Elizabeth Mechcatie

SILVER SPRING, MD. – The boxed warning about the risk of serious neuropsychiatric effects associated with the smoking cessation drug varenicline should remain on the drug’s label, and the need for this warning can be reevaluated when the results of a postmarketing safety study become available next year, according to the majority of a Food and Drug Administration advisory panel.

On Oct. 16, at a joint meeting of the FDA’s Psychopharmacologic Drugs and the Drug Safety and Risk Management Advisory committees, 11 of the 18 panelists voted to retain the boxed warning about neuropsychiatric symptoms and suicidality, agreeing that a decision about whether to retain the warning should not be made until the results of the study are available.

Pfizer, which manufactures varenicline, a nicotinic receptor partial agonist in a tablet formulation, as Chantix, is conducting the prospective, randomized, double-blind study comparing neuropsychiatric events in 8,000 smokers, with and without a psychiatric history, treated with varenicline, nicotine replacement therapy, bupropion, or placebo. Although the results are expected in 2015, the company maintained that the boxed warning is no longer justified and can be put in the warnings and precautions section, based on analyses of observational studies and randomized clinical trials. The company submitted those analyses to the FDA earlier this year.

The boxed warning in the drug’s prescribing information states that the serious events reported in patients taking the drug include but “are not limited to” depression, suicidal ideation, suicide attempts, and completed suicides; and that some cases “may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.” The reason the boxed warning is used for this drug is that there is a “serious adverse reaction that can be prevented or reduced in frequency or severity,” the FDA said.

Because the precedent for removing a boxed warning from a drug label is limited and the FDA’s view that the decision should consider the final results of the postmarketing trial, the agency convened the joint meeting to review the analyses submitted by the company. Overall, the panelists were not convinced by the analyses. They cited various weaknesses in the observational studies and the meta-analysis, including questions about whether the correct outcomes were being captured.

Six panelists voted to modify (but not weaken) the language in the boxed warning, and most recommended that the last few lines about the health benefits of quitting smoking be removed and argued that the wording had a promotional tone and did not belong in a boxed warning. Several panelists recommended adding sleep disruption and disorders, and recognized adverse events of the drugs to the boxed warning.

Among those who voted to retain the boxed warning, Dr. Jeanmarie Perrone, director of the medical toxicology division in the emergency medicine department at the University of Pennsylvania, Philadelphia, said there was biologic plausibility for these events. Her biggest concern, she said, was that removing the boxed warning might be interpreted as “an endorsement of safety and that has not been demonstrated.” In the emergency department, she said, she sees many patients who have been prescribed varenicline “by a myriad of clinicians,” and the presence of a boxed warning helps keep this safety issue in mind.

Dr. Rajiv N. Rimal, professor and chair of the department of prevention and community health, George Washington University, Washington, who voted to retain the warning with modified wording, said: “I heard enough compelling evidence to suggest that even some of the more rare events were severe enough” that revisiting the labeling change would be necessary once the other data became available.

Varenicline, approved by the FDA in 2006 as an aid to smoking-cessation treatment, provides a “low level” of dopamine release as people try to quit smoking, according to Pfizer. The boxed warning was added to the label in July 2009, based on the FDA’s review of spontaneous adverse event reports, conducted after an alert about suicidality reports associated with the drug from European regulators about 1 year after FDA approval. About the same time, there was a widely publicized case of a Texas musician who was taking varenicline and was shot and killed by a neighbor while exhibiting uncharacteristic aggressive behavior in the fall of 2007.

The reports provided by the company at that time included 102 suicide-related cases, and 525 reports of aggressive/irrational behavior. A review of the reports in the FDA’s adverse events database included many cases with “hallmarks of drug relatedness,” patients reporting unusual symptoms with “similar distinctive language,” and positive dechallenges and rechallenges, said Dr. Celia Winchell, the medical team leader of addiction products in the FDA’s division of anesthesia, analgesia, and addiction products. Not all cases involved suicidality, depression, or aggression. Postmarketing reports have provided a “rich narrative with detail” about patient experiences, including descriptions that are relatively easy to describe or classify, such as suicide and aggression, while others “defy coding,” such as one person who reported feeling “like a zombie,” she told the panel.

“Based on a review of the cases, there appears to be a syndrome of debilitating symptoms that interfere with people’s ability to function in their daily lives that is associated with the use of Chantix,” Dr. Winchell said.

The company agreed that the spontaneous reports in late 2007 raised concerns about whether the drug was associated with an increase in serious neuropsychiatric events. But since 2009, this issue has been evaluated in controlled studies, which “consistently show no evidence of an increased risk,” Dr. Christopher Wohlberg, the head of Pfizer’s safety surveillance and risk management group, told the panel.

These include a meta-analysis of adverse events in 18 controlled studies of about 5,000 patients treated with varenicline and about 3,500 on placebo, which found no significant difference in the rate of neuropsychiatric events (with the exception of sleep disorders and disturbance) among those on the drug vs. those on placebo; and a meta-analysis of 5 placebo-controlled studies that used the Columbia-Suicide Severity Rating Scale to evaluate suicidal ideation and behavior, which also found no significant differences between the two groups.

In addition, four observational studies that included patients with psychiatric illnesses showed that the rates of serious neuropsychiatric events in patients treated with varenicline were not significantly different from those treated with nicotine replacement therapy or bupropion for smoking cessation. In individual studies of patients with psychiatric illnesses (schizophrenia, schizoaffective disorder, or major depressive disorder), no evidence was found of an increased risk among those treated with varenicline, compared with those on placebo, according to the company.

But the FDA reviewers raised issues with the meta-analysis of the 18 studies and the observational data. The observational data have limitations and “preclude” a conclusion that there is no association of varenicline and an increased risk of neuropsychiatric events, said Natasha Chen, Ph.D., an epidemiologist in the FDA’s office of surveillance and epidemiology. The ongoing postmarketing safety trial “is likely to offer better insights into varenicline’s neuropsychiatric risks,” she added.

The one panelist who voted to remove the warning, Dr. Andrew J. Saxon, said while there “may be some serious adverse or neuropsychiatric effects, the data, while not perfect,” do not show a signal in his view. He added that in his experience working daily with patients who are trying to quit smoking, “patients are afraid to take this medication because of the boxed warning, and it does deter use.” Moreover, in the Veterans Affairs system, there are restrictions on prescribing the drug because of the boxed warning, including a limitation on prescriptions to a 28-day supply, with no refills. Such restrictions increase hassles for patients and prescribers, and often result in patients stopping treatment after 4 weeks.

“If I’m doing a good job as a physician, I’m going to monitor the patient,” said Dr. Saxon, director of the addiction psychiatry residency program, University of Washington, Seattle.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Members of these two panels had no conflicts to disclose. Occasionally, panelists with a conflict are given a waiver, but not at this meeting.

In a statementissued by Pfizer after the meeting, Dr. Steven Romano, senior vice president and head of the medicines development group for Pfizer, said the “completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication.”

The varenicline label is available at http://labeling.pfizer.com/ShowLabeling.aspx?id=557. Serious adverse events associated with this drug should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/default.htm.

[email protected]

SILVER SPRING, MD. – The boxed warning about the risk of serious neuropsychiatric effects associated with the smoking cessation drug varenicline should remain on the drug’s label, and the need for this warning can be reevaluated when the results of a postmarketing safety study become available next year, according to the majority of a Food and Drug Administration advisory panel.

On Oct. 16, at a joint meeting of the FDA’s Psychopharmacologic Drugs and the Drug Safety and Risk Management Advisory committees, 11 of the 18 panelists voted to retain the boxed warning about neuropsychiatric symptoms and suicidality, agreeing that a decision about whether to retain the warning should not be made until the results of the study are available.

Pfizer, which manufactures varenicline, a nicotinic receptor partial agonist in a tablet formulation, as Chantix, is conducting the prospective, randomized, double-blind study comparing neuropsychiatric events in 8,000 smokers, with and without a psychiatric history, treated with varenicline, nicotine replacement therapy, bupropion, or placebo. Although the results are expected in 2015, the company maintained that the boxed warning is no longer justified and can be put in the warnings and precautions section, based on analyses of observational studies and randomized clinical trials. The company submitted those analyses to the FDA earlier this year.

The boxed warning in the drug’s prescribing information states that the serious events reported in patients taking the drug include but “are not limited to” depression, suicidal ideation, suicide attempts, and completed suicides; and that some cases “may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.” The reason the boxed warning is used for this drug is that there is a “serious adverse reaction that can be prevented or reduced in frequency or severity,” the FDA said.

Because the precedent for removing a boxed warning from a drug label is limited and the FDA’s view that the decision should consider the final results of the postmarketing trial, the agency convened the joint meeting to review the analyses submitted by the company. Overall, the panelists were not convinced by the analyses. They cited various weaknesses in the observational studies and the meta-analysis, including questions about whether the correct outcomes were being captured.

Six panelists voted to modify (but not weaken) the language in the boxed warning, and most recommended that the last few lines about the health benefits of quitting smoking be removed and argued that the wording had a promotional tone and did not belong in a boxed warning. Several panelists recommended adding sleep disruption and disorders, and recognized adverse events of the drugs to the boxed warning.

Among those who voted to retain the boxed warning, Dr. Jeanmarie Perrone, director of the medical toxicology division in the emergency medicine department at the University of Pennsylvania, Philadelphia, said there was biologic plausibility for these events. Her biggest concern, she said, was that removing the boxed warning might be interpreted as “an endorsement of safety and that has not been demonstrated.” In the emergency department, she said, she sees many patients who have been prescribed varenicline “by a myriad of clinicians,” and the presence of a boxed warning helps keep this safety issue in mind.

Dr. Rajiv N. Rimal, professor and chair of the department of prevention and community health, George Washington University, Washington, who voted to retain the warning with modified wording, said: “I heard enough compelling evidence to suggest that even some of the more rare events were severe enough” that revisiting the labeling change would be necessary once the other data became available.

Varenicline, approved by the FDA in 2006 as an aid to smoking-cessation treatment, provides a “low level” of dopamine release as people try to quit smoking, according to Pfizer. The boxed warning was added to the label in July 2009, based on the FDA’s review of spontaneous adverse event reports, conducted after an alert about suicidality reports associated with the drug from European regulators about 1 year after FDA approval. About the same time, there was a widely publicized case of a Texas musician who was taking varenicline and was shot and killed by a neighbor while exhibiting uncharacteristic aggressive behavior in the fall of 2007.

The reports provided by the company at that time included 102 suicide-related cases, and 525 reports of aggressive/irrational behavior. A review of the reports in the FDA’s adverse events database included many cases with “hallmarks of drug relatedness,” patients reporting unusual symptoms with “similar distinctive language,” and positive dechallenges and rechallenges, said Dr. Celia Winchell, the medical team leader of addiction products in the FDA’s division of anesthesia, analgesia, and addiction products. Not all cases involved suicidality, depression, or aggression. Postmarketing reports have provided a “rich narrative with detail” about patient experiences, including descriptions that are relatively easy to describe or classify, such as suicide and aggression, while others “defy coding,” such as one person who reported feeling “like a zombie,” she told the panel.

“Based on a review of the cases, there appears to be a syndrome of debilitating symptoms that interfere with people’s ability to function in their daily lives that is associated with the use of Chantix,” Dr. Winchell said.

The company agreed that the spontaneous reports in late 2007 raised concerns about whether the drug was associated with an increase in serious neuropsychiatric events. But since 2009, this issue has been evaluated in controlled studies, which “consistently show no evidence of an increased risk,” Dr. Christopher Wohlberg, the head of Pfizer’s safety surveillance and risk management group, told the panel.

These include a meta-analysis of adverse events in 18 controlled studies of about 5,000 patients treated with varenicline and about 3,500 on placebo, which found no significant difference in the rate of neuropsychiatric events (with the exception of sleep disorders and disturbance) among those on the drug vs. those on placebo; and a meta-analysis of 5 placebo-controlled studies that used the Columbia-Suicide Severity Rating Scale to evaluate suicidal ideation and behavior, which also found no significant differences between the two groups.

In addition, four observational studies that included patients with psychiatric illnesses showed that the rates of serious neuropsychiatric events in patients treated with varenicline were not significantly different from those treated with nicotine replacement therapy or bupropion for smoking cessation. In individual studies of patients with psychiatric illnesses (schizophrenia, schizoaffective disorder, or major depressive disorder), no evidence was found of an increased risk among those treated with varenicline, compared with those on placebo, according to the company.

But the FDA reviewers raised issues with the meta-analysis of the 18 studies and the observational data. The observational data have limitations and “preclude” a conclusion that there is no association of varenicline and an increased risk of neuropsychiatric events, said Natasha Chen, Ph.D., an epidemiologist in the FDA’s office of surveillance and epidemiology. The ongoing postmarketing safety trial “is likely to offer better insights into varenicline’s neuropsychiatric risks,” she added.

The one panelist who voted to remove the warning, Dr. Andrew J. Saxon, said while there “may be some serious adverse or neuropsychiatric effects, the data, while not perfect,” do not show a signal in his view. He added that in his experience working daily with patients who are trying to quit smoking, “patients are afraid to take this medication because of the boxed warning, and it does deter use.” Moreover, in the Veterans Affairs system, there are restrictions on prescribing the drug because of the boxed warning, including a limitation on prescriptions to a 28-day supply, with no refills. Such restrictions increase hassles for patients and prescribers, and often result in patients stopping treatment after 4 weeks.

“If I’m doing a good job as a physician, I’m going to monitor the patient,” said Dr. Saxon, director of the addiction psychiatry residency program, University of Washington, Seattle.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Members of these two panels had no conflicts to disclose. Occasionally, panelists with a conflict are given a waiver, but not at this meeting.

In a statementissued by Pfizer after the meeting, Dr. Steven Romano, senior vice president and head of the medicines development group for Pfizer, said the “completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication.”

The varenicline label is available at http://labeling.pfizer.com/ShowLabeling.aspx?id=557. Serious adverse events associated with this drug should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/default.htm.

[email protected]

SILVER SPRING, MD. – The boxed warning about the risk of serious neuropsychiatric effects associated with the smoking cessation drug varenicline should remain on the drug’s label, and the need for this warning can be reevaluated when the results of a postmarketing safety study become available next year, according to the majority of a Food and Drug Administration advisory panel.

On Oct. 16, at a joint meeting of the FDA’s Psychopharmacologic Drugs and the Drug Safety and Risk Management Advisory committees, 11 of the 18 panelists voted to retain the boxed warning about neuropsychiatric symptoms and suicidality, agreeing that a decision about whether to retain the warning should not be made until the results of the study are available.

Pfizer, which manufactures varenicline, a nicotinic receptor partial agonist in a tablet formulation, as Chantix, is conducting the prospective, randomized, double-blind study comparing neuropsychiatric events in 8,000 smokers, with and without a psychiatric history, treated with varenicline, nicotine replacement therapy, bupropion, or placebo. Although the results are expected in 2015, the company maintained that the boxed warning is no longer justified and can be put in the warnings and precautions section, based on analyses of observational studies and randomized clinical trials. The company submitted those analyses to the FDA earlier this year.

The boxed warning in the drug’s prescribing information states that the serious events reported in patients taking the drug include but “are not limited to” depression, suicidal ideation, suicide attempts, and completed suicides; and that some cases “may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.” The reason the boxed warning is used for this drug is that there is a “serious adverse reaction that can be prevented or reduced in frequency or severity,” the FDA said.

Because the precedent for removing a boxed warning from a drug label is limited and the FDA’s view that the decision should consider the final results of the postmarketing trial, the agency convened the joint meeting to review the analyses submitted by the company. Overall, the panelists were not convinced by the analyses. They cited various weaknesses in the observational studies and the meta-analysis, including questions about whether the correct outcomes were being captured.

Six panelists voted to modify (but not weaken) the language in the boxed warning, and most recommended that the last few lines about the health benefits of quitting smoking be removed and argued that the wording had a promotional tone and did not belong in a boxed warning. Several panelists recommended adding sleep disruption and disorders, and recognized adverse events of the drugs to the boxed warning.

Among those who voted to retain the boxed warning, Dr. Jeanmarie Perrone, director of the medical toxicology division in the emergency medicine department at the University of Pennsylvania, Philadelphia, said there was biologic plausibility for these events. Her biggest concern, she said, was that removing the boxed warning might be interpreted as “an endorsement of safety and that has not been demonstrated.” In the emergency department, she said, she sees many patients who have been prescribed varenicline “by a myriad of clinicians,” and the presence of a boxed warning helps keep this safety issue in mind.

Dr. Rajiv N. Rimal, professor and chair of the department of prevention and community health, George Washington University, Washington, who voted to retain the warning with modified wording, said: “I heard enough compelling evidence to suggest that even some of the more rare events were severe enough” that revisiting the labeling change would be necessary once the other data became available.

Varenicline, approved by the FDA in 2006 as an aid to smoking-cessation treatment, provides a “low level” of dopamine release as people try to quit smoking, according to Pfizer. The boxed warning was added to the label in July 2009, based on the FDA’s review of spontaneous adverse event reports, conducted after an alert about suicidality reports associated with the drug from European regulators about 1 year after FDA approval. About the same time, there was a widely publicized case of a Texas musician who was taking varenicline and was shot and killed by a neighbor while exhibiting uncharacteristic aggressive behavior in the fall of 2007.

The reports provided by the company at that time included 102 suicide-related cases, and 525 reports of aggressive/irrational behavior. A review of the reports in the FDA’s adverse events database included many cases with “hallmarks of drug relatedness,” patients reporting unusual symptoms with “similar distinctive language,” and positive dechallenges and rechallenges, said Dr. Celia Winchell, the medical team leader of addiction products in the FDA’s division of anesthesia, analgesia, and addiction products. Not all cases involved suicidality, depression, or aggression. Postmarketing reports have provided a “rich narrative with detail” about patient experiences, including descriptions that are relatively easy to describe or classify, such as suicide and aggression, while others “defy coding,” such as one person who reported feeling “like a zombie,” she told the panel.

“Based on a review of the cases, there appears to be a syndrome of debilitating symptoms that interfere with people’s ability to function in their daily lives that is associated with the use of Chantix,” Dr. Winchell said.

The company agreed that the spontaneous reports in late 2007 raised concerns about whether the drug was associated with an increase in serious neuropsychiatric events. But since 2009, this issue has been evaluated in controlled studies, which “consistently show no evidence of an increased risk,” Dr. Christopher Wohlberg, the head of Pfizer’s safety surveillance and risk management group, told the panel.

These include a meta-analysis of adverse events in 18 controlled studies of about 5,000 patients treated with varenicline and about 3,500 on placebo, which found no significant difference in the rate of neuropsychiatric events (with the exception of sleep disorders and disturbance) among those on the drug vs. those on placebo; and a meta-analysis of 5 placebo-controlled studies that used the Columbia-Suicide Severity Rating Scale to evaluate suicidal ideation and behavior, which also found no significant differences between the two groups.

In addition, four observational studies that included patients with psychiatric illnesses showed that the rates of serious neuropsychiatric events in patients treated with varenicline were not significantly different from those treated with nicotine replacement therapy or bupropion for smoking cessation. In individual studies of patients with psychiatric illnesses (schizophrenia, schizoaffective disorder, or major depressive disorder), no evidence was found of an increased risk among those treated with varenicline, compared with those on placebo, according to the company.

But the FDA reviewers raised issues with the meta-analysis of the 18 studies and the observational data. The observational data have limitations and “preclude” a conclusion that there is no association of varenicline and an increased risk of neuropsychiatric events, said Natasha Chen, Ph.D., an epidemiologist in the FDA’s office of surveillance and epidemiology. The ongoing postmarketing safety trial “is likely to offer better insights into varenicline’s neuropsychiatric risks,” she added.

The one panelist who voted to remove the warning, Dr. Andrew J. Saxon, said while there “may be some serious adverse or neuropsychiatric effects, the data, while not perfect,” do not show a signal in his view. He added that in his experience working daily with patients who are trying to quit smoking, “patients are afraid to take this medication because of the boxed warning, and it does deter use.” Moreover, in the Veterans Affairs system, there are restrictions on prescribing the drug because of the boxed warning, including a limitation on prescriptions to a 28-day supply, with no refills. Such restrictions increase hassles for patients and prescribers, and often result in patients stopping treatment after 4 weeks.

“If I’m doing a good job as a physician, I’m going to monitor the patient,” said Dr. Saxon, director of the addiction psychiatry residency program, University of Washington, Seattle.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Members of these two panels had no conflicts to disclose. Occasionally, panelists with a conflict are given a waiver, but not at this meeting.

In a statementissued by Pfizer after the meeting, Dr. Steven Romano, senior vice president and head of the medicines development group for Pfizer, said the “completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication.”

The varenicline label is available at http://labeling.pfizer.com/ShowLabeling.aspx?id=557. Serious adverse events associated with this drug should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/default.htm.

[email protected]

A rectal foam formulation of 2% budesonide has been approved by the Food and Drug Administration for treating distal ulcerative colitis, the manufacturer, Salix Pharmaceuticals, has announced.

The approved indication is for the induction of remission in patients with mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The foam is administered rectally and “overcomes treatment limitations associated with currently approved therapies which are often ineffective due to insufficient distribution of active drug to the distal colon,” the company said in a statement announcing the final approval on Oct. 8.

The company will be marketing the product as Uceris.

The company also markets budesonide oral extended-release tablets under the same name.

A rectal foam formulation of 2% budesonide has been approved by the Food and Drug Administration for treating distal ulcerative colitis, the manufacturer, Salix Pharmaceuticals, has announced.

The approved indication is for the induction of remission in patients with mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The foam is administered rectally and “overcomes treatment limitations associated with currently approved therapies which are often ineffective due to insufficient distribution of active drug to the distal colon,” the company said in a statement announcing the final approval on Oct. 8.

The company will be marketing the product as Uceris.

The company also markets budesonide oral extended-release tablets under the same name.

A rectal foam formulation of 2% budesonide has been approved by the Food and Drug Administration for treating distal ulcerative colitis, the manufacturer, Salix Pharmaceuticals, has announced.

The approved indication is for the induction of remission in patients with mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The foam is administered rectally and “overcomes treatment limitations associated with currently approved therapies which are often ineffective due to insufficient distribution of active drug to the distal colon,” the company said in a statement announcing the final approval on Oct. 8.

The company will be marketing the product as Uceris.

The company also markets budesonide oral extended-release tablets under the same name.

A rectal foam formulation of 2% budesonide has been approved by the Food and Drug Administration for treating distal ulcerative colitis, the manufacturer, Salix Pharmaceuticals, has announced.

The approved indication is for the induction of remission in patients with mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The foam is administered rectally and “overcomes treatment limitations associated with currently approved therapies which are often ineffective due to insufficient distribution of active drug to the distal colon,” the company said in a statement announcing the final approval on Oct. 8.

The company will be marketing the product as Uceris.

The company also markets budesonide oral extended-release tablets under the same name.

[email protected]

A rectal foam formulation of 2% budesonide has been approved by the Food and Drug Administration for treating distal ulcerative colitis, the manufacturer, Salix Pharmaceuticals, has announced.

The approved indication is for the induction of remission in patients with mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The foam is administered rectally and “overcomes treatment limitations associated with currently approved therapies which are often ineffective due to insufficient distribution of active drug to the distal colon,” the company said in a statement announcing the final approval on Oct. 8.

The company will be marketing the product as Uceris.

The company also markets budesonide oral extended-release tablets under the same name.

[email protected]

A rectal foam formulation of 2% budesonide has been approved by the Food and Drug Administration for treating distal ulcerative colitis, the manufacturer, Salix Pharmaceuticals, has announced.

The approved indication is for the induction of remission in patients with mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The foam is administered rectally and “overcomes treatment limitations associated with currently approved therapies which are often ineffective due to insufficient distribution of active drug to the distal colon,” the company said in a statement announcing the final approval on Oct. 8.

The company will be marketing the product as Uceris.

The company also markets budesonide oral extended-release tablets under the same name.

[email protected]

Treatment of relapsing or recurrent Clostridium difficile infection with frozen, orally administered capsules containing a solution of fecal matter from healthy unrelated donors had promising results, with diarrhea resolving in 90% of patients after one or two rounds of treatment.

“We demonstrated the feasibility of oral administration of frozen encapsulated fecal material from unrelated donors to treat patients with recurrent [Clostridium difficile infection (CDI)],” concluded Dr. Ilan Youngster, of the division of infectious diseases at Massachusetts General Hospital, Boston, and his associates. While the study was limited by the small number patients (20) and the lack of a placebo or comparator group, “if reproduced in future studies with active controls, these results may help make FMT accessible to a wider population of patients, in addition to potentially making the procedure safer.”

The study was published Oct. 11 in JAMA, in conjunction with its presenation at ID Week 2014 (doi:10.1001/jama.2014.13875)

Instead of the most common type of fecal microbiota transplantation (FMT) procedures, which use a suspension of fresh stool from donors related to the patient to reconstitute the normal flora, this feasibility study evaluated the safety and effectiveness of FMT with fecal matter from unrelated, carefully screened healthy donors, which was processed into a solution that was placed into small capsules and then frozen.

The study enrolled 20 patients whose mean age was 64.5 years (one patient was aged 11, the rest were aged 17-89) between August 2013 and June 2014 at Massachusetts General. Patient had had at least three episodes of mild to moderate CDI and failed treatment with vancomycin, with or without an alternative antibiotic; or had been hospitalized with at least 2 episodes of severe CDI.

After one round of treatment with 15 capsules over 2 days, diarrhea resolved (defined as fewer than three bowel movements over 24 hours) in 14 of the 20 patients (70%); at 8 weeks, they remained symptom free. The remaining 6 patients were treated again, a mean of 7 days after the first treatment, and diarrhea resolved in 5. One of the 5 patients relapsed within the 8 week follow-up period, so the overall rate of diarrhea resolution at 8 weeks was 90%.

Overall health score before treatment was the only factor significantly associated with treatment response. Those who required a second treatment had more symptoms and had lower health scores before treatment than those who responded to the first treatment.

The number of daily bowel movements dropped from a median of five per day before treatment to a median of 2 at day 3, and one at 8 weeks, both statistically significant reductions from baseline. Patients also felt better, reflected in improvements in scores on health questionnaires evaluating overall and gastrointestinal health.

There were no cases of vomiting or aspiration and no serious adverse events were observed, Dr. Youngster said. Six patients experienced abdominal cramping and bloating after treatment, which were considered to be treatment related, but resolved.

The 90% clinical resolution rate with this treatment are comparable those in case studies and a randomized study using fresh stool preparations to treat CDI, Dr. Youngster said. “Larger studied are needed to confirm these results and to evaluate long-term safety and effectiveness.

The study was funded with internal hospital division funds. One author is a recipient of a research award sponsored by Seres Health, Cambridge, Mass., for an unrelated clinical trial of a C. difficile colitis treatment. No other author disclosures were reported.

Treatment of relapsing or recurrent Clostridium difficile infection with frozen, orally administered capsules containing a solution of fecal matter from healthy unrelated donors had promising results, with diarrhea resolving in 90% of patients after one or two rounds of treatment.

“We demonstrated the feasibility of oral administration of frozen encapsulated fecal material from unrelated donors to treat patients with recurrent [Clostridium difficile infection (CDI)],” concluded Dr. Ilan Youngster, of the division of infectious diseases at Massachusetts General Hospital, Boston, and his associates. While the study was limited by the small number patients (20) and the lack of a placebo or comparator group, “if reproduced in future studies with active controls, these results may help make FMT accessible to a wider population of patients, in addition to potentially making the procedure safer.”

The study was published Oct. 11 in JAMA, in conjunction with its presenation at ID Week 2014 (doi:10.1001/jama.2014.13875)

Instead of the most common type of fecal microbiota transplantation (FMT) procedures, which use a suspension of fresh stool from donors related to the patient to reconstitute the normal flora, this feasibility study evaluated the safety and effectiveness of FMT with fecal matter from unrelated, carefully screened healthy donors, which was processed into a solution that was placed into small capsules and then frozen.

The study enrolled 20 patients whose mean age was 64.5 years (one patient was aged 11, the rest were aged 17-89) between August 2013 and June 2014 at Massachusetts General. Patient had had at least three episodes of mild to moderate CDI and failed treatment with vancomycin, with or without an alternative antibiotic; or had been hospitalized with at least 2 episodes of severe CDI.

After one round of treatment with 15 capsules over 2 days, diarrhea resolved (defined as fewer than three bowel movements over 24 hours) in 14 of the 20 patients (70%); at 8 weeks, they remained symptom free. The remaining 6 patients were treated again, a mean of 7 days after the first treatment, and diarrhea resolved in 5. One of the 5 patients relapsed within the 8 week follow-up period, so the overall rate of diarrhea resolution at 8 weeks was 90%.

Overall health score before treatment was the only factor significantly associated with treatment response. Those who required a second treatment had more symptoms and had lower health scores before treatment than those who responded to the first treatment.

The number of daily bowel movements dropped from a median of five per day before treatment to a median of 2 at day 3, and one at 8 weeks, both statistically significant reductions from baseline. Patients also felt better, reflected in improvements in scores on health questionnaires evaluating overall and gastrointestinal health.

There were no cases of vomiting or aspiration and no serious adverse events were observed, Dr. Youngster said. Six patients experienced abdominal cramping and bloating after treatment, which were considered to be treatment related, but resolved.

The 90% clinical resolution rate with this treatment are comparable those in case studies and a randomized study using fresh stool preparations to treat CDI, Dr. Youngster said. “Larger studied are needed to confirm these results and to evaluate long-term safety and effectiveness.

The study was funded with internal hospital division funds. One author is a recipient of a research award sponsored by Seres Health, Cambridge, Mass., for an unrelated clinical trial of a C. difficile colitis treatment. No other author disclosures were reported.

Treatment of relapsing or recurrent Clostridium difficile infection with frozen, orally administered capsules containing a solution of fecal matter from healthy unrelated donors had promising results, with diarrhea resolving in 90% of patients after one or two rounds of treatment.

“We demonstrated the feasibility of oral administration of frozen encapsulated fecal material from unrelated donors to treat patients with recurrent [Clostridium difficile infection (CDI)],” concluded Dr. Ilan Youngster, of the division of infectious diseases at Massachusetts General Hospital, Boston, and his associates. While the study was limited by the small number patients (20) and the lack of a placebo or comparator group, “if reproduced in future studies with active controls, these results may help make FMT accessible to a wider population of patients, in addition to potentially making the procedure safer.”

The study was published Oct. 11 in JAMA, in conjunction with its presenation at ID Week 2014 (doi:10.1001/jama.2014.13875)

Instead of the most common type of fecal microbiota transplantation (FMT) procedures, which use a suspension of fresh stool from donors related to the patient to reconstitute the normal flora, this feasibility study evaluated the safety and effectiveness of FMT with fecal matter from unrelated, carefully screened healthy donors, which was processed into a solution that was placed into small capsules and then frozen.

The study enrolled 20 patients whose mean age was 64.5 years (one patient was aged 11, the rest were aged 17-89) between August 2013 and June 2014 at Massachusetts General. Patient had had at least three episodes of mild to moderate CDI and failed treatment with vancomycin, with or without an alternative antibiotic; or had been hospitalized with at least 2 episodes of severe CDI.

After one round of treatment with 15 capsules over 2 days, diarrhea resolved (defined as fewer than three bowel movements over 24 hours) in 14 of the 20 patients (70%); at 8 weeks, they remained symptom free. The remaining 6 patients were treated again, a mean of 7 days after the first treatment, and diarrhea resolved in 5. One of the 5 patients relapsed within the 8 week follow-up period, so the overall rate of diarrhea resolution at 8 weeks was 90%.

Overall health score before treatment was the only factor significantly associated with treatment response. Those who required a second treatment had more symptoms and had lower health scores before treatment than those who responded to the first treatment.

The number of daily bowel movements dropped from a median of five per day before treatment to a median of 2 at day 3, and one at 8 weeks, both statistically significant reductions from baseline. Patients also felt better, reflected in improvements in scores on health questionnaires evaluating overall and gastrointestinal health.

There were no cases of vomiting or aspiration and no serious adverse events were observed, Dr. Youngster said. Six patients experienced abdominal cramping and bloating after treatment, which were considered to be treatment related, but resolved.

The 90% clinical resolution rate with this treatment are comparable those in case studies and a randomized study using fresh stool preparations to treat CDI, Dr. Youngster said. “Larger studied are needed to confirm these results and to evaluate long-term safety and effectiveness.

The study was funded with internal hospital division funds. One author is a recipient of a research award sponsored by Seres Health, Cambridge, Mass., for an unrelated clinical trial of a C. difficile colitis treatment. No other author disclosures were reported.

Treatment of relapsing or recurrent Clostridium difficile infection with frozen, orally administered capsules containing a solution of fecal matter from healthy unrelated donors had promising results, with diarrhea resolving in 90% of patients after one or two rounds of treatment.

“We demonstrated the feasibility of oral administration of frozen encapsulated fecal material from unrelated donors to treat patients with recurrent [Clostridium difficile infection (CDI)],” concluded Dr. Ilan Youngster, of the division of infectious diseases at Massachusetts General Hospital, Boston, and his associates. While the study was limited by the small number patients (20) and the lack of a placebo or comparator group, “if reproduced in future studies with active controls, these results may help make FMT accessible to a wider population of patients, in addition to potentially making the procedure safer.”

Courtesy CDC/Dr. Gilda Jones

The study was published Oct. 11 in JAMA, in conjunction with its presenation at ID Week 2014 (doi:10.1001/jama.2014.13875)

Instead of the most common type of fecal microbiota transplantation (FMT) procedures, which use a suspension of fresh stool from donors related to the patient to reconstitute the normal flora, this feasibility study evaluated the safety and effectiveness of FMT with fecal matter from unrelated, carefully screened healthy donors, which was processed into a solution that was placed into small capsules and then frozen.

The study enrolled 20 patients whose mean age was 64.5 years (one patient was aged 11, the rest were aged 17-89) between August 2013 and June 2014 at Massachusetts General. Patient had had at least three episodes of mild to moderate CDI and failed treatment with vancomycin, with or without an alternative antibiotic; or had been hospitalized with at least 2 episodes of severe CDI.

After one round of treatment with 15 capsules over 2 days, diarrhea resolved (defined as fewer than three bowel movements over 24 hours) in 14 of the 20 patients (70%); at 8 weeks, they remained symptom free. The remaining 6 patients were treated again, a mean of 7 days after the first treatment, and diarrhea resolved in 5. One of the 5 patients relapsed within the 8 week follow-up period, so the overall rate of diarrhea resolution at 8 weeks was 90%.

Overall health score before treatment was the only factor significantly associated with treatment response. Those who required a second treatment had more symptoms and had lower health scores before treatment than those who responded to the first treatment.

The number of daily bowel movements dropped from a median of five per day before treatment to a median of 2 at day 3, and one at 8 weeks, both statistically significant reductions from baseline. Patients also felt better, reflected in improvements in scores on health questionnaires evaluating overall and gastrointestinal health.

There were no cases of vomiting or aspiration and no serious adverse events were observed, Dr. Youngster said. Six patients experienced abdominal cramping and bloating after treatment, which were considered to be treatment related, but resolved.

The 90% clinical resolution rate with this treatment are comparable those in case studies and a randomized study using fresh stool preparations to treat CDI, Dr. Youngster said. “Larger studied are needed to confirm these results and to evaluate long-term safety and effectiveness.

The study was funded with internal hospital division funds. One author is a recipient of a research award sponsored by Seres Health, Cambridge, Mass., for an unrelated clinical trial of a C. difficile colitis treatment. No other author disclosures were reported.

[email protected]

Treatment of relapsing or recurrent Clostridium difficile infection with frozen, orally administered capsules containing a solution of fecal matter from healthy unrelated donors had promising results, with diarrhea resolving in 90% of patients after one or two rounds of treatment.

“We demonstrated the feasibility of oral administration of frozen encapsulated fecal material from unrelated donors to treat patients with recurrent [Clostridium difficile infection (CDI)],” concluded Dr. Ilan Youngster, of the division of infectious diseases at Massachusetts General Hospital, Boston, and his associates. While the study was limited by the small number patients (20) and the lack of a placebo or comparator group, “if reproduced in future studies with active controls, these results may help make FMT accessible to a wider population of patients, in addition to potentially making the procedure safer.”

Courtesy CDC/Dr. Gilda Jones

The study was published Oct. 11 in JAMA, in conjunction with its presenation at ID Week 2014 (doi:10.1001/jama.2014.13875)

Instead of the most common type of fecal microbiota transplantation (FMT) procedures, which use a suspension of fresh stool from donors related to the patient to reconstitute the normal flora, this feasibility study evaluated the safety and effectiveness of FMT with fecal matter from unrelated, carefully screened healthy donors, which was processed into a solution that was placed into small capsules and then frozen.

The study enrolled 20 patients whose mean age was 64.5 years (one patient was aged 11, the rest were aged 17-89) between August 2013 and June 2014 at Massachusetts General. Patient had had at least three episodes of mild to moderate CDI and failed treatment with vancomycin, with or without an alternative antibiotic; or had been hospitalized with at least 2 episodes of severe CDI.

After one round of treatment with 15 capsules over 2 days, diarrhea resolved (defined as fewer than three bowel movements over 24 hours) in 14 of the 20 patients (70%); at 8 weeks, they remained symptom free. The remaining 6 patients were treated again, a mean of 7 days after the first treatment, and diarrhea resolved in 5. One of the 5 patients relapsed within the 8 week follow-up period, so the overall rate of diarrhea resolution at 8 weeks was 90%.

Overall health score before treatment was the only factor significantly associated with treatment response. Those who required a second treatment had more symptoms and had lower health scores before treatment than those who responded to the first treatment.

The number of daily bowel movements dropped from a median of five per day before treatment to a median of 2 at day 3, and one at 8 weeks, both statistically significant reductions from baseline. Patients also felt better, reflected in improvements in scores on health questionnaires evaluating overall and gastrointestinal health.

There were no cases of vomiting or aspiration and no serious adverse events were observed, Dr. Youngster said. Six patients experienced abdominal cramping and bloating after treatment, which were considered to be treatment related, but resolved.

The 90% clinical resolution rate with this treatment are comparable those in case studies and a randomized study using fresh stool preparations to treat CDI, Dr. Youngster said. “Larger studied are needed to confirm these results and to evaluate long-term safety and effectiveness.

The study was funded with internal hospital division funds. One author is a recipient of a research award sponsored by Seres Health, Cambridge, Mass., for an unrelated clinical trial of a C. difficile colitis treatment. No other author disclosures were reported.

[email protected]

Treatment of relapsing or recurrent Clostridium difficile infection with frozen, orally administered capsules containing a solution of fecal matter from healthy unrelated donors had promising results, with diarrhea resolving in 90% of patients after one or two rounds of treatment.

“We demonstrated the feasibility of oral administration of frozen encapsulated fecal material from unrelated donors to treat patients with recurrent [Clostridium difficile infection (CDI)],” concluded Dr. Ilan Youngster, of the division of infectious diseases at Massachusetts General Hospital, Boston, and his associates. While the study was limited by the small number patients (20) and the lack of a placebo or comparator group, “if reproduced in future studies with active controls, these results may help make FMT accessible to a wider population of patients, in addition to potentially making the procedure safer.”

Courtesy CDC/Dr. Gilda Jones

The study was published Oct. 11 in JAMA, in conjunction with its presenation at ID Week 2014 (doi:10.1001/jama.2014.13875)

Instead of the most common type of fecal microbiota transplantation (FMT) procedures, which use a suspension of fresh stool from donors related to the patient to reconstitute the normal flora, this feasibility study evaluated the safety and effectiveness of FMT with fecal matter from unrelated, carefully screened healthy donors, which was processed into a solution that was placed into small capsules and then frozen.

The study enrolled 20 patients whose mean age was 64.5 years (one patient was aged 11, the rest were aged 17-89) between August 2013 and June 2014 at Massachusetts General. Patient had had at least three episodes of mild to moderate CDI and failed treatment with vancomycin, with or without an alternative antibiotic; or had been hospitalized with at least 2 episodes of severe CDI.

After one round of treatment with 15 capsules over 2 days, diarrhea resolved (defined as fewer than three bowel movements over 24 hours) in 14 of the 20 patients (70%); at 8 weeks, they remained symptom free. The remaining 6 patients were treated again, a mean of 7 days after the first treatment, and diarrhea resolved in 5. One of the 5 patients relapsed within the 8 week follow-up period, so the overall rate of diarrhea resolution at 8 weeks was 90%.

Overall health score before treatment was the only factor significantly associated with treatment response. Those who required a second treatment had more symptoms and had lower health scores before treatment than those who responded to the first treatment.

The number of daily bowel movements dropped from a median of five per day before treatment to a median of 2 at day 3, and one at 8 weeks, both statistically significant reductions from baseline. Patients also felt better, reflected in improvements in scores on health questionnaires evaluating overall and gastrointestinal health.

There were no cases of vomiting or aspiration and no serious adverse events were observed, Dr. Youngster said. Six patients experienced abdominal cramping and bloating after treatment, which were considered to be treatment related, but resolved.

The 90% clinical resolution rate with this treatment are comparable those in case studies and a randomized study using fresh stool preparations to treat CDI, Dr. Youngster said. “Larger studied are needed to confirm these results and to evaluate long-term safety and effectiveness.

The study was funded with internal hospital division funds. One author is a recipient of a research award sponsored by Seres Health, Cambridge, Mass., for an unrelated clinical trial of a C. difficile colitis treatment. No other author disclosures were reported.

[email protected]

GAITHERSBURG, MD.– A Food and Drug Administration advisory panel narrowly voted to support approval of the Watchman left atrial appendage closure device for patients with nonvalvular atrial fibrillation, a sharp contrast to the panel’s nearly unanimous vote to recommend approval just 10 months earlier.

At the meeting on Oct. 8, the FDA’s Circulatory System Devices panel voted 6-5 with 1 abstention that the benefits of the device outweighed the risks for the proposed indication, to prevent thromboembolism from the left atrial appendage (LAA), with the following statement: The device “may be considered for patients with nonvalvular atrial fibrillation (AF) who, based on CHADS2 or CHA2DS2-VASc scores, would be recommended for warfarin therapy to reduce the risk of stroke and systemic embolism.”

Voting separately on safety and effectiveness, the panel voted 12-0 that there was “reasonable assurance” that the device was safe for use in this population, but voted 6-6 that there was not reasonable assurance that it was effective; the panel chair then voted no to break the tie. (Device panel chairs vote only when the vote is tied). The shift in the panel’s support for approving the device was because of an increase in new ischemic strokes reported in patients treated with the Watchman device in the PREVAIL study, between January and June 2014, after the study was reviewed at the previous panel meeting in December 2013. It was to review these data that the FDA convened the latest meeting.

Panelists voting on both sides of the risk-benefit question said the indication was too broad and should be revised to describe the device as a second-line alternative to warfarin, making clear it is not appropriate for all warfarin-eligible patients. Several of those voting no said they would support approval of a second-line indication.

“As excited as we were last time about the benefits of the device – to the point that the indication was expanded to include all Coumadin-eligible patients now, with these new concerning data from PREVAIL about not preventing ischemic strokes, the device seems to be more appropriate as a second-line therapy for patients who cannot take Coumadin,” one of the panelists, Dr. Ralph Brindis, said in an interview after the meeting. Dr. Brindis, of the University of California, San Francisco, abstained on the risk-benefit question.

The Watchman is a percutaneously delivered permanent cardiac implant placed in the LAA to prevent the embolization of thrombi formed in the LAA, reducing the risk of ischemic stroke and systemic embolism. It was approved in Europe in 2005 and is now approved in more than 70 countries, according to Boston Scientific, the manufacturer.

At the meeting in December, the panel voted 13-1 to recommend approval of the device, based on data from the PREVAIL and PROTECT-AF studies, which compared the device to chronic warfarin, and information from the Continued Access to PREVAIL (CAP2) registry. PREVAIL compared implantation of the device – with 45 days of warfarin plus 81 mg of aspirin for 45 days, followed by 325 mg of aspirin and 75 mg of clopidogrel through 6 months, followed by 325 mg of aspirin a day indefinitely – to chronic warfarin. PREVAIL, which was designed to address limitations of PROTECT-AF, enrolled higher-risk patients.

At that time, patients in PREVAIL had been followed up for an average of 12 months, and only 28% had reached the 18-month follow-up period. The safety endpoint (all-cause death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring surgery or endovascular intervention within 7 days of the procedure) and one of the two primary effectiveness, noninferiority endpoints (18-month rate of ischemic stroke and systemic embolism at least 7 days after randomization) had been met. But the other effectiveness endpoint (a composite of all stroke, systemic embolism, and CV or unexplained death) was not met.

Between January and June 2014, when all the patients had been followed for at least 18 months, there were 8 additional cases of ischemic strokes in the Watchman group, all at least 1 year after the device was implanted, for a total of 13, and no new ischemic strokes in the warfarin-treated group, yielding event rates per 100 patient-years of 2.30 in the Watchman group and 0.34 in the control group. These additional cases “raise questions about the long-term effectiveness of the Watchman device for protecting patients from ischemic stroke,” according to the FDA.

With the additional data, as of June, the safety endpoint was still met, but the data on the device did not meet the noninferiority criteria for either of the two primary effectiveness endpoints, and the FDA convened the meeting for the panel to address whether the totality of the data would change the panel’s conclusion in December that the device had a favorable risk-benefit profile.

The panel chair, Dr. Richard L. Page, chair of the department of medicine at the University of Wisconsin, Madison, said he would have voted positively on the risk-benefit question but would also change the indication, which as written, reflects the patients that were studied. “I have heard consensus from everyone in the room, including the sponsor, that this is not first-line [therapy]. ... We just need the FDA and sponsor to work together to develop a description ... or indication that’s appropriate and gives this important technology a place in our armamentarium to care for our patients with atrial fibrillation.”

The FDA usually follows the recommendations of its advisory panels. The panel members had no potential conflicts to disclose. If approved, the Watchman device would be the first device available that is an alternative to medical therapy for the prevention of stroke in patients with AF.

[email protected]

GAITHERSBURG, MD.– A Food and Drug Administration advisory panel narrowly voted to support approval of the Watchman left atrial appendage closure device for patients with nonvalvular atrial fibrillation, a sharp contrast to the panel’s nearly unanimous vote to recommend approval just 10 months earlier.

At the meeting on Oct. 8, the FDA’s Circulatory System Devices panel voted 6-5 with 1 abstention that the benefits of the device outweighed the risks for the proposed indication, to prevent thromboembolism from the left atrial appendage (LAA), with the following statement: The device “may be considered for patients with nonvalvular atrial fibrillation (AF) who, based on CHADS2 or CHA2DS2-VASc scores, would be recommended for warfarin therapy to reduce the risk of stroke and systemic embolism.”

Voting separately on safety and effectiveness, the panel voted 12-0 that there was “reasonable assurance” that the device was safe for use in this population, but voted 6-6 that there was not reasonable assurance that it was effective; the panel chair then voted no to break the tie. (Device panel chairs vote only when the vote is tied). The shift in the panel’s support for approving the device was because of an increase in new ischemic strokes reported in patients treated with the Watchman device in the PREVAIL study, between January and June 2014, after the study was reviewed at the previous panel meeting in December 2013. It was to review these data that the FDA convened the latest meeting.

Panelists voting on both sides of the risk-benefit question said the indication was too broad and should be revised to describe the device as a second-line alternative to warfarin, making clear it is not appropriate for all warfarin-eligible patients. Several of those voting no said they would support approval of a second-line indication.

“As excited as we were last time about the benefits of the device – to the point that the indication was expanded to include all Coumadin-eligible patients now, with these new concerning data from PREVAIL about not preventing ischemic strokes, the device seems to be more appropriate as a second-line therapy for patients who cannot take Coumadin,” one of the panelists, Dr. Ralph Brindis, said in an interview after the meeting. Dr. Brindis, of the University of California, San Francisco, abstained on the risk-benefit question.

The Watchman is a percutaneously delivered permanent cardiac implant placed in the LAA to prevent the embolization of thrombi formed in the LAA, reducing the risk of ischemic stroke and systemic embolism. It was approved in Europe in 2005 and is now approved in more than 70 countries, according to Boston Scientific, the manufacturer.

At the meeting in December, the panel voted 13-1 to recommend approval of the device, based on data from the PREVAIL and PROTECT-AF studies, which compared the device to chronic warfarin, and information from the Continued Access to PREVAIL (CAP2) registry. PREVAIL compared implantation of the device – with 45 days of warfarin plus 81 mg of aspirin for 45 days, followed by 325 mg of aspirin and 75 mg of clopidogrel through 6 months, followed by 325 mg of aspirin a day indefinitely – to chronic warfarin. PREVAIL, which was designed to address limitations of PROTECT-AF, enrolled higher-risk patients.

At that time, patients in PREVAIL had been followed up for an average of 12 months, and only 28% had reached the 18-month follow-up period. The safety endpoint (all-cause death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring surgery or endovascular intervention within 7 days of the procedure) and one of the two primary effectiveness, noninferiority endpoints (18-month rate of ischemic stroke and systemic embolism at least 7 days after randomization) had been met. But the other effectiveness endpoint (a composite of all stroke, systemic embolism, and CV or unexplained death) was not met.

Between January and June 2014, when all the patients had been followed for at least 18 months, there were 8 additional cases of ischemic strokes in the Watchman group, all at least 1 year after the device was implanted, for a total of 13, and no new ischemic strokes in the warfarin-treated group, yielding event rates per 100 patient-years of 2.30 in the Watchman group and 0.34 in the control group. These additional cases “raise questions about the long-term effectiveness of the Watchman device for protecting patients from ischemic stroke,” according to the FDA.

With the additional data, as of June, the safety endpoint was still met, but the data on the device did not meet the noninferiority criteria for either of the two primary effectiveness endpoints, and the FDA convened the meeting for the panel to address whether the totality of the data would change the panel’s conclusion in December that the device had a favorable risk-benefit profile.

The panel chair, Dr. Richard L. Page, chair of the department of medicine at the University of Wisconsin, Madison, said he would have voted positively on the risk-benefit question but would also change the indication, which as written, reflects the patients that were studied. “I have heard consensus from everyone in the room, including the sponsor, that this is not first-line [therapy]. ... We just need the FDA and sponsor to work together to develop a description ... or indication that’s appropriate and gives this important technology a place in our armamentarium to care for our patients with atrial fibrillation.”

The FDA usually follows the recommendations of its advisory panels. The panel members had no potential conflicts to disclose. If approved, the Watchman device would be the first device available that is an alternative to medical therapy for the prevention of stroke in patients with AF.

[email protected]

GAITHERSBURG, MD.– A Food and Drug Administration advisory panel narrowly voted to support approval of the Watchman left atrial appendage closure device for patients with nonvalvular atrial fibrillation, a sharp contrast to the panel’s nearly unanimous vote to recommend approval just 10 months earlier.

At the meeting on Oct. 8, the FDA’s Circulatory System Devices panel voted 6-5 with 1 abstention that the benefits of the device outweighed the risks for the proposed indication, to prevent thromboembolism from the left atrial appendage (LAA), with the following statement: The device “may be considered for patients with nonvalvular atrial fibrillation (AF) who, based on CHADS2 or CHA2DS2-VASc scores, would be recommended for warfarin therapy to reduce the risk of stroke and systemic embolism.”

Voting separately on safety and effectiveness, the panel voted 12-0 that there was “reasonable assurance” that the device was safe for use in this population, but voted 6-6 that there was not reasonable assurance that it was effective; the panel chair then voted no to break the tie. (Device panel chairs vote only when the vote is tied). The shift in the panel’s support for approving the device was because of an increase in new ischemic strokes reported in patients treated with the Watchman device in the PREVAIL study, between January and June 2014, after the study was reviewed at the previous panel meeting in December 2013. It was to review these data that the FDA convened the latest meeting.

Panelists voting on both sides of the risk-benefit question said the indication was too broad and should be revised to describe the device as a second-line alternative to warfarin, making clear it is not appropriate for all warfarin-eligible patients. Several of those voting no said they would support approval of a second-line indication.

“As excited as we were last time about the benefits of the device – to the point that the indication was expanded to include all Coumadin-eligible patients now, with these new concerning data from PREVAIL about not preventing ischemic strokes, the device seems to be more appropriate as a second-line therapy for patients who cannot take Coumadin,” one of the panelists, Dr. Ralph Brindis, said in an interview after the meeting. Dr. Brindis, of the University of California, San Francisco, abstained on the risk-benefit question.

The Watchman is a percutaneously delivered permanent cardiac implant placed in the LAA to prevent the embolization of thrombi formed in the LAA, reducing the risk of ischemic stroke and systemic embolism. It was approved in Europe in 2005 and is now approved in more than 70 countries, according to Boston Scientific, the manufacturer.

At the meeting in December, the panel voted 13-1 to recommend approval of the device, based on data from the PREVAIL and PROTECT-AF studies, which compared the device to chronic warfarin, and information from the Continued Access to PREVAIL (CAP2) registry. PREVAIL compared implantation of the device – with 45 days of warfarin plus 81 mg of aspirin for 45 days, followed by 325 mg of aspirin and 75 mg of clopidogrel through 6 months, followed by 325 mg of aspirin a day indefinitely – to chronic warfarin. PREVAIL, which was designed to address limitations of PROTECT-AF, enrolled higher-risk patients.

At that time, patients in PREVAIL had been followed up for an average of 12 months, and only 28% had reached the 18-month follow-up period. The safety endpoint (all-cause death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring surgery or endovascular intervention within 7 days of the procedure) and one of the two primary effectiveness, noninferiority endpoints (18-month rate of ischemic stroke and systemic embolism at least 7 days after randomization) had been met. But the other effectiveness endpoint (a composite of all stroke, systemic embolism, and CV or unexplained death) was not met.

Between January and June 2014, when all the patients had been followed for at least 18 months, there were 8 additional cases of ischemic strokes in the Watchman group, all at least 1 year after the device was implanted, for a total of 13, and no new ischemic strokes in the warfarin-treated group, yielding event rates per 100 patient-years of 2.30 in the Watchman group and 0.34 in the control group. These additional cases “raise questions about the long-term effectiveness of the Watchman device for protecting patients from ischemic stroke,” according to the FDA.

With the additional data, as of June, the safety endpoint was still met, but the data on the device did not meet the noninferiority criteria for either of the two primary effectiveness endpoints, and the FDA convened the meeting for the panel to address whether the totality of the data would change the panel’s conclusion in December that the device had a favorable risk-benefit profile.

The panel chair, Dr. Richard L. Page, chair of the department of medicine at the University of Wisconsin, Madison, said he would have voted positively on the risk-benefit question but would also change the indication, which as written, reflects the patients that were studied. “I have heard consensus from everyone in the room, including the sponsor, that this is not first-line [therapy]. ... We just need the FDA and sponsor to work together to develop a description ... or indication that’s appropriate and gives this important technology a place in our armamentarium to care for our patients with atrial fibrillation.”

The FDA usually follows the recommendations of its advisory panels. The panel members had no potential conflicts to disclose. If approved, the Watchman device would be the first device available that is an alternative to medical therapy for the prevention of stroke in patients with AF.

[email protected]

BETHESDA, MD. – Providing naloxone to illicit drug users has been successfully used to reduce risk in this population for about 20 years and is increasingly being used as a risk mitigation strategy in patients on opioids for chronic pain.

Coprescribing naloxone for patients already on opioids for chronic pain to reduce overdoses and mortality is not yet common practice, but “lay naloxone for patients prescribed opioids has a unique and compelling rationale, is expanding around the country, and may be important to have in place prior to interventions restricting access to opioids,” Dr. Phillip Coffin said at a National Institutes of Health Pathways to Prevention Workshop on the role of opioids in chronic pain treatment. Dr. Coffin, of the University of California, San Francisco, spoke during a session on the effectiveness of risk mitigation strategies for opioid treatment.

Preliminary results of a 2014 survey showed that this practice exists at some level in at least 16 states. In San Francisco, providing a prescription for take-home naloxone is now recommended for all patients on opioids for chronic pain at public health primary care clinics, said Dr. Coffin, who also serves as director of substance abuse research at the San Francisco Department of Public Health. The program has been well received by primary care providers, based on early survey results, he said.

In addition to the San Francisco Health Network, sites that provide naloxone to patients on chronic opioids for pain include the U.S. Department of Veterans Affairs, where it is widely implemented; the U.S. Army base in Fort Bragg, N.C.; and the Denver Health Medical Center.

The effectiveness of take-home naloxone in heroin users is well established and “is one of the few interventions with data that suggest a direct impact on opioid overdose mortality,” Dr. Coffin said, citing the precipitous drop in the number of heroin-related deaths in San Francisco and other cities after the distribution of naloxone to heroin users.

As with other strategies to reduce risk in patients on chronic opioid therapy, data on the effectiveness of the naloxone strategy are limited, Dr. Coffin noted. In San Francisco, he is conducting a study – the Naloxone Prescription for Opioid Safety Evaluation (NOSE) – which is evaluating the impact of providing take-home naloxone to patients on chronic opioid therapy at six San Francisco Department of Public Health primary care clinics.

Although randomized controlled trials evaluating this intervention would be ideal, there is a “compelling rationale” for using this approach in this population, and “it’s hard to argue against it logically,” Dr. Coffin said. There are no randomized trial data on the use of epinephrine pens for anaphylaxis, which is used widely as a preventive measure, he pointed out.

The increase in opioid prescribing for pain has been accompanied by an increase in prescription opioid overdose deaths in San Francisco, where more than 90% of the deaths from opioid overdoses are caused by opioid analgesics, Dr. Coffin said.

The decision to offer naloxone to all primary care patients on chronic opioid treatment in the San Francisco Health Network makes it simple, with the mind-set of prescribing it for “risky drugs, not risky patients,” he explained. He noted that it is difficult to accurately assess an individual’s risk of an overdose when starting treatment. This also “reduces the cognitive dissonance among providers, who might think, ‘I’m not going to prescribe naloxone because that means I think the person is at risk of an overdose,’ ” he added.

The language has been adjusted away from the use of the term “overdose,” toward “opioid safety,” because patients on prescription opioids do not perceive themselves as being at risk for an overdose, he said.

In the San Francisco program to date, take-home naloxone has been prescribed to more than 600 patients on opioids for pain. Data from a survey of 105 providers at clinics offering naloxone to these patients revealed that 77% had prescribed naloxone to at least one patient, and 98% said they would likely prescribe it again. In addition, 75% said that prescribing naloxone helped them open the communication about opioids with the patient, and 75% said it helped open a discussion about the alternatives to opioids for pain. None said that they thought prescribing naloxone had a negative effect on their relationship with their pain patients, Dr. Coffin said.

Examples of specific clinician responses provided in the survey included the following: “The act of prescribing naloxone has made clear to my patients that I really am concerned about the very real risk of overdose, and it has also shown them that I really do care,” and “The ability to prescribe naloxone has been the most positive change to our management of chronic pain.”

Naloxone is one of the safest drugs in the U.S. Pharmacopeial Convention, with minimal toxicity, and it is not a controlled substance, Dr. Coffin noted. It is available in a vial for injection, as an intranasal formulation given off-label, and as an autoinjector specifically designed for lay administration that was recently approved by the U.S. Food and Drug Administration. Two intranasal formulations are being developed.

Randomized, feasibility, and qualitative studies of the naloxone approach are underway. Obtaining data on the impact of take-home naloxone on events such as opioid analgesic overdoses and behavioral effects is a critical research need, Dr. Coffin said.

Dr. Coffin had no disclosures. The NOSE study is being funded by the National Institute on Drug Abuse (NIDA). The workshop was sponsored by the National Institutes of Health (NIH) Office of Disease Prevention, the NIH Pain Consortium, NIDA, and the National Institute of Neurological Disorders and Stroke.

[email protected]

BETHESDA, MD. – Providing naloxone to illicit drug users has been successfully used to reduce risk in this population for about 20 years and is increasingly being used as a risk mitigation strategy in patients on opioids for chronic pain.

Coprescribing naloxone for patients already on opioids for chronic pain to reduce overdoses and mortality is not yet common practice, but “lay naloxone for patients prescribed opioids has a unique and compelling rationale, is expanding around the country, and may be important to have in place prior to interventions restricting access to opioids,” Dr. Phillip Coffin said at a National Institutes of Health Pathways to Prevention Workshop on the role of opioids in chronic pain treatment. Dr. Coffin, of the University of California, San Francisco, spoke during a session on the effectiveness of risk mitigation strategies for opioid treatment.

Preliminary results of a 2014 survey showed that this practice exists at some level in at least 16 states. In San Francisco, providing a prescription for take-home naloxone is now recommended for all patients on opioids for chronic pain at public health primary care clinics, said Dr. Coffin, who also serves as director of substance abuse research at the San Francisco Department of Public Health. The program has been well received by primary care providers, based on early survey results, he said.

In addition to the San Francisco Health Network, sites that provide naloxone to patients on chronic opioids for pain include the U.S. Department of Veterans Affairs, where it is widely implemented; the U.S. Army base in Fort Bragg, N.C.; and the Denver Health Medical Center.

The effectiveness of take-home naloxone in heroin users is well established and “is one of the few interventions with data that suggest a direct impact on opioid overdose mortality,” Dr. Coffin said, citing the precipitous drop in the number of heroin-related deaths in San Francisco and other cities after the distribution of naloxone to heroin users.

As with other strategies to reduce risk in patients on chronic opioid therapy, data on the effectiveness of the naloxone strategy are limited, Dr. Coffin noted. In San Francisco, he is conducting a study – the Naloxone Prescription for Opioid Safety Evaluation (NOSE) – which is evaluating the impact of providing take-home naloxone to patients on chronic opioid therapy at six San Francisco Department of Public Health primary care clinics.

Although randomized controlled trials evaluating this intervention would be ideal, there is a “compelling rationale” for using this approach in this population, and “it’s hard to argue against it logically,” Dr. Coffin said. There are no randomized trial data on the use of epinephrine pens for anaphylaxis, which is used widely as a preventive measure, he pointed out.

The increase in opioid prescribing for pain has been accompanied by an increase in prescription opioid overdose deaths in San Francisco, where more than 90% of the deaths from opioid overdoses are caused by opioid analgesics, Dr. Coffin said.

The decision to offer naloxone to all primary care patients on chronic opioid treatment in the San Francisco Health Network makes it simple, with the mind-set of prescribing it for “risky drugs, not risky patients,” he explained. He noted that it is difficult to accurately assess an individual’s risk of an overdose when starting treatment. This also “reduces the cognitive dissonance among providers, who might think, ‘I’m not going to prescribe naloxone because that means I think the person is at risk of an overdose,’ ” he added.

The language has been adjusted away from the use of the term “overdose,” toward “opioid safety,” because patients on prescription opioids do not perceive themselves as being at risk for an overdose, he said.

In the San Francisco program to date, take-home naloxone has been prescribed to more than 600 patients on opioids for pain. Data from a survey of 105 providers at clinics offering naloxone to these patients revealed that 77% had prescribed naloxone to at least one patient, and 98% said they would likely prescribe it again. In addition, 75% said that prescribing naloxone helped them open the communication about opioids with the patient, and 75% said it helped open a discussion about the alternatives to opioids for pain. None said that they thought prescribing naloxone had a negative effect on their relationship with their pain patients, Dr. Coffin said.

Examples of specific clinician responses provided in the survey included the following: “The act of prescribing naloxone has made clear to my patients that I really am concerned about the very real risk of overdose, and it has also shown them that I really do care,” and “The ability to prescribe naloxone has been the most positive change to our management of chronic pain.”

Naloxone is one of the safest drugs in the U.S. Pharmacopeial Convention, with minimal toxicity, and it is not a controlled substance, Dr. Coffin noted. It is available in a vial for injection, as an intranasal formulation given off-label, and as an autoinjector specifically designed for lay administration that was recently approved by the U.S. Food and Drug Administration. Two intranasal formulations are being developed.

Randomized, feasibility, and qualitative studies of the naloxone approach are underway. Obtaining data on the impact of take-home naloxone on events such as opioid analgesic overdoses and behavioral effects is a critical research need, Dr. Coffin said.

Dr. Coffin had no disclosures. The NOSE study is being funded by the National Institute on Drug Abuse (NIDA). The workshop was sponsored by the National Institutes of Health (NIH) Office of Disease Prevention, the NIH Pain Consortium, NIDA, and the National Institute of Neurological Disorders and Stroke.

[email protected]

BETHESDA, MD. – Providing naloxone to illicit drug users has been successfully used to reduce risk in this population for about 20 years and is increasingly being used as a risk mitigation strategy in patients on opioids for chronic pain.

Coprescribing naloxone for patients already on opioids for chronic pain to reduce overdoses and mortality is not yet common practice, but “lay naloxone for patients prescribed opioids has a unique and compelling rationale, is expanding around the country, and may be important to have in place prior to interventions restricting access to opioids,” Dr. Phillip Coffin said at a National Institutes of Health Pathways to Prevention Workshop on the role of opioids in chronic pain treatment. Dr. Coffin, of the University of California, San Francisco, spoke during a session on the effectiveness of risk mitigation strategies for opioid treatment.

Preliminary results of a 2014 survey showed that this practice exists at some level in at least 16 states. In San Francisco, providing a prescription for take-home naloxone is now recommended for all patients on opioids for chronic pain at public health primary care clinics, said Dr. Coffin, who also serves as director of substance abuse research at the San Francisco Department of Public Health. The program has been well received by primary care providers, based on early survey results, he said.

In addition to the San Francisco Health Network, sites that provide naloxone to patients on chronic opioids for pain include the U.S. Department of Veterans Affairs, where it is widely implemented; the U.S. Army base in Fort Bragg, N.C.; and the Denver Health Medical Center.

The effectiveness of take-home naloxone in heroin users is well established and “is one of the few interventions with data that suggest a direct impact on opioid overdose mortality,” Dr. Coffin said, citing the precipitous drop in the number of heroin-related deaths in San Francisco and other cities after the distribution of naloxone to heroin users.

As with other strategies to reduce risk in patients on chronic opioid therapy, data on the effectiveness of the naloxone strategy are limited, Dr. Coffin noted. In San Francisco, he is conducting a study – the Naloxone Prescription for Opioid Safety Evaluation (NOSE) – which is evaluating the impact of providing take-home naloxone to patients on chronic opioid therapy at six San Francisco Department of Public Health primary care clinics.

Although randomized controlled trials evaluating this intervention would be ideal, there is a “compelling rationale” for using this approach in this population, and “it’s hard to argue against it logically,” Dr. Coffin said. There are no randomized trial data on the use of epinephrine pens for anaphylaxis, which is used widely as a preventive measure, he pointed out.

The increase in opioid prescribing for pain has been accompanied by an increase in prescription opioid overdose deaths in San Francisco, where more than 90% of the deaths from opioid overdoses are caused by opioid analgesics, Dr. Coffin said.

The decision to offer naloxone to all primary care patients on chronic opioid treatment in the San Francisco Health Network makes it simple, with the mind-set of prescribing it for “risky drugs, not risky patients,” he explained. He noted that it is difficult to accurately assess an individual’s risk of an overdose when starting treatment. This also “reduces the cognitive dissonance among providers, who might think, ‘I’m not going to prescribe naloxone because that means I think the person is at risk of an overdose,’ ” he added.

The language has been adjusted away from the use of the term “overdose,” toward “opioid safety,” because patients on prescription opioids do not perceive themselves as being at risk for an overdose, he said.

In the San Francisco program to date, take-home naloxone has been prescribed to more than 600 patients on opioids for pain. Data from a survey of 105 providers at clinics offering naloxone to these patients revealed that 77% had prescribed naloxone to at least one patient, and 98% said they would likely prescribe it again. In addition, 75% said that prescribing naloxone helped them open the communication about opioids with the patient, and 75% said it helped open a discussion about the alternatives to opioids for pain. None said that they thought prescribing naloxone had a negative effect on their relationship with their pain patients, Dr. Coffin said.

Examples of specific clinician responses provided in the survey included the following: “The act of prescribing naloxone has made clear to my patients that I really am concerned about the very real risk of overdose, and it has also shown them that I really do care,” and “The ability to prescribe naloxone has been the most positive change to our management of chronic pain.”

Naloxone is one of the safest drugs in the U.S. Pharmacopeial Convention, with minimal toxicity, and it is not a controlled substance, Dr. Coffin noted. It is available in a vial for injection, as an intranasal formulation given off-label, and as an autoinjector specifically designed for lay administration that was recently approved by the U.S. Food and Drug Administration. Two intranasal formulations are being developed.

Randomized, feasibility, and qualitative studies of the naloxone approach are underway. Obtaining data on the impact of take-home naloxone on events such as opioid analgesic overdoses and behavioral effects is a critical research need, Dr. Coffin said.

Dr. Coffin had no disclosures. The NOSE study is being funded by the National Institute on Drug Abuse (NIDA). The workshop was sponsored by the National Institutes of Health (NIH) Office of Disease Prevention, the NIH Pain Consortium, NIDA, and the National Institute of Neurological Disorders and Stroke.

[email protected]

The tumor necrosis factor blocker adalimumab is now approved for treating children with Crohn’s disease, down to age 6 years, AbbVie, the manufacturer, announced on Sept. 25.

The approved indication is for “reducing signs and symptoms and inducing and maintaining clinical remission in patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.”

Approval of the pediatric indication was based on a phase III study of almost 200 patients aged 6-17 years with moderately to severely active disease, the IMAGINE-1 trial, the company said in the statement.

No new safety signals were seen in the study, according to the company.

As with other immunomodulators like adalimumab, the label includes a boxed warning about the increased risks of serious infections and malignancies associated with treatment, which are also explained in the adalimumab medication guide, distributed with each filled prescription.

Adalimumab is administered subcutaneously, with a maintenance dose administered every other week starting at 4 weeks, after induction doses are administered 2 weeks apart during the first month.

Adalimumab, marketed as Humira, was first approved in the United States in 2002. In Europe, it was approved for pediatric patients aged 6-17 years with severe active Crohn’s in 2012.

The updated prescribing information is available at http://www.rxabbvie.com/pdf/humira.pdf.

[email protected]

The tumor necrosis factor blocker adalimumab is now approved for treating children with Crohn’s disease, down to age 6 years, AbbVie, the manufacturer, announced on Sept. 25.

The approved indication is for “reducing signs and symptoms and inducing and maintaining clinical remission in patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.”

Approval of the pediatric indication was based on a phase III study of almost 200 patients aged 6-17 years with moderately to severely active disease, the IMAGINE-1 trial, the company said in the statement.

No new safety signals were seen in the study, according to the company.

As with other immunomodulators like adalimumab, the label includes a boxed warning about the increased risks of serious infections and malignancies associated with treatment, which are also explained in the adalimumab medication guide, distributed with each filled prescription.

Adalimumab is administered subcutaneously, with a maintenance dose administered every other week starting at 4 weeks, after induction doses are administered 2 weeks apart during the first month.

Adalimumab, marketed as Humira, was first approved in the United States in 2002. In Europe, it was approved for pediatric patients aged 6-17 years with severe active Crohn’s in 2012.

The updated prescribing information is available at http://www.rxabbvie.com/pdf/humira.pdf.

[email protected]

The tumor necrosis factor blocker adalimumab is now approved for treating children with Crohn’s disease, down to age 6 years, AbbVie, the manufacturer, announced on Sept. 25.

The approved indication is for “reducing signs and symptoms and inducing and maintaining clinical remission in patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.”

Approval of the pediatric indication was based on a phase III study of almost 200 patients aged 6-17 years with moderately to severely active disease, the IMAGINE-1 trial, the company said in the statement.

No new safety signals were seen in the study, according to the company.

As with other immunomodulators like adalimumab, the label includes a boxed warning about the increased risks of serious infections and malignancies associated with treatment, which are also explained in the adalimumab medication guide, distributed with each filled prescription.

Adalimumab is administered subcutaneously, with a maintenance dose administered every other week starting at 4 weeks, after induction doses are administered 2 weeks apart during the first month.

Adalimumab, marketed as Humira, was first approved in the United States in 2002. In Europe, it was approved for pediatric patients aged 6-17 years with severe active Crohn’s in 2012.

The updated prescribing information is available at http://www.rxabbvie.com/pdf/humira.pdf.

[email protected]