impairment given its least dependence on renal clearance," he noted.
He said that all three agents have been shown to have a modest benefit on mortality, and that the mortality benefit was statistically significant only with apixaban because of the size of the ARISTOTLE study. Although an increased risk of MI was a signal reported with dabigatran, but not with Rivaroxaban and apixaban, "the clinical relevance of this observation is not clear," he said.
The approval comes with a Risk Evaluation and Mitigation Strategy (REMS), required by the FDA to ensure that the drug’s benefits drug outweigh its risks, which includes a patient medication guide describing the risks of the drug to be distributed to patients with each filled prescription.
Apixaban should be "widely available" in the United States by the end of January 2013, according to a statement issued by BMS on Jan. 2.
The wholesale acquisition cost for apixaban is $8.35 per day, for both doses, according to a spokesperson for Pfizer.
Dr. Kaul said he had no disclosures relevant to apixaban. He is a stockholder in Johnson & Johnson, a cosponsor for rivaroxaban, and sat on the FDA advisory committees that reviewed dabigatran and rivaroxaban. There was no advisory panel meeting on apixaban.
Dr. Bhatt said that he has received research grants from BMS, and has served on the steering committee of APPRAISE-2 (apixaban studied in acute coronary syndromes). His other disclosures include being a member of the clinical trial steering committees of the Duke Clinical Research Institute.
The prescribing information is available here. The patient medication guide is available at the FDA.
Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program or at 800-332-1088.
The approval of the factor Xa inhibitor apixaban provides another oral anticoagulant that is available to treat patients with atrial fibrillation.
Apixaban was approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in people with nonvalvular atrial fibrillation. It will be marketed as Eliquis, by Bristol-Myers Squibb and Pfizer.
The recommended dose is 5 mg twice daily; a lower dose, 2.5 mg twice daily, is recommended for people with at least two of the following features: age 80 years or older, body weight of 60 kg or less, or a serum creatinine of at least 1.5 mg/dL, according to the prescribing information. The lower dose is also recommended when administered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole and clarithromycin.
Rivaroxaban (Xarelto), a factor Xa inhibitor first approved in 2011, and dabigatran (Pradaxa), a direct thrombin inhibitor approved in 2010, are also indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Rivaroxaban is also approved for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reducing the risk of recurrence of DVT and of PE; and for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.
The FDA statement announcing the approval on Dec. 28 said that the safety and efficacy of apixaban was studied in a trial of more than 18,000 patients with nonvalvular atrial fibrillation, which determined that the rate of strokes among those treated with apixaban was lower than among those on warfarin.
In that study, the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 18,201 patients were treated with 5 mg or 2.5 mg of apixaban twice a day, or warfarin, targeted to an INR range of 2.0-3.0, for a median of 89 weeks. Apixaban was superior to warfarin in reducing the risk of ischemic or hemorrhagic stroke, and systemic embolism: 1.27%/year for those on apixaban vs. 1.60%/year among those on warfarin, a 21% reduced risk that was statistically significant.
Superiority over warfarin in ARISTOTLE was "primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin," and the rates of "purely ischemic strokes" were similar in patients on warfarin and those on apixaban, according to the prescribing information.
The rate of major bleeds was also significantly lower among those on apixaban (2.13% per year) than in those on warfarin (3.09% per year).
The FDA statement points out that apixaban should not be used to treat patients with prosthetic heart valves or with atrial fibrillation that is caused by a heart valve problem, who were not studied. In addition, "there is no agent that can reverse the anticoagulant effect" of apixaban, according to the FDA.
"The randomized clinical trial data for apixaban are quite strong and as doctors gain more familiarity with this medication, it will be a valuable alternative to warfarin for many patients with atrial fibrillation," Dr. Deepak Bhatt, professor of medicine, Harvard Medical School, Boston, and chief of cardiology at the Veterans Affairs Boston Healthcare System, said in an interview.
"Overall, it is good to have therapeutic choices but it is up to the physician community to optimize the use of these agents," said Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at Cedars-Sinai Medical Center, Los Angeles.
"With the approval of apixaban, the anticoagulant space has become somewhat crowded," he said in an interview, noting that in the absence of studies directly comparing these drugs, "physicians will have to figure out which patients are best treated with which agent." For now, he cautioned about manufacturers marketing the advantages of their individual agents. For example, rivaroxaban, approved for nonvalvular atrial fibrillation and for prevention and treatment of venous thromboembolism, has the broadest indication and with the once-daily recommended dosing, has a potential dose advantage, he noted. And while all agents reduce hemorrhagic stroke, "dabigatran at the 150-mg dose is the only agent that significantly reduces the risk of ischemic stroke compared with warfarin."
With the reduced stroke and bleeding risk, apixaban has "the most desirable benefit-risk balance ... and might be preferable in patients with mild to moderate renal impairment given its least dependence on renal clearance," he noted.
He said that all three agents have been shown to have a modest benefit on mortality, and that the mortality benefit was statistically significant only with apixaban because of the size of the ARISTOTLE study. Although an increased risk of MI was a signal reported with dabigatran, but not with Rivaroxaban and apixaban, "the clinical relevance of this observation is not clear," he said.
The approval comes with a Risk Evaluation and Mitigation Strategy (REMS), required by the FDA to ensure that the drug’s benefits drug outweigh its risks, which includes a patient medication guide describing the risks of the drug to be distributed to patients with each filled prescription.
Apixaban should be "widely available" in the United States by the end of January 2013, according to a statement issued by BMS on Jan. 2.
The wholesale acquisition cost for apixaban is $8.35 per day, for both doses, according to a spokesperson for Pfizer.
Dr. Kaul said he had no disclosures relevant to apixaban. He is a stockholder in Johnson & Johnson, a cosponsor for rivaroxaban, and sat on the FDA advisory committees that reviewed dabigatran and rivaroxaban. There was no advisory panel meeting on apixaban.
Dr. Bhatt said that he has received research grants from BMS, and has served on the steering committee of APPRAISE-2 (apixaban studied in acute coronary syndromes). His other disclosures include being a member of the clinical trial steering committees of the Duke Clinical Research Institute.
The prescribing information is available here. The patient medication guide is available at the FDA.
Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program or at 800-332-1088.
The approval of the factor Xa inhibitor apixaban provides another oral anticoagulant that is available to treat patients with atrial fibrillation.
Apixaban was approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in people with nonvalvular atrial fibrillation. It will be marketed as Eliquis, by Bristol-Myers Squibb and Pfizer.
The recommended dose is 5 mg twice daily; a lower dose, 2.5 mg twice daily, is recommended for people with at least two of the following features: age 80 years or older, body weight of 60 kg or less, or a serum creatinine of at least 1.5 mg/dL, according to the prescribing information. The lower dose is also recommended when administered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole and clarithromycin.
Rivaroxaban (Xarelto), a factor Xa inhibitor first approved in 2011, and dabigatran (Pradaxa), a direct thrombin inhibitor approved in 2010, are also indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Rivaroxaban is also approved for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reducing the risk of recurrence of DVT and of PE; and for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.
The FDA statement announcing the approval on Dec. 28 said that the safety and efficacy of apixaban was studied in a trial of more than 18,000 patients with nonvalvular atrial fibrillation, which determined that the rate of strokes among those treated with apixaban was lower than among those on warfarin.
In that study, the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 18,201 patients were treated with 5 mg or 2.5 mg of apixaban twice a day, or warfarin, targeted to an INR range of 2.0-3.0, for a median of 89 weeks. Apixaban was superior to warfarin in reducing the risk of ischemic or hemorrhagic stroke, and systemic embolism: 1.27%/year for those on apixaban vs. 1.60%/year among those on warfarin, a 21% reduced risk that was statistically significant.
Superiority over warfarin in ARISTOTLE was "primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin," and the rates of "purely ischemic strokes" were similar in patients on warfarin and those on apixaban, according to the prescribing information.
The rate of major bleeds was also significantly lower among those on apixaban (2.13% per year) than in those on warfarin (3.09% per year).
The FDA statement points out that apixaban should not be used to treat patients with prosthetic heart valves or with atrial fibrillation that is caused by a heart valve problem, who were not studied. In addition, "there is no agent that can reverse the anticoagulant effect" of apixaban, according to the FDA.
"The randomized clinical trial data for apixaban are quite strong and as doctors gain more familiarity with this medication, it will be a valuable alternative to warfarin for many patients with atrial fibrillation," Dr. Deepak Bhatt, professor of medicine, Harvard Medical School, Boston, and chief of cardiology at the Veterans Affairs Boston Healthcare System, said in an interview.
"Overall, it is good to have therapeutic choices but it is up to the physician community to optimize the use of these agents," said Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at Cedars-Sinai Medical Center, Los Angeles.
"With the approval of apixaban, the anticoagulant space has become somewhat crowded," he said in an interview, noting that in the absence of studies directly comparing these drugs, "physicians will have to figure out which patients are best treated with which agent." For now, he cautioned about manufacturers marketing the advantages of their individual agents. For example, rivaroxaban, approved for nonvalvular atrial fibrillation and for prevention and treatment of venous thromboembolism, has the broadest indication and with the once-daily recommended dosing, has a potential dose advantage, he noted. And while all agents reduce hemorrhagic stroke, "dabigatran at the 150-mg dose is the only agent that significantly reduces the risk of ischemic stroke compared with warfarin."
With the reduced stroke and bleeding risk, apixaban has "the most desirable benefit-risk balance ... and might be preferable in patients with mild to moderate renal impairment given its least dependence on renal clearance," he noted.
He said that all three agents have been shown to have a modest benefit on mortality, and that the mortality benefit was statistically significant only with apixaban because of the size of the ARISTOTLE study. Although an increased risk of MI was a signal reported with dabigatran, but not with Rivaroxaban and apixaban, "the clinical relevance of this observation is not clear," he said.
The approval comes with a Risk Evaluation and Mitigation Strategy (REMS), required by the FDA to ensure that the drug’s benefits drug outweigh its risks, which includes a patient medication guide describing the risks of the drug to be distributed to patients with each filled prescription.
Apixaban should be "widely available" in the United States by the end of January 2013, according to a statement issued by BMS on Jan. 2.
The wholesale acquisition cost for apixaban is $8.35 per day, for both doses, according to a spokesperson for Pfizer.
Dr. Kaul said he had no disclosures relevant to apixaban. He is a stockholder in Johnson & Johnson, a cosponsor for rivaroxaban, and sat on the FDA advisory committees that reviewed dabigatran and rivaroxaban. There was no advisory panel meeting on apixaban.
Dr. Bhatt said that he has received research grants from BMS, and has served on the steering committee of APPRAISE-2 (apixaban studied in acute coronary syndromes). His other disclosures include being a member of the clinical trial steering committees of the Duke Clinical Research Institute.
The prescribing information is available here. The patient medication guide is available at the FDA.
Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program or at 800-332-1088.
