Elizabeth Mechcatie

The quadrivalent version of the Fluarix influenza vaccine has been approved by the Food and Drug Administration, the second quadrivalent seasonal influenza vaccine approved by the agency.

The FDA approved Fluarix Quadrivalent vaccine Dec. 14 for vaccination against seasonal influenza in people aged 3 years and older. Quadrivalent seasonal influenza vaccines contain two influenza A and two influenza B strains, instead of trivalent seasonal influenza vaccines’ two A strains and one B strain.

The newly approved quadrivalent vaccine contains two strains of type A influenza (A/H1N1 and A/H3N2) and two type B strains, a Yamagata lineage strain and a Victoria lineage strain.

This is second quadrivalent influenza vaccine to be approved by the agency. In February, the FDA approved a quadrivalent version of the FluMist influenza vaccine, the intranasal influenza vaccine manufactured by MedImmune, in people aged 2-49 years.

The Fluarix Quadrivalent vaccine will be available in time for the 2013-2014 influenza season, manufacturer GlaxoSmithKline said in a statement Dec. 17. GSK also plans to fulfill orders for the trivalent version of Fluarix, because health care providers typically order influenza vaccine about a year before the next influenza season.

Every year, public health officials have had the difficult task of choosing which B strain to include in the annual seasonal influenza vaccine, based on the different B strains circulating worldwide. The ability to include the two B lineage strains should increase the likelihood that the vaccine will protect people from the influenza B strains that circulate during the influenza season.

The Fluarix Quadrivalent vaccine has not been approved in any country other than the United States, according to GSK.

More information on the two quadrivalent influenza vaccines approved to date is available here.

The quadrivalent version of the Fluarix influenza vaccine has been approved by the Food and Drug Administration, the second quadrivalent seasonal influenza vaccine approved by the agency.

The FDA approved Fluarix Quadrivalent vaccine Dec. 14 for vaccination against seasonal influenza in people aged 3 years and older. Quadrivalent seasonal influenza vaccines contain two influenza A and two influenza B strains, instead of trivalent seasonal influenza vaccines’ two A strains and one B strain.

The newly approved quadrivalent vaccine contains two strains of type A influenza (A/H1N1 and A/H3N2) and two type B strains, a Yamagata lineage strain and a Victoria lineage strain.

This is second quadrivalent influenza vaccine to be approved by the agency. In February, the FDA approved a quadrivalent version of the FluMist influenza vaccine, the intranasal influenza vaccine manufactured by MedImmune, in people aged 2-49 years.

The Fluarix Quadrivalent vaccine will be available in time for the 2013-2014 influenza season, manufacturer GlaxoSmithKline said in a statement Dec. 17. GSK also plans to fulfill orders for the trivalent version of Fluarix, because health care providers typically order influenza vaccine about a year before the next influenza season.

Every year, public health officials have had the difficult task of choosing which B strain to include in the annual seasonal influenza vaccine, based on the different B strains circulating worldwide. The ability to include the two B lineage strains should increase the likelihood that the vaccine will protect people from the influenza B strains that circulate during the influenza season.

The Fluarix Quadrivalent vaccine has not been approved in any country other than the United States, according to GSK.

More information on the two quadrivalent influenza vaccines approved to date is available here.

The quadrivalent version of the Fluarix influenza vaccine has been approved by the Food and Drug Administration, the second quadrivalent seasonal influenza vaccine approved by the agency.

The FDA approved Fluarix Quadrivalent vaccine Dec. 14 for vaccination against seasonal influenza in people aged 3 years and older. Quadrivalent seasonal influenza vaccines contain two influenza A and two influenza B strains, instead of trivalent seasonal influenza vaccines’ two A strains and one B strain.

The newly approved quadrivalent vaccine contains two strains of type A influenza (A/H1N1 and A/H3N2) and two type B strains, a Yamagata lineage strain and a Victoria lineage strain.

This is second quadrivalent influenza vaccine to be approved by the agency. In February, the FDA approved a quadrivalent version of the FluMist influenza vaccine, the intranasal influenza vaccine manufactured by MedImmune, in people aged 2-49 years.

The Fluarix Quadrivalent vaccine will be available in time for the 2013-2014 influenza season, manufacturer GlaxoSmithKline said in a statement Dec. 17. GSK also plans to fulfill orders for the trivalent version of Fluarix, because health care providers typically order influenza vaccine about a year before the next influenza season.

Every year, public health officials have had the difficult task of choosing which B strain to include in the annual seasonal influenza vaccine, based on the different B strains circulating worldwide. The ability to include the two B lineage strains should increase the likelihood that the vaccine will protect people from the influenza B strains that circulate during the influenza season.

The Fluarix Quadrivalent vaccine has not been approved in any country other than the United States, according to GSK.

More information on the two quadrivalent influenza vaccines approved to date is available here.

Pasireotide, a somatostatin analogue, has been approved by the Food and Drug Administration as a treatment for Cushing’s disease in adults "for whom pituitary surgery is not an option or has not been curative."

Pasireotide, which will be marketed as Signifor by Novartis Pharmaceuticals, is administered subcutaneously twice a day. "Although surgery tends to be first-line therapy to treat Cushing’s disease, Signifor is a new treatment option for patients when surgery hasn’t worked or isn’t an option," Dr. Mary Parks, director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing approval on Dec. 14.

t has been approved with a Medication Guide, which will be provided to patients with each filled prescription, describing the risks and adverse reactions associated with treatment, according to the statement.

In the study that was the basis of the approval, treatment was associated with hyperglycemia, detected as early as 2 weeks after patients started the drug, and resulted in exacerbations of diabetes with continued treatment in some patients. Hence, "patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin," the FDA statement said. The recommended dosage is 600 mcg or 900 mcg twice a day, with a recommended dosage range of 300-900 mcg twice a day.

Approval was based on a phase III study of 162 people with Cushing’s disease, with mean urinary cortisol levels at least 1.5 times the upper limit of normal (ULN), who received one of two doses of pasireotide. At 6 months, 15% of the patients treated with 600 mcg twice a day and 26% of those treated with 900 mcg twice a day met the primary endpoint of a urinary free cortisol level at or below the ULN. Treatment was also associated with improvement in the clinical signs and symptoms of Cushing’s disease (N. Engl. J. Med. 2012;366:914-24).

The most common adverse events associated with the treatment reported in at least 20% of patients were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes; 25% of patients had a serious adverse event, and 17% of the patients in the study discontinued treatment because of an adverse event, according to the prescribing information.

In November, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously supported approval of pasireotide, based on the results of the study, although the committee members were concerned about the marked hyperglycemia and abnormal liver enzymes reported in some patients.

Reflecting the panel’s recommendations to further study the long-term adverse effects of hyperglycemia and diabetes associated with the drug after approval, the FDA is requiring the company to conduct three postmarketing studies: a study that evaluates the management of hyperglycemia in treated patients; a long-term registry study of people with Cushing’s disease treated with the drug; and a safety study that will monitor reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency in treated patients.

The prescribing information includes the recommendation to monitor liver tests after 1-2 weeks of treatment, followed by once a month for 3 months and then every 6 months; and dosing recommendations for patients with hepatic impairment.

Pasireotide binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. Lanreotide and octreotide are the two somatostatin analogues that have been previously approved; they are approved for acromegaly, and bind primarily to somatostatin receptor 2. Pasireotide was studied in Cushing’s disease because of its broader binding profile, according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels.

The prescribing information for pasireotide is available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch program at 800-332-1088 or here.

Pasireotide, a somatostatin analogue, has been approved by the Food and Drug Administration as a treatment for Cushing’s disease in adults "for whom pituitary surgery is not an option or has not been curative."

Pasireotide, which will be marketed as Signifor by Novartis Pharmaceuticals, is administered subcutaneously twice a day. "Although surgery tends to be first-line therapy to treat Cushing’s disease, Signifor is a new treatment option for patients when surgery hasn’t worked or isn’t an option," Dr. Mary Parks, director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing approval on Dec. 14.

t has been approved with a Medication Guide, which will be provided to patients with each filled prescription, describing the risks and adverse reactions associated with treatment, according to the statement.

In the study that was the basis of the approval, treatment was associated with hyperglycemia, detected as early as 2 weeks after patients started the drug, and resulted in exacerbations of diabetes with continued treatment in some patients. Hence, "patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin," the FDA statement said. The recommended dosage is 600 mcg or 900 mcg twice a day, with a recommended dosage range of 300-900 mcg twice a day.

Approval was based on a phase III study of 162 people with Cushing’s disease, with mean urinary cortisol levels at least 1.5 times the upper limit of normal (ULN), who received one of two doses of pasireotide. At 6 months, 15% of the patients treated with 600 mcg twice a day and 26% of those treated with 900 mcg twice a day met the primary endpoint of a urinary free cortisol level at or below the ULN. Treatment was also associated with improvement in the clinical signs and symptoms of Cushing’s disease (N. Engl. J. Med. 2012;366:914-24).

The most common adverse events associated with the treatment reported in at least 20% of patients were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes; 25% of patients had a serious adverse event, and 17% of the patients in the study discontinued treatment because of an adverse event, according to the prescribing information.

In November, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously supported approval of pasireotide, based on the results of the study, although the committee members were concerned about the marked hyperglycemia and abnormal liver enzymes reported in some patients.

Reflecting the panel’s recommendations to further study the long-term adverse effects of hyperglycemia and diabetes associated with the drug after approval, the FDA is requiring the company to conduct three postmarketing studies: a study that evaluates the management of hyperglycemia in treated patients; a long-term registry study of people with Cushing’s disease treated with the drug; and a safety study that will monitor reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency in treated patients.

The prescribing information includes the recommendation to monitor liver tests after 1-2 weeks of treatment, followed by once a month for 3 months and then every 6 months; and dosing recommendations for patients with hepatic impairment.

Pasireotide binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. Lanreotide and octreotide are the two somatostatin analogues that have been previously approved; they are approved for acromegaly, and bind primarily to somatostatin receptor 2. Pasireotide was studied in Cushing’s disease because of its broader binding profile, according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels.

The prescribing information for pasireotide is available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch program at 800-332-1088 or here.

Pasireotide, a somatostatin analogue, has been approved by the Food and Drug Administration as a treatment for Cushing’s disease in adults "for whom pituitary surgery is not an option or has not been curative."

Pasireotide, which will be marketed as Signifor by Novartis Pharmaceuticals, is administered subcutaneously twice a day. "Although surgery tends to be first-line therapy to treat Cushing’s disease, Signifor is a new treatment option for patients when surgery hasn’t worked or isn’t an option," Dr. Mary Parks, director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing approval on Dec. 14.

t has been approved with a Medication Guide, which will be provided to patients with each filled prescription, describing the risks and adverse reactions associated with treatment, according to the statement.

In the study that was the basis of the approval, treatment was associated with hyperglycemia, detected as early as 2 weeks after patients started the drug, and resulted in exacerbations of diabetes with continued treatment in some patients. Hence, "patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin," the FDA statement said. The recommended dosage is 600 mcg or 900 mcg twice a day, with a recommended dosage range of 300-900 mcg twice a day.

Approval was based on a phase III study of 162 people with Cushing’s disease, with mean urinary cortisol levels at least 1.5 times the upper limit of normal (ULN), who received one of two doses of pasireotide. At 6 months, 15% of the patients treated with 600 mcg twice a day and 26% of those treated with 900 mcg twice a day met the primary endpoint of a urinary free cortisol level at or below the ULN. Treatment was also associated with improvement in the clinical signs and symptoms of Cushing’s disease (N. Engl. J. Med. 2012;366:914-24).

The most common adverse events associated with the treatment reported in at least 20% of patients were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes; 25% of patients had a serious adverse event, and 17% of the patients in the study discontinued treatment because of an adverse event, according to the prescribing information.

In November, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously supported approval of pasireotide, based on the results of the study, although the committee members were concerned about the marked hyperglycemia and abnormal liver enzymes reported in some patients.

Reflecting the panel’s recommendations to further study the long-term adverse effects of hyperglycemia and diabetes associated with the drug after approval, the FDA is requiring the company to conduct three postmarketing studies: a study that evaluates the management of hyperglycemia in treated patients; a long-term registry study of people with Cushing’s disease treated with the drug; and a safety study that will monitor reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency in treated patients.

The prescribing information includes the recommendation to monitor liver tests after 1-2 weeks of treatment, followed by once a month for 3 months and then every 6 months; and dosing recommendations for patients with hepatic impairment.

Pasireotide binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. Lanreotide and octreotide are the two somatostatin analogues that have been previously approved; they are approved for acromegaly, and bind primarily to somatostatin receptor 2. Pasireotide was studied in Cushing’s disease because of its broader binding profile, according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels.

The prescribing information for pasireotide is available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch program at 800-332-1088 or here.

Health care workers spent less time with patients who were on contact precautions, based on results from a prospective study in the January 2013 issue of Infection Control and Hospital Epidemiology.

Patients on contact precautions for drug-resistant infections had almost 40% fewer visits from health care workers. Further, when they did visit, health care workers spent significantly less time in the rooms of patients on precautions, reported Dr. Daniel Morgan and his associates.

On a positive note, handwashing hygiene improved when health care workers saw patient on contact precautions (Infect. Control Hosp. Epidemiol. 2013;34:69-73).

"Contact precautions modify health care workers’ behavior. This has positive and negative consequences," Dr. Morgan, the lead author, said in an interview.

"Health care workers should be aware of the tendency to visit patients less often and question their own behavior when caring for these patients," said Dr. Morgan of the University of Maryland and the Veterans Affairs (VA) Maryland Health Care System, Baltimore. "Do they visit them less often? Are they at risk of missing anything because a patient is on precautions? Are they creating workarounds for the inconvenience that may impact the patient?"

Research is underway looking at outcomes of patients on isolation and ways to improve these outcomes, "but for a start, it is important that health care workers consider how their behavior may be shaped by contact precautions," he added.

In the prospective cohort study, the activity of health care workers at four acute hospitals was observed for 1-hour periods over 19 months. The trained observers – so-called "secret shoppers" – observed a total of 7,743 visits over 1,989 hours in seven intensive care units and six medical surgical wards at three VA Hospitals and at one medical center, the University of Maryland Medical Center in Baltimore.

Patients on contact precautions had 2.78 visits per hour from health care workers, compared with 4.37 visits per hour among those not on precautions, a statistically significant difference.

Health care workers also spent significantly less time – nearly 18% less – with patients on contact precautions. Time spent per hour was 14 minutes for patients on precautions and 17 minutes for other patients. The time spent with patients in ICUs, however, was similar irrespective of contact precautions.

Health care workers were almost 16% more likely to comply with proper hand hygiene techniques when exiting the rooms of patients on contact precautions. Proper hand washing was observed 63% of the time when leaving the room of a patient on precautions and 47% of the time when exiting the room of a patient not on precautions. This statistically significant difference was "more pronounced" in the ICU setting, the authors wrote.

Contact precautions did not appear to affect compliance with hand hygiene when entering a patient’s room. Overall, the compliance rate with gowns and gloves was 66% for patients on contact precautions.

The compliance rates for hand hygiene and use of gown and gloves recorded in the study were lower than the rates hospitals often report to hospital regulators, but they are in the range of what is routinely reported in more rigorous research, Dr. Morgan said in an interview.

The reduced contact between patients on contact precautions and health care workers was "likely" caused by the "inconvenience of donning gowns and gloves," the authors wrote. The lack of a difference in contact in the ICU could be the "higher acuity of care" or the higher nurse-to-patient ratio, whereby gloves and gowns do not need to be changed as frequently.

The "unintended consequences" of contact precautions are a particular concern now that contact precautions have become more common with programs like the Department of Veterans Affairs MRSA Prevention Initiative, Dr. Morgan and his associates said. The decrease in contact with health care workers "may lead to increased adverse events and a lower quality of patient care due to less consistent patient monitoring and poorer adherence to standard adverse event prevention methods" such as protocols to prevent pressure ulcers, they suggested.

The only non-ICU units observed in the study were in VA hospitals, which was one of the limitations of the study cited by the authors. The strengths of the study included the nearly 2,000 hours of observations at hospitals in different parts of the country.

"We don’t know whether less frequent visits to the patient room necessarily means more adverse events," Dr. Anthony Harris, professor of epidemiology and public health at the University of Maryland, said in an interview. Previous research indicating that contact precautions led to adverse events had some serious methodological flaws.

Dr. Harris, acting medical director of infection control at the University of Maryland Medical Center, is involved in a randomized study evaluating whether universal glove and gown precautions lead to improved or worse outcomes. The study, funded by the Agency for Healthcare Research and Quality (AHRQ), also is examining the frequency of health care worker visits and adverse events and should "provide more definitive answers to the important question of whether contact precautions lead to more adverse events," he said.

Financial support for Dr. Morgan’s study was provided by the VA Health Affairs Services Research and Development Investigator Initiated Research, Association of American Medical Colleges/Centers for Disease Control and Prevention, and AHRQ. Dr. Morgan disclosed having received an unrestricted research grant from Merck; the other authors had no relevant conflicts of interest to disclose. Dr. Harris is on the board of the Society for Healthcare Epidemiology of America, which publishes Infection Control and Hospital Epidemiology.

[email protected]

Health care workers spent less time with patients who were on contact precautions, based on results from a prospective study in the January 2013 issue of Infection Control and Hospital Epidemiology.

Patients on contact precautions for drug-resistant infections had almost 40% fewer visits from health care workers. Further, when they did visit, health care workers spent significantly less time in the rooms of patients on precautions, reported Dr. Daniel Morgan and his associates.

On a positive note, handwashing hygiene improved when health care workers saw patient on contact precautions (Infect. Control Hosp. Epidemiol. 2013;34:69-73).

"Contact precautions modify health care workers’ behavior. This has positive and negative consequences," Dr. Morgan, the lead author, said in an interview.

"Health care workers should be aware of the tendency to visit patients less often and question their own behavior when caring for these patients," said Dr. Morgan of the University of Maryland and the Veterans Affairs (VA) Maryland Health Care System, Baltimore. "Do they visit them less often? Are they at risk of missing anything because a patient is on precautions? Are they creating workarounds for the inconvenience that may impact the patient?"

Research is underway looking at outcomes of patients on isolation and ways to improve these outcomes, "but for a start, it is important that health care workers consider how their behavior may be shaped by contact precautions," he added.

In the prospective cohort study, the activity of health care workers at four acute hospitals was observed for 1-hour periods over 19 months. The trained observers – so-called "secret shoppers" – observed a total of 7,743 visits over 1,989 hours in seven intensive care units and six medical surgical wards at three VA Hospitals and at one medical center, the University of Maryland Medical Center in Baltimore.

Patients on contact precautions had 2.78 visits per hour from health care workers, compared with 4.37 visits per hour among those not on precautions, a statistically significant difference.

Health care workers also spent significantly less time – nearly 18% less – with patients on contact precautions. Time spent per hour was 14 minutes for patients on precautions and 17 minutes for other patients. The time spent with patients in ICUs, however, was similar irrespective of contact precautions.

Health care workers were almost 16% more likely to comply with proper hand hygiene techniques when exiting the rooms of patients on contact precautions. Proper hand washing was observed 63% of the time when leaving the room of a patient on precautions and 47% of the time when exiting the room of a patient not on precautions. This statistically significant difference was "more pronounced" in the ICU setting, the authors wrote.

Contact precautions did not appear to affect compliance with hand hygiene when entering a patient’s room. Overall, the compliance rate with gowns and gloves was 66% for patients on contact precautions.

The compliance rates for hand hygiene and use of gown and gloves recorded in the study were lower than the rates hospitals often report to hospital regulators, but they are in the range of what is routinely reported in more rigorous research, Dr. Morgan said in an interview.

The reduced contact between patients on contact precautions and health care workers was "likely" caused by the "inconvenience of donning gowns and gloves," the authors wrote. The lack of a difference in contact in the ICU could be the "higher acuity of care" or the higher nurse-to-patient ratio, whereby gloves and gowns do not need to be changed as frequently.

The "unintended consequences" of contact precautions are a particular concern now that contact precautions have become more common with programs like the Department of Veterans Affairs MRSA Prevention Initiative, Dr. Morgan and his associates said. The decrease in contact with health care workers "may lead to increased adverse events and a lower quality of patient care due to less consistent patient monitoring and poorer adherence to standard adverse event prevention methods" such as protocols to prevent pressure ulcers, they suggested.

The only non-ICU units observed in the study were in VA hospitals, which was one of the limitations of the study cited by the authors. The strengths of the study included the nearly 2,000 hours of observations at hospitals in different parts of the country.

"We don’t know whether less frequent visits to the patient room necessarily means more adverse events," Dr. Anthony Harris, professor of epidemiology and public health at the University of Maryland, said in an interview. Previous research indicating that contact precautions led to adverse events had some serious methodological flaws.

Dr. Harris, acting medical director of infection control at the University of Maryland Medical Center, is involved in a randomized study evaluating whether universal glove and gown precautions lead to improved or worse outcomes. The study, funded by the Agency for Healthcare Research and Quality (AHRQ), also is examining the frequency of health care worker visits and adverse events and should "provide more definitive answers to the important question of whether contact precautions lead to more adverse events," he said.

Financial support for Dr. Morgan’s study was provided by the VA Health Affairs Services Research and Development Investigator Initiated Research, Association of American Medical Colleges/Centers for Disease Control and Prevention, and AHRQ. Dr. Morgan disclosed having received an unrestricted research grant from Merck; the other authors had no relevant conflicts of interest to disclose. Dr. Harris is on the board of the Society for Healthcare Epidemiology of America, which publishes Infection Control and Hospital Epidemiology.

[email protected]

Health care workers spent less time with patients who were on contact precautions, based on results from a prospective study in the January 2013 issue of Infection Control and Hospital Epidemiology.

Patients on contact precautions for drug-resistant infections had almost 40% fewer visits from health care workers. Further, when they did visit, health care workers spent significantly less time in the rooms of patients on precautions, reported Dr. Daniel Morgan and his associates.

On a positive note, handwashing hygiene improved when health care workers saw patient on contact precautions (Infect. Control Hosp. Epidemiol. 2013;34:69-73).

"Contact precautions modify health care workers’ behavior. This has positive and negative consequences," Dr. Morgan, the lead author, said in an interview.

"Health care workers should be aware of the tendency to visit patients less often and question their own behavior when caring for these patients," said Dr. Morgan of the University of Maryland and the Veterans Affairs (VA) Maryland Health Care System, Baltimore. "Do they visit them less often? Are they at risk of missing anything because a patient is on precautions? Are they creating workarounds for the inconvenience that may impact the patient?"

Research is underway looking at outcomes of patients on isolation and ways to improve these outcomes, "but for a start, it is important that health care workers consider how their behavior may be shaped by contact precautions," he added.

In the prospective cohort study, the activity of health care workers at four acute hospitals was observed for 1-hour periods over 19 months. The trained observers – so-called "secret shoppers" – observed a total of 7,743 visits over 1,989 hours in seven intensive care units and six medical surgical wards at three VA Hospitals and at one medical center, the University of Maryland Medical Center in Baltimore.

Patients on contact precautions had 2.78 visits per hour from health care workers, compared with 4.37 visits per hour among those not on precautions, a statistically significant difference.

Health care workers also spent significantly less time – nearly 18% less – with patients on contact precautions. Time spent per hour was 14 minutes for patients on precautions and 17 minutes for other patients. The time spent with patients in ICUs, however, was similar irrespective of contact precautions.

Health care workers were almost 16% more likely to comply with proper hand hygiene techniques when exiting the rooms of patients on contact precautions. Proper hand washing was observed 63% of the time when leaving the room of a patient on precautions and 47% of the time when exiting the room of a patient not on precautions. This statistically significant difference was "more pronounced" in the ICU setting, the authors wrote.

Contact precautions did not appear to affect compliance with hand hygiene when entering a patient’s room. Overall, the compliance rate with gowns and gloves was 66% for patients on contact precautions.

The compliance rates for hand hygiene and use of gown and gloves recorded in the study were lower than the rates hospitals often report to hospital regulators, but they are in the range of what is routinely reported in more rigorous research, Dr. Morgan said in an interview.

The reduced contact between patients on contact precautions and health care workers was "likely" caused by the "inconvenience of donning gowns and gloves," the authors wrote. The lack of a difference in contact in the ICU could be the "higher acuity of care" or the higher nurse-to-patient ratio, whereby gloves and gowns do not need to be changed as frequently.

The "unintended consequences" of contact precautions are a particular concern now that contact precautions have become more common with programs like the Department of Veterans Affairs MRSA Prevention Initiative, Dr. Morgan and his associates said. The decrease in contact with health care workers "may lead to increased adverse events and a lower quality of patient care due to less consistent patient monitoring and poorer adherence to standard adverse event prevention methods" such as protocols to prevent pressure ulcers, they suggested.

The only non-ICU units observed in the study were in VA hospitals, which was one of the limitations of the study cited by the authors. The strengths of the study included the nearly 2,000 hours of observations at hospitals in different parts of the country.

"We don’t know whether less frequent visits to the patient room necessarily means more adverse events," Dr. Anthony Harris, professor of epidemiology and public health at the University of Maryland, said in an interview. Previous research indicating that contact precautions led to adverse events had some serious methodological flaws.

Dr. Harris, acting medical director of infection control at the University of Maryland Medical Center, is involved in a randomized study evaluating whether universal glove and gown precautions lead to improved or worse outcomes. The study, funded by the Agency for Healthcare Research and Quality (AHRQ), also is examining the frequency of health care worker visits and adverse events and should "provide more definitive answers to the important question of whether contact precautions lead to more adverse events," he said.

Financial support for Dr. Morgan’s study was provided by the VA Health Affairs Services Research and Development Investigator Initiated Research, Association of American Medical Colleges/Centers for Disease Control and Prevention, and AHRQ. Dr. Morgan disclosed having received an unrestricted research grant from Merck; the other authors had no relevant conflicts of interest to disclose. Dr. Harris is on the board of the Society for Healthcare Epidemiology of America, which publishes Infection Control and Hospital Epidemiology.

[email protected]

Ponatinib, an oral tyrosine kinase inhibitor, has been approved for treating chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia in adults, the Food and Drug Administration announced on Dec. 14.

The expedited approval – which came 3 months ahead of the agency’s target date for action on ponatinib – gives a new option to patients who have stopped responding to other approved therapies for these fatal blood cancers. A BCR-ABL inhibitor, ponatinib is the only drug to date that has shown efficacy in chronic myeloid leukemia (CML) with the T315I mutation.

Ponatinib will be marketed as Iclusig by Ariad Pharmaceuticals. The company said it will be available in the United States in about 2 weeks via "select specialty pharmacies." It also announced establishment of the ARIAD PASS (Patient Access and Support Services) program to help patients who are without insurance or underinsured gain access to ponatinib.

The approved indication is for "chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy."

The recommended dose is 45 mg once daily.

The prescribing information notes that the approved indication is based upon response rate, and that "there are no trials verifying an improvement in disease-related symptoms or increased survival," with treatment.

The expedited approval was based on the results of one study of 449 patients with various phases of CML and Ph+ALL, who were treated with ponatinib.

Dr. Jorge Cortes of the University of Texas M.D. Anderson Cancer Center in Houston reported 12-month outcomes of the pivotal phase II PACE trial earlier in December at the American Society of Hematology annual meeting in Atlanta.

"These results suggest that ponatinib has outstanding clinical activity in patients with chronic myeloid leukemia, or Philadelphia-positive patients with acute lymphoblastic leukemia," he said at a press briefing during the meeting.

"These responses have been regardless of the stage of disease and regardless of the presence or absence of mutations. And the responses are very deep, rapid, and sustained to the extent of the follow-up we have so far, with a drug that is very well tolerated."

In the study, 54% of all patients and 70% of those with the T315I mutation had a major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PcyR). At the time the data were analyzed, the median duration of MCyR had not been reached, according to the FDA.

In addition, 52% of those with accelerated phase CML had a major hematologic response (MaHR) that lasted for a median of 9.5 months; 31% of those with blast-phase CML had a MaHR that lasted for a median duration of 4.7 months; and 41% of those with Ph-positive ALL had a MaHR that lasted for a median of 3.2 months.

The most common side effects in the study included hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. The label includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

It is the third drug approved for CML and the second drug approved for ALL this year. The other treatments approved for various phases of CML this year are bosutinib (Bosulif) in September and omacetaxine mepesuccinate (Synribo) in October. In August, vincristine sulfate liposome injection (Marqibo) was approved to treat Philadelphia chromosome–negative ALL.

About 5,000 people a year develop CML, which has become a chronic condition for most patients since the introduction of imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) – all approved as first-line therapies. But some people cannot tolerate or become resistant to these drugs, and those with T315I did not respond.

Consequently, ponatinib was granted a priority review, which is completed in 6 months instead of the standard 12 months, and is used for drugs "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," the FDA said.

"The approval of Iclusig is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have had few therapeutic options," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement.

Ponatinib, an oral tyrosine kinase inhibitor, has been approved for treating chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia in adults, the Food and Drug Administration announced on Dec. 14.

The expedited approval – which came 3 months ahead of the agency’s target date for action on ponatinib – gives a new option to patients who have stopped responding to other approved therapies for these fatal blood cancers. A BCR-ABL inhibitor, ponatinib is the only drug to date that has shown efficacy in chronic myeloid leukemia (CML) with the T315I mutation.

Ponatinib will be marketed as Iclusig by Ariad Pharmaceuticals. The company said it will be available in the United States in about 2 weeks via "select specialty pharmacies." It also announced establishment of the ARIAD PASS (Patient Access and Support Services) program to help patients who are without insurance or underinsured gain access to ponatinib.

The approved indication is for "chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy."

The recommended dose is 45 mg once daily.

The prescribing information notes that the approved indication is based upon response rate, and that "there are no trials verifying an improvement in disease-related symptoms or increased survival," with treatment.

The expedited approval was based on the results of one study of 449 patients with various phases of CML and Ph+ALL, who were treated with ponatinib.

Dr. Jorge Cortes of the University of Texas M.D. Anderson Cancer Center in Houston reported 12-month outcomes of the pivotal phase II PACE trial earlier in December at the American Society of Hematology annual meeting in Atlanta.

"These results suggest that ponatinib has outstanding clinical activity in patients with chronic myeloid leukemia, or Philadelphia-positive patients with acute lymphoblastic leukemia," he said at a press briefing during the meeting.

"These responses have been regardless of the stage of disease and regardless of the presence or absence of mutations. And the responses are very deep, rapid, and sustained to the extent of the follow-up we have so far, with a drug that is very well tolerated."

In the study, 54% of all patients and 70% of those with the T315I mutation had a major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PcyR). At the time the data were analyzed, the median duration of MCyR had not been reached, according to the FDA.

In addition, 52% of those with accelerated phase CML had a major hematologic response (MaHR) that lasted for a median of 9.5 months; 31% of those with blast-phase CML had a MaHR that lasted for a median duration of 4.7 months; and 41% of those with Ph-positive ALL had a MaHR that lasted for a median of 3.2 months.

The most common side effects in the study included hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. The label includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

It is the third drug approved for CML and the second drug approved for ALL this year. The other treatments approved for various phases of CML this year are bosutinib (Bosulif) in September and omacetaxine mepesuccinate (Synribo) in October. In August, vincristine sulfate liposome injection (Marqibo) was approved to treat Philadelphia chromosome–negative ALL.

About 5,000 people a year develop CML, which has become a chronic condition for most patients since the introduction of imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) – all approved as first-line therapies. But some people cannot tolerate or become resistant to these drugs, and those with T315I did not respond.

Consequently, ponatinib was granted a priority review, which is completed in 6 months instead of the standard 12 months, and is used for drugs "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," the FDA said.

"The approval of Iclusig is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have had few therapeutic options," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement.

Ponatinib, an oral tyrosine kinase inhibitor, has been approved for treating chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia in adults, the Food and Drug Administration announced on Dec. 14.

The expedited approval – which came 3 months ahead of the agency’s target date for action on ponatinib – gives a new option to patients who have stopped responding to other approved therapies for these fatal blood cancers. A BCR-ABL inhibitor, ponatinib is the only drug to date that has shown efficacy in chronic myeloid leukemia (CML) with the T315I mutation.

Ponatinib will be marketed as Iclusig by Ariad Pharmaceuticals. The company said it will be available in the United States in about 2 weeks via "select specialty pharmacies." It also announced establishment of the ARIAD PASS (Patient Access and Support Services) program to help patients who are without insurance or underinsured gain access to ponatinib.

The approved indication is for "chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy."

The recommended dose is 45 mg once daily.

The prescribing information notes that the approved indication is based upon response rate, and that "there are no trials verifying an improvement in disease-related symptoms or increased survival," with treatment.

The expedited approval was based on the results of one study of 449 patients with various phases of CML and Ph+ALL, who were treated with ponatinib.

Dr. Jorge Cortes of the University of Texas M.D. Anderson Cancer Center in Houston reported 12-month outcomes of the pivotal phase II PACE trial earlier in December at the American Society of Hematology annual meeting in Atlanta.

"These results suggest that ponatinib has outstanding clinical activity in patients with chronic myeloid leukemia, or Philadelphia-positive patients with acute lymphoblastic leukemia," he said at a press briefing during the meeting.

"These responses have been regardless of the stage of disease and regardless of the presence or absence of mutations. And the responses are very deep, rapid, and sustained to the extent of the follow-up we have so far, with a drug that is very well tolerated."

In the study, 54% of all patients and 70% of those with the T315I mutation had a major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PcyR). At the time the data were analyzed, the median duration of MCyR had not been reached, according to the FDA.

In addition, 52% of those with accelerated phase CML had a major hematologic response (MaHR) that lasted for a median of 9.5 months; 31% of those with blast-phase CML had a MaHR that lasted for a median duration of 4.7 months; and 41% of those with Ph-positive ALL had a MaHR that lasted for a median of 3.2 months.

The most common side effects in the study included hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and nausea. The label includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

It is the third drug approved for CML and the second drug approved for ALL this year. The other treatments approved for various phases of CML this year are bosutinib (Bosulif) in September and omacetaxine mepesuccinate (Synribo) in October. In August, vincristine sulfate liposome injection (Marqibo) was approved to treat Philadelphia chromosome–negative ALL.

About 5,000 people a year develop CML, which has become a chronic condition for most patients since the introduction of imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) – all approved as first-line therapies. But some people cannot tolerate or become resistant to these drugs, and those with T315I did not respond.

Consequently, ponatinib was granted a priority review, which is completed in 6 months instead of the standard 12 months, and is used for drugs "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," the FDA said.

"The approval of Iclusig is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have had few therapeutic options," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement.

The rate of major adverse cardiovascular events was higher among patients treated with varenicline than those on placebo in a meta-analysis, but the difference was not statistically significant, according to the latest Food and Drug Administration statement on the cardiovascular safety of the smoking cessation drug.

In the study, conducted by the manufacturer at the request of the FDA, major adverse cardiovascular events (MACEs), a composite endpoint of cardiovascular-related death, nonfatal MI, and nonfatal stroke, "were uncommon in both the Chantix and placebo groups, and the increased risk was not statistically significant, which means it is uncertain whether the excess risk for the Chantix group was due to the drug or due to chance," the FDA statement said. Varenicline, a nicotinic receptor partial agonist marketed as Chantix by Pfizer, was approved in 2006.

Courtesy CDC/Debora Cartagena

The first notice issued by the FDA about the drug’s possible cardiac risks was in June 2011. That notice reported the increased risk in a smoking cessation trial of patients with stable cardiovascular disease, prompting the FDA to require the company to conduct the meta-analysis. The FDA statement, dated Dec. 12, says the findings of the meta-analysis are similar to the findings of the smoking cessation study.

The meta-analysis compared the MACE incidence of patients treated for at least 12 weeks, in 15 randomized, double-blind, placebo-controlled studies conducted by Pfizer. Within 30 days of stopping the drug, the incidence of MACE was 0.31% (13 cases among 4,190 patients) in those on the drug, compared with 0.21% (6 cases among 2,812 on placebo). This is comparable to an increase of 6.3 MACE cases per 1,000 patient years of exposure, the FDA said.

In the study, the rates of composite outcomes were higher among those on varenicline "across different time frames and prespecified sensitivity analyses, including various study groupings and cardiovascular endpoints," and while not significantly different, they were consistent, the statement said.

The FDA also points out that cardiovascular mortality and all-cause mortality, components of the MACE endpoint, were lower among the patients on varenicline, although the differences were not significant. The rate of cardiovascular mortality was 0.05% (two cases) among those on varenicline, compared with 0.07% (two cases) among those on placebo. The rate of all-cause mortality was 0.14% among those on varenicline (6 cases), compared with 0.25% (7 cases) among those on placebo.

In the statement, the FDA advises that when weighing the risks and benefits of varenicline, health care professionals should consider the "immediate and substantial" health benefits of quitting smoking, and that "Chantix is effective in helping patients to quit smoking and abstain from it for as long as one year," the FDA advised in the statement. Patients should also be counseled to seek medical help if they develop new or worsening cardiovascular disease symptoms during treatment with varenicline, the statement added.

The results of the meta-analysis have been added to the warnings and precautions section of the drug’s label.

About 2.3 million varenicline prescriptions were dispensed and about 1.26 million patients received prescriptions for the drug from outpatient retail pharmacies in the United States, during the 12-month period ending in September 2012, according to the FDA.

The safety communication is available here. Serious adverse events associated with varenicline should be reported to the FDA at 800-332-1088 or here.

The rate of major adverse cardiovascular events was higher among patients treated with varenicline than those on placebo in a meta-analysis, but the difference was not statistically significant, according to the latest Food and Drug Administration statement on the cardiovascular safety of the smoking cessation drug.

In the study, conducted by the manufacturer at the request of the FDA, major adverse cardiovascular events (MACEs), a composite endpoint of cardiovascular-related death, nonfatal MI, and nonfatal stroke, "were uncommon in both the Chantix and placebo groups, and the increased risk was not statistically significant, which means it is uncertain whether the excess risk for the Chantix group was due to the drug or due to chance," the FDA statement said. Varenicline, a nicotinic receptor partial agonist marketed as Chantix by Pfizer, was approved in 2006.

Courtesy CDC/Debora Cartagena

The first notice issued by the FDA about the drug’s possible cardiac risks was in June 2011. That notice reported the increased risk in a smoking cessation trial of patients with stable cardiovascular disease, prompting the FDA to require the company to conduct the meta-analysis. The FDA statement, dated Dec. 12, says the findings of the meta-analysis are similar to the findings of the smoking cessation study.

The meta-analysis compared the MACE incidence of patients treated for at least 12 weeks, in 15 randomized, double-blind, placebo-controlled studies conducted by Pfizer. Within 30 days of stopping the drug, the incidence of MACE was 0.31% (13 cases among 4,190 patients) in those on the drug, compared with 0.21% (6 cases among 2,812 on placebo). This is comparable to an increase of 6.3 MACE cases per 1,000 patient years of exposure, the FDA said.

In the study, the rates of composite outcomes were higher among those on varenicline "across different time frames and prespecified sensitivity analyses, including various study groupings and cardiovascular endpoints," and while not significantly different, they were consistent, the statement said.

The FDA also points out that cardiovascular mortality and all-cause mortality, components of the MACE endpoint, were lower among the patients on varenicline, although the differences were not significant. The rate of cardiovascular mortality was 0.05% (two cases) among those on varenicline, compared with 0.07% (two cases) among those on placebo. The rate of all-cause mortality was 0.14% among those on varenicline (6 cases), compared with 0.25% (7 cases) among those on placebo.

In the statement, the FDA advises that when weighing the risks and benefits of varenicline, health care professionals should consider the "immediate and substantial" health benefits of quitting smoking, and that "Chantix is effective in helping patients to quit smoking and abstain from it for as long as one year," the FDA advised in the statement. Patients should also be counseled to seek medical help if they develop new or worsening cardiovascular disease symptoms during treatment with varenicline, the statement added.

The results of the meta-analysis have been added to the warnings and precautions section of the drug’s label.

About 2.3 million varenicline prescriptions were dispensed and about 1.26 million patients received prescriptions for the drug from outpatient retail pharmacies in the United States, during the 12-month period ending in September 2012, according to the FDA.

The safety communication is available here. Serious adverse events associated with varenicline should be reported to the FDA at 800-332-1088 or here.

The rate of major adverse cardiovascular events was higher among patients treated with varenicline than those on placebo in a meta-analysis, but the difference was not statistically significant, according to the latest Food and Drug Administration statement on the cardiovascular safety of the smoking cessation drug.

In the study, conducted by the manufacturer at the request of the FDA, major adverse cardiovascular events (MACEs), a composite endpoint of cardiovascular-related death, nonfatal MI, and nonfatal stroke, "were uncommon in both the Chantix and placebo groups, and the increased risk was not statistically significant, which means it is uncertain whether the excess risk for the Chantix group was due to the drug or due to chance," the FDA statement said. Varenicline, a nicotinic receptor partial agonist marketed as Chantix by Pfizer, was approved in 2006.

Courtesy CDC/Debora Cartagena

The first notice issued by the FDA about the drug’s possible cardiac risks was in June 2011. That notice reported the increased risk in a smoking cessation trial of patients with stable cardiovascular disease, prompting the FDA to require the company to conduct the meta-analysis. The FDA statement, dated Dec. 12, says the findings of the meta-analysis are similar to the findings of the smoking cessation study.

The meta-analysis compared the MACE incidence of patients treated for at least 12 weeks, in 15 randomized, double-blind, placebo-controlled studies conducted by Pfizer. Within 30 days of stopping the drug, the incidence of MACE was 0.31% (13 cases among 4,190 patients) in those on the drug, compared with 0.21% (6 cases among 2,812 on placebo). This is comparable to an increase of 6.3 MACE cases per 1,000 patient years of exposure, the FDA said.

In the study, the rates of composite outcomes were higher among those on varenicline "across different time frames and prespecified sensitivity analyses, including various study groupings and cardiovascular endpoints," and while not significantly different, they were consistent, the statement said.

The FDA also points out that cardiovascular mortality and all-cause mortality, components of the MACE endpoint, were lower among the patients on varenicline, although the differences were not significant. The rate of cardiovascular mortality was 0.05% (two cases) among those on varenicline, compared with 0.07% (two cases) among those on placebo. The rate of all-cause mortality was 0.14% among those on varenicline (6 cases), compared with 0.25% (7 cases) among those on placebo.

In the statement, the FDA advises that when weighing the risks and benefits of varenicline, health care professionals should consider the "immediate and substantial" health benefits of quitting smoking, and that "Chantix is effective in helping patients to quit smoking and abstain from it for as long as one year," the FDA advised in the statement. Patients should also be counseled to seek medical help if they develop new or worsening cardiovascular disease symptoms during treatment with varenicline, the statement added.

The results of the meta-analysis have been added to the warnings and precautions section of the drug’s label.

About 2.3 million varenicline prescriptions were dispensed and about 1.26 million patients received prescriptions for the drug from outpatient retail pharmacies in the United States, during the 12-month period ending in September 2012, according to the FDA.

The safety communication is available here. Serious adverse events associated with varenicline should be reported to the FDA at 800-332-1088 or here.

In a study of 400 healthy adults, measurements indicating the presence of what has been thought to be aspirin resistance were evident only with enteric-coated aspirin, not immediate-release aspirin, which the authors have described as aspirin "pseudoresistance."

The researchers used several measurements to evaluate responses reflecting the activity of cyclooxygenase-1 (COX-1), the molecular target of aspirin, including platelet aggregation and serum thromboxane formation, which could indicate a genetic cause of aspirin resistance. Still, "we failed to find a single person who satisfied" the criteria for true aspirin resistance, reported Dr. Tilo Grosser, of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine in Philadelphia, and his associates. "By contrast, pseudoresistance, due to delayed and reduced drug absorption, was common after ingestion of enteric-coated aspirin," they said.

"These observations question the value of seeking to diagnose aspirin resistance with single point-of-care diagnostic approaches and support the finding of inconsistent platelet inhibition following enteric-coated preparations of aspirin," they concluded. The study appeared in Circulation online Dec. 4 (2012 [doi: 10.1161/CIRCULATIONAHA.112.117283]).

The concept of aspirin resistance has been used to explain treatment failures occurring in patients, with estimates of incidence ranging from 5% to 20% in studies, they noted.

The study had several phases, which included screening the study participants, aged 18-55 years, for their response to a single 325-mg dose of immediate-release or enteric-coated aspirin, repeating testing among those who appeared to be resistant to aspirin, and comparing responses in responders and nonresponders.

Among the specific findings: All of the individuals who received a dose of immediate-release aspirin were responders, but up to 49% of those who received enteric aspirin were considered nonresponders. With repeated exposure, individuals categorized as nonresponders when given enteric-coated aspirin showed evidence of responses when administered immediate-release aspirin.

"What they have shown in an extremely elegant way is that aspirin resistance, at least in healthy volunteers, doesn’t exist," Dr. Deepak Bhatt said in an interview.

Of great interest to physicians and patients is the finding that in the individuals who appeared to be aspirin resistant, enteric coating on aspirin was delaying and reducing absorption, which is consistent with old data that indicate enteric coating can interfere with aspirin absorption, he said. While this may have been suspected as an explanation for so-called aspirin resistance, "this is the first time someone has really nailed it down in a scientifically unassailable way," said Dr. Bhatt, professor of medicine at Harvard University, Boston, and chief of cardiology at VA Boston Healthcare System.

Although the results need to be replicated in patients with actual disease, such as diabetes or atherosclerosis, he said the results will potentially impact practice, although immediate-release aspirin is recommended for patients who are being stented or are having a myocardial infarction, for the rapid pharmacologic effect.

But the results raise further questions about more chronic administration of aspirin in patients who are not acutely ill and how many of these patients may not be fully absorbing aspirin if they are taking an enteric-coated formulation. "If there is a proportion of patients who are not getting the full anticlotting effect of aspirin ... that means potentially millions of patients are taking enteric-coated aspirin and not getting the protection they or their doctors are assuming they are getting," he said.

Another consideration, which he said is not widely appreciated, is that evidence that enteric coating reduces stomach bleeding "is quite scant, some might even say nonexistent." While enteric coated aspirin does reduce stomach upset, it is used for GI bleeding protection, "but if you’re not getting the GI benefit, and now potentially there is this issue of pseudoresistance these authors are raising, you’ve got to think twice about whether enteric coating is doing anything useful or good."

Dr. Bhatt’s recommendation to clinicians, which predates the publication of this study, is to make sure that patients who are prescribed the immediate-release aspirin get the correct formulation, and not end up with an enteric-coated formulation unintentionally.

Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, also advised caution about extrapolating the results of a study of healthy volunteers to patients with heart disease or chronic illnesses that may affect how aspirin works in the body. The study was not designed to address comparative clinical efficacy or safety between the two formulations, and he views it as "a mechanistic study demonstrating a pharmacokinetic reason for variability in aspirin responsiveness."

In an interview, he added that testing for aspirin resistance is "of dubious value," and the concept, like resistance to clopidogrel, "is driven to a large extent by marketing considerations," and the development of tests to assess aspirin responsiveness.

Dr. Kaul said he will continue to recommend immediate-release formulation for rapid onset of action and switch to enteric-coated aspirin for chronic use, especially in patients with a history of gastric intolerance or side effects. Although "unequivocal evidence" of safety advantages over immediate-release aspirin, such as GI bleeding, is lacking, data have shown reduced rates of gastric erosions on endoscopy associated with enteric-coated aspirin, although the clinical relevance of the erosions is unclear, he said.

The study was funded by the National Heart, Lung, and Blood Institute; the National Center for Research Resources; the American Heart Association; and Bayer HealthCare. Coauthor Dr. Garret FitzGerald of the University of Pennsylvania, Philadelphia, received research funding from Bayer HealthCare to support partial funding of this study, and Dr. Grosser received consultancy fees from PLx Pharma. The four remaining coauthors had no potential conflicts of interest to disclose.

Dr. Bhatt said his disclosures include being an unpaid consultant to PLx Pharma. Dr. Kaul said he had no relevant disclosures.

In a study of 400 healthy adults, measurements indicating the presence of what has been thought to be aspirin resistance were evident only with enteric-coated aspirin, not immediate-release aspirin, which the authors have described as aspirin "pseudoresistance."

The researchers used several measurements to evaluate responses reflecting the activity of cyclooxygenase-1 (COX-1), the molecular target of aspirin, including platelet aggregation and serum thromboxane formation, which could indicate a genetic cause of aspirin resistance. Still, "we failed to find a single person who satisfied" the criteria for true aspirin resistance, reported Dr. Tilo Grosser, of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine in Philadelphia, and his associates. "By contrast, pseudoresistance, due to delayed and reduced drug absorption, was common after ingestion of enteric-coated aspirin," they said.

"These observations question the value of seeking to diagnose aspirin resistance with single point-of-care diagnostic approaches and support the finding of inconsistent platelet inhibition following enteric-coated preparations of aspirin," they concluded. The study appeared in Circulation online Dec. 4 (2012 [doi: 10.1161/CIRCULATIONAHA.112.117283]).

The concept of aspirin resistance has been used to explain treatment failures occurring in patients, with estimates of incidence ranging from 5% to 20% in studies, they noted.

The study had several phases, which included screening the study participants, aged 18-55 years, for their response to a single 325-mg dose of immediate-release or enteric-coated aspirin, repeating testing among those who appeared to be resistant to aspirin, and comparing responses in responders and nonresponders.

Among the specific findings: All of the individuals who received a dose of immediate-release aspirin were responders, but up to 49% of those who received enteric aspirin were considered nonresponders. With repeated exposure, individuals categorized as nonresponders when given enteric-coated aspirin showed evidence of responses when administered immediate-release aspirin.

"What they have shown in an extremely elegant way is that aspirin resistance, at least in healthy volunteers, doesn’t exist," Dr. Deepak Bhatt said in an interview.

Of great interest to physicians and patients is the finding that in the individuals who appeared to be aspirin resistant, enteric coating on aspirin was delaying and reducing absorption, which is consistent with old data that indicate enteric coating can interfere with aspirin absorption, he said. While this may have been suspected as an explanation for so-called aspirin resistance, "this is the first time someone has really nailed it down in a scientifically unassailable way," said Dr. Bhatt, professor of medicine at Harvard University, Boston, and chief of cardiology at VA Boston Healthcare System.

Although the results need to be replicated in patients with actual disease, such as diabetes or atherosclerosis, he said the results will potentially impact practice, although immediate-release aspirin is recommended for patients who are being stented or are having a myocardial infarction, for the rapid pharmacologic effect.

But the results raise further questions about more chronic administration of aspirin in patients who are not acutely ill and how many of these patients may not be fully absorbing aspirin if they are taking an enteric-coated formulation. "If there is a proportion of patients who are not getting the full anticlotting effect of aspirin ... that means potentially millions of patients are taking enteric-coated aspirin and not getting the protection they or their doctors are assuming they are getting," he said.

Another consideration, which he said is not widely appreciated, is that evidence that enteric coating reduces stomach bleeding "is quite scant, some might even say nonexistent." While enteric coated aspirin does reduce stomach upset, it is used for GI bleeding protection, "but if you’re not getting the GI benefit, and now potentially there is this issue of pseudoresistance these authors are raising, you’ve got to think twice about whether enteric coating is doing anything useful or good."

Dr. Bhatt’s recommendation to clinicians, which predates the publication of this study, is to make sure that patients who are prescribed the immediate-release aspirin get the correct formulation, and not end up with an enteric-coated formulation unintentionally.

Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, also advised caution about extrapolating the results of a study of healthy volunteers to patients with heart disease or chronic illnesses that may affect how aspirin works in the body. The study was not designed to address comparative clinical efficacy or safety between the two formulations, and he views it as "a mechanistic study demonstrating a pharmacokinetic reason for variability in aspirin responsiveness."

In an interview, he added that testing for aspirin resistance is "of dubious value," and the concept, like resistance to clopidogrel, "is driven to a large extent by marketing considerations," and the development of tests to assess aspirin responsiveness.

Dr. Kaul said he will continue to recommend immediate-release formulation for rapid onset of action and switch to enteric-coated aspirin for chronic use, especially in patients with a history of gastric intolerance or side effects. Although "unequivocal evidence" of safety advantages over immediate-release aspirin, such as GI bleeding, is lacking, data have shown reduced rates of gastric erosions on endoscopy associated with enteric-coated aspirin, although the clinical relevance of the erosions is unclear, he said.

The study was funded by the National Heart, Lung, and Blood Institute; the National Center for Research Resources; the American Heart Association; and Bayer HealthCare. Coauthor Dr. Garret FitzGerald of the University of Pennsylvania, Philadelphia, received research funding from Bayer HealthCare to support partial funding of this study, and Dr. Grosser received consultancy fees from PLx Pharma. The four remaining coauthors had no potential conflicts of interest to disclose.

Dr. Bhatt said his disclosures include being an unpaid consultant to PLx Pharma. Dr. Kaul said he had no relevant disclosures.

In a study of 400 healthy adults, measurements indicating the presence of what has been thought to be aspirin resistance were evident only with enteric-coated aspirin, not immediate-release aspirin, which the authors have described as aspirin "pseudoresistance."

The researchers used several measurements to evaluate responses reflecting the activity of cyclooxygenase-1 (COX-1), the molecular target of aspirin, including platelet aggregation and serum thromboxane formation, which could indicate a genetic cause of aspirin resistance. Still, "we failed to find a single person who satisfied" the criteria for true aspirin resistance, reported Dr. Tilo Grosser, of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine in Philadelphia, and his associates. "By contrast, pseudoresistance, due to delayed and reduced drug absorption, was common after ingestion of enteric-coated aspirin," they said.

"These observations question the value of seeking to diagnose aspirin resistance with single point-of-care diagnostic approaches and support the finding of inconsistent platelet inhibition following enteric-coated preparations of aspirin," they concluded. The study appeared in Circulation online Dec. 4 (2012 [doi: 10.1161/CIRCULATIONAHA.112.117283]).

The concept of aspirin resistance has been used to explain treatment failures occurring in patients, with estimates of incidence ranging from 5% to 20% in studies, they noted.

The study had several phases, which included screening the study participants, aged 18-55 years, for their response to a single 325-mg dose of immediate-release or enteric-coated aspirin, repeating testing among those who appeared to be resistant to aspirin, and comparing responses in responders and nonresponders.

Among the specific findings: All of the individuals who received a dose of immediate-release aspirin were responders, but up to 49% of those who received enteric aspirin were considered nonresponders. With repeated exposure, individuals categorized as nonresponders when given enteric-coated aspirin showed evidence of responses when administered immediate-release aspirin.

"What they have shown in an extremely elegant way is that aspirin resistance, at least in healthy volunteers, doesn’t exist," Dr. Deepak Bhatt said in an interview.

Of great interest to physicians and patients is the finding that in the individuals who appeared to be aspirin resistant, enteric coating on aspirin was delaying and reducing absorption, which is consistent with old data that indicate enteric coating can interfere with aspirin absorption, he said. While this may have been suspected as an explanation for so-called aspirin resistance, "this is the first time someone has really nailed it down in a scientifically unassailable way," said Dr. Bhatt, professor of medicine at Harvard University, Boston, and chief of cardiology at VA Boston Healthcare System.

Although the results need to be replicated in patients with actual disease, such as diabetes or atherosclerosis, he said the results will potentially impact practice, although immediate-release aspirin is recommended for patients who are being stented or are having a myocardial infarction, for the rapid pharmacologic effect.

But the results raise further questions about more chronic administration of aspirin in patients who are not acutely ill and how many of these patients may not be fully absorbing aspirin if they are taking an enteric-coated formulation. "If there is a proportion of patients who are not getting the full anticlotting effect of aspirin ... that means potentially millions of patients are taking enteric-coated aspirin and not getting the protection they or their doctors are assuming they are getting," he said.

Another consideration, which he said is not widely appreciated, is that evidence that enteric coating reduces stomach bleeding "is quite scant, some might even say nonexistent." While enteric coated aspirin does reduce stomach upset, it is used for GI bleeding protection, "but if you’re not getting the GI benefit, and now potentially there is this issue of pseudoresistance these authors are raising, you’ve got to think twice about whether enteric coating is doing anything useful or good."

Dr. Bhatt’s recommendation to clinicians, which predates the publication of this study, is to make sure that patients who are prescribed the immediate-release aspirin get the correct formulation, and not end up with an enteric-coated formulation unintentionally.

Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, also advised caution about extrapolating the results of a study of healthy volunteers to patients with heart disease or chronic illnesses that may affect how aspirin works in the body. The study was not designed to address comparative clinical efficacy or safety between the two formulations, and he views it as "a mechanistic study demonstrating a pharmacokinetic reason for variability in aspirin responsiveness."

In an interview, he added that testing for aspirin resistance is "of dubious value," and the concept, like resistance to clopidogrel, "is driven to a large extent by marketing considerations," and the development of tests to assess aspirin responsiveness.

Dr. Kaul said he will continue to recommend immediate-release formulation for rapid onset of action and switch to enteric-coated aspirin for chronic use, especially in patients with a history of gastric intolerance or side effects. Although "unequivocal evidence" of safety advantages over immediate-release aspirin, such as GI bleeding, is lacking, data have shown reduced rates of gastric erosions on endoscopy associated with enteric-coated aspirin, although the clinical relevance of the erosions is unclear, he said.

The study was funded by the National Heart, Lung, and Blood Institute; the National Center for Research Resources; the American Heart Association; and Bayer HealthCare. Coauthor Dr. Garret FitzGerald of the University of Pennsylvania, Philadelphia, received research funding from Bayer HealthCare to support partial funding of this study, and Dr. Grosser received consultancy fees from PLx Pharma. The four remaining coauthors had no potential conflicts of interest to disclose.

Dr. Bhatt said his disclosures include being an unpaid consultant to PLx Pharma. Dr. Kaul said he had no relevant disclosures.

Treatment options for advanced prostate cancer have expanded again with Food and Drug Administration approval of abiraterone acetate for use in men who have not yet received chemotherapy for late-stage castration-resistant disease.

The agency initially approved abiraterone (Zytiga) in April 2011 for treatment of metastatic castration-resistant prostate cancer that had previously been treated with chemotherapy containing docetaxel (Taxotere) with prednisone.

The new indication, announced Dec. 10, endorses earlier treatment of patients with metastatic castration-resistant prostate cancer at the same oral dose of 1,000 mg twice daily in combination with 5 mg of prednisone.

European regulatory authorities also have expressed support for an expanded indication there, according to Janssen Biotech Inc., which markets abiraterone.

Opens Door for Broader Use

Abiraterone is part of an arsenal of recently approved prostate cancer therapies that are transforming care of men with advanced malignancy. These include the new immunotherapy sipuleucel-T (Provenge), cabazitaxel (Jevtana), and enzalutamide (Xtandi) for the disease itself – and denosumab (Prolia, Xgeva) for related bone-related indications.

The expanded approval for abiraterone "will allow many more men to benefit from this exciting new agent," Dr. Judd Moul, director of the Duke Prostate Center at Duke University, Durham, N.C., said in an interview.

Since it was approved in 2011 for use after chemotherapy, abiraterone has been used extensively, mostly by medical oncologists, he noted. In this setting, there was about a 4-month average survival benefit, compared with placebo.

The survival benefit was "even more robust" in the prechemotherapy setting in men with advanced prostate cancer becoming resistant to traditional hormonal therapy, such as leuprolide and oral antiandrogens, he added.

The approval also will "open up the door for more urologists to gain experience using the drug, since urologists commonly treat men with advanced prostate cancer before they start chemotherapy," predicted Dr. Moul, the James H. Semans, M.D. professor of surgery at Duke.

Expanded Indication Followed Priority Review

The FDA considered the expanded indication in a priority review, completed in 6 months instead of the standard 12-month review and used for drugs that "may offer major advances in treatment or provide a treatment when no adequate therapy exists," according to the agency.

Abiraterone is an androgen suppressant. It decreases production of testosterone by inhibiting CYP17A1, an enzyme that is expressed in testicular, adrenal, and prostatic tumor tissues and needed for androgen biosynthesis.

The new approval was based on the results of the placebo-controlled international COU-AA-302 trial (N. Engl. J. Med. Dec. 10 [doi:10.1056/NEJMoa1209096]).

Investigators randomized 1,088 men who had late-stage castration-resistant prostate cancer and had not yet received chemotherapy. The men were randomized to treatment with abiraterone (1,000 mg/day) and prednisone (5 mg twice a day) or prednisone alone.

Median overall survival was 35.3 months among those who received abiraterone, compared with 30.1 months among those on placebo, according to the FDA statement. The median radiographic progression-free survival was 8.3 months among those on placebo but had not yet been reached among those on abiraterone at the time the analysis was conducted.

Overall survival and radiographic progression-free survival were the coprimary end points of the trial.

Treatment with abiraterone also was associated with significant improvements in the median time to opiate use for cancer pain (not reached with abiraterone vs. 23.7 months with placebo) and initiation of cytotoxic chemotherapy (25.2 months with abiraterone vs. 16.8 months with placebo), according to the prescribing information.

Among the most common side effects reported among those on abiraterone were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and bruising.

The most common laboratory abnormalities included anemia; elevations in alkaline phosphatase, triglycerides, and cholesterol; hyperglycemia; lymphopenia; hypophosphatemia; and hypokalemia.

The expanded approval "demonstrates the benefit of further evaluating a drug in an earlier disease setting and provides patients and health care providers the option of using Zytiga earlier in the course of treatment," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA’s statement announcing the approval.

First-Line Use Possible in Future

In the interview, Dr. Moul predicted that abiraterone may have a role as a first-line treatment in the future, referring to a clinical study of abiraterone combined with traditional androgen deprivation prior to radical prostatectomy "that showed a fairly dramatic shrinkage of the tumor."

The new options for treating advanced prostate cancer that have become available since the spring of 2010 have generated questions over the use and sequencing of these agents, he said.

"For example, should doctors use Provenge before or after Zytiga? Should doctors use Provenge and Zytiga together since they are now both FDA approved in the same setting, prechemotherapy? Should some patients still start with chemotherapy first?" he asked.

Dr. Moul described enzalutamide as another "very promising" oral cancer therapy, which also may eventually be approved in the prechemotherapy setting for castration-resistant prostate cancer. "Then doctors and patients will have three choices in Provenge, Zytiga, and Xtandi, and they will have to figure out how to sequence this new feast of agents," he said.

Dr. Moul is a paid consultant to Janssen; he was not an investigator in the study that was the basis of the expanded approval. One of the study investigators, Dr. Daniel George, is the director of the section of genitourinary medical oncology at Duke University Medical Center.

Treatment options for advanced prostate cancer have expanded again with Food and Drug Administration approval of abiraterone acetate for use in men who have not yet received chemotherapy for late-stage castration-resistant disease.

The agency initially approved abiraterone (Zytiga) in April 2011 for treatment of metastatic castration-resistant prostate cancer that had previously been treated with chemotherapy containing docetaxel (Taxotere) with prednisone.

The new indication, announced Dec. 10, endorses earlier treatment of patients with metastatic castration-resistant prostate cancer at the same oral dose of 1,000 mg twice daily in combination with 5 mg of prednisone.

European regulatory authorities also have expressed support for an expanded indication there, according to Janssen Biotech Inc., which markets abiraterone.

Opens Door for Broader Use

Abiraterone is part of an arsenal of recently approved prostate cancer therapies that are transforming care of men with advanced malignancy. These include the new immunotherapy sipuleucel-T (Provenge), cabazitaxel (Jevtana), and enzalutamide (Xtandi) for the disease itself – and denosumab (Prolia, Xgeva) for related bone-related indications.

The expanded approval for abiraterone "will allow many more men to benefit from this exciting new agent," Dr. Judd Moul, director of the Duke Prostate Center at Duke University, Durham, N.C., said in an interview.

Since it was approved in 2011 for use after chemotherapy, abiraterone has been used extensively, mostly by medical oncologists, he noted. In this setting, there was about a 4-month average survival benefit, compared with placebo.

The survival benefit was "even more robust" in the prechemotherapy setting in men with advanced prostate cancer becoming resistant to traditional hormonal therapy, such as leuprolide and oral antiandrogens, he added.

The approval also will "open up the door for more urologists to gain experience using the drug, since urologists commonly treat men with advanced prostate cancer before they start chemotherapy," predicted Dr. Moul, the James H. Semans, M.D. professor of surgery at Duke.

Expanded Indication Followed Priority Review

The FDA considered the expanded indication in a priority review, completed in 6 months instead of the standard 12-month review and used for drugs that "may offer major advances in treatment or provide a treatment when no adequate therapy exists," according to the agency.

Abiraterone is an androgen suppressant. It decreases production of testosterone by inhibiting CYP17A1, an enzyme that is expressed in testicular, adrenal, and prostatic tumor tissues and needed for androgen biosynthesis.

The new approval was based on the results of the placebo-controlled international COU-AA-302 trial (N. Engl. J. Med. Dec. 10 [doi:10.1056/NEJMoa1209096]).

Investigators randomized 1,088 men who had late-stage castration-resistant prostate cancer and had not yet received chemotherapy. The men were randomized to treatment with abiraterone (1,000 mg/day) and prednisone (5 mg twice a day) or prednisone alone.

Median overall survival was 35.3 months among those who received abiraterone, compared with 30.1 months among those on placebo, according to the FDA statement. The median radiographic progression-free survival was 8.3 months among those on placebo but had not yet been reached among those on abiraterone at the time the analysis was conducted.

Overall survival and radiographic progression-free survival were the coprimary end points of the trial.

Treatment with abiraterone also was associated with significant improvements in the median time to opiate use for cancer pain (not reached with abiraterone vs. 23.7 months with placebo) and initiation of cytotoxic chemotherapy (25.2 months with abiraterone vs. 16.8 months with placebo), according to the prescribing information.

Among the most common side effects reported among those on abiraterone were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and bruising.

The most common laboratory abnormalities included anemia; elevations in alkaline phosphatase, triglycerides, and cholesterol; hyperglycemia; lymphopenia; hypophosphatemia; and hypokalemia.

The expanded approval "demonstrates the benefit of further evaluating a drug in an earlier disease setting and provides patients and health care providers the option of using Zytiga earlier in the course of treatment," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA’s statement announcing the approval.

First-Line Use Possible in Future

In the interview, Dr. Moul predicted that abiraterone may have a role as a first-line treatment in the future, referring to a clinical study of abiraterone combined with traditional androgen deprivation prior to radical prostatectomy "that showed a fairly dramatic shrinkage of the tumor."

The new options for treating advanced prostate cancer that have become available since the spring of 2010 have generated questions over the use and sequencing of these agents, he said.

"For example, should doctors use Provenge before or after Zytiga? Should doctors use Provenge and Zytiga together since they are now both FDA approved in the same setting, prechemotherapy? Should some patients still start with chemotherapy first?" he asked.

Dr. Moul described enzalutamide as another "very promising" oral cancer therapy, which also may eventually be approved in the prechemotherapy setting for castration-resistant prostate cancer. "Then doctors and patients will have three choices in Provenge, Zytiga, and Xtandi, and they will have to figure out how to sequence this new feast of agents," he said.

Dr. Moul is a paid consultant to Janssen; he was not an investigator in the study that was the basis of the expanded approval. One of the study investigators, Dr. Daniel George, is the director of the section of genitourinary medical oncology at Duke University Medical Center.

Treatment options for advanced prostate cancer have expanded again with Food and Drug Administration approval of abiraterone acetate for use in men who have not yet received chemotherapy for late-stage castration-resistant disease.

The agency initially approved abiraterone (Zytiga) in April 2011 for treatment of metastatic castration-resistant prostate cancer that had previously been treated with chemotherapy containing docetaxel (Taxotere) with prednisone.

The new indication, announced Dec. 10, endorses earlier treatment of patients with metastatic castration-resistant prostate cancer at the same oral dose of 1,000 mg twice daily in combination with 5 mg of prednisone.

European regulatory authorities also have expressed support for an expanded indication there, according to Janssen Biotech Inc., which markets abiraterone.

Opens Door for Broader Use

Abiraterone is part of an arsenal of recently approved prostate cancer therapies that are transforming care of men with advanced malignancy. These include the new immunotherapy sipuleucel-T (Provenge), cabazitaxel (Jevtana), and enzalutamide (Xtandi) for the disease itself – and denosumab (Prolia, Xgeva) for related bone-related indications.

The expanded approval for abiraterone "will allow many more men to benefit from this exciting new agent," Dr. Judd Moul, director of the Duke Prostate Center at Duke University, Durham, N.C., said in an interview.

Since it was approved in 2011 for use after chemotherapy, abiraterone has been used extensively, mostly by medical oncologists, he noted. In this setting, there was about a 4-month average survival benefit, compared with placebo.

The survival benefit was "even more robust" in the prechemotherapy setting in men with advanced prostate cancer becoming resistant to traditional hormonal therapy, such as leuprolide and oral antiandrogens, he added.

The approval also will "open up the door for more urologists to gain experience using the drug, since urologists commonly treat men with advanced prostate cancer before they start chemotherapy," predicted Dr. Moul, the James H. Semans, M.D. professor of surgery at Duke.

Expanded Indication Followed Priority Review

The FDA considered the expanded indication in a priority review, completed in 6 months instead of the standard 12-month review and used for drugs that "may offer major advances in treatment or provide a treatment when no adequate therapy exists," according to the agency.

Abiraterone is an androgen suppressant. It decreases production of testosterone by inhibiting CYP17A1, an enzyme that is expressed in testicular, adrenal, and prostatic tumor tissues and needed for androgen biosynthesis.

The new approval was based on the results of the placebo-controlled international COU-AA-302 trial (N. Engl. J. Med. Dec. 10 [doi:10.1056/NEJMoa1209096]).

Investigators randomized 1,088 men who had late-stage castration-resistant prostate cancer and had not yet received chemotherapy. The men were randomized to treatment with abiraterone (1,000 mg/day) and prednisone (5 mg twice a day) or prednisone alone.

Median overall survival was 35.3 months among those who received abiraterone, compared with 30.1 months among those on placebo, according to the FDA statement. The median radiographic progression-free survival was 8.3 months among those on placebo but had not yet been reached among those on abiraterone at the time the analysis was conducted.

Overall survival and radiographic progression-free survival were the coprimary end points of the trial.

Treatment with abiraterone also was associated with significant improvements in the median time to opiate use for cancer pain (not reached with abiraterone vs. 23.7 months with placebo) and initiation of cytotoxic chemotherapy (25.2 months with abiraterone vs. 16.8 months with placebo), according to the prescribing information.

Among the most common side effects reported among those on abiraterone were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and bruising.

The most common laboratory abnormalities included anemia; elevations in alkaline phosphatase, triglycerides, and cholesterol; hyperglycemia; lymphopenia; hypophosphatemia; and hypokalemia.

The expanded approval "demonstrates the benefit of further evaluating a drug in an earlier disease setting and provides patients and health care providers the option of using Zytiga earlier in the course of treatment," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA’s statement announcing the approval.

First-Line Use Possible in Future

In the interview, Dr. Moul predicted that abiraterone may have a role as a first-line treatment in the future, referring to a clinical study of abiraterone combined with traditional androgen deprivation prior to radical prostatectomy "that showed a fairly dramatic shrinkage of the tumor."

The new options for treating advanced prostate cancer that have become available since the spring of 2010 have generated questions over the use and sequencing of these agents, he said.

"For example, should doctors use Provenge before or after Zytiga? Should doctors use Provenge and Zytiga together since they are now both FDA approved in the same setting, prechemotherapy? Should some patients still start with chemotherapy first?" he asked.

Dr. Moul described enzalutamide as another "very promising" oral cancer therapy, which also may eventually be approved in the prechemotherapy setting for castration-resistant prostate cancer. "Then doctors and patients will have three choices in Provenge, Zytiga, and Xtandi, and they will have to figure out how to sequence this new feast of agents," he said.

Dr. Moul is a paid consultant to Janssen; he was not an investigator in the study that was the basis of the expanded approval. One of the study investigators, Dr. Daniel George, is the director of the section of genitourinary medical oncology at Duke University Medical Center.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel voted against approval of an extended-release, single-ingredient capsule formulation of hydrocodone for the treatment of chronic pain, citing the need for a tamper-proof formulation and a stronger risk mitigation strategy to address the high potential for abuse and misuse of the product.

At a Dec. 7 meeting of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee, the panelists voted 11 to 2, with 1 abstention, against approval of the product, although they agreed that the manufacturer had met the current standards for approval for the proposed indication, the management of moderate to severe chronic pain when a continuous around-the-clock opioid analgesic is needed for an extended period. However, concerns about the potential public health impact of the availability of an extended-release formulation of hydrocodone that does not contain acetaminophen – which would make it more attractive as a drug of abuse, particularly for intravenous drug abusers – or a tamper-resistant design, swayed their votes.

Panelists voting against approval also said that the Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting opioids, which was approved by the FDA in July 2012 to minimize abuse and misuse of these drugs, was not stringent enough to assure the drug would be used safely, citing the need to make prescriber education mandatory and limit distribution of the drug.

Currently, the FDA cannot require that opioids be made tamper resistant, although this is something that the agency is considering making a condition of approval for opioid products. Since 2010, OxyContin (controlled-release oxycodone) has been available in a formulation designed to prevent it from being chewed, crushed, or dissolved.

The manufacturer of the extended-release, single-ingredient hydrocodone formulation, Zogenix, has proposed that it be approved at doses of 10 to 50 mg administered twice a day, with a proposed risk management strategy that goes beyond the REMS now required by the FDA for all extended-release and long-acting opioids, including features such as a locked bottle cap.

If approved, this product would be the first product that contains hydrocodone alone, and the first extended-release form of hydrocodone, according to the FDA. It would be regulated as a schedule II narcotic. Currently, marketed hydrocodone products contain limited amounts of hydrocodone and are regulated as schedule III narcotics.

The panel voted 8 to 5 with 1 abstention that the manufacturer had shown that the product was effective for the chronic pain indication, based on the pivotal phase III, randomized, double-blind, 12-week study comparing hydrocodone ER against placebo in patients with chronic low back pain. They voted 9 to 5 that it had not been shown to be safe, however.

Panelist Dr. James Ramsay, director of critical care services in the department of anesthesiology at Emory University Hospital, Duluth, Ga., said that hydrocodone is the most widely used and abused opioid, and if marketed, the extended-release product "will be the choice drug for diversion and extraction."

Making this available without an abuse deterrent would be like "opening up Pandora’s box," added another panelist, Dr. Alan Kaye, professor and chairman of the department of anesthesia at Louisiana State University, New Orleans.

In 2008, based on U.S. emergency department (ED) visits from the Drug Abuse Warning Network and retail pharmacy sales data, the FDA estimated that for hydrocodone combination products, the abuse ratio was 14 ED visits per million tablets dispensed. For oxycodone combination products, the ratio was 24 ED visits per million tablets dispensed, but for single-entity oxycodone extended-release products, the ratio increased to 85 ED visits per million tablets dispensed. This is a "substantial" difference, and "it is likely that similar patterns will be observed" between hydrocodone products and the extended-release, single-ingredient hydrocodone product, according to the FDA’s briefing documents.

During the open public hearing portion of the meeting, parents whose children died because they became addicted to prescription pain relievers, including hydrocodone, pleaded with the FDA not to approve the product.

The FDA usually follows the recommendations of its advisory panels, which are not binding. A decision is expected by March 1, 2013, according to Zogenix, which plans to market the product as Zohydro ER if approved. A statement released by Zogenix after the meeting said that the company remained confident in its plans to support safe use of the drug, and was committed to continue working with the FDA to make the product available for the proposed patient population.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may occasionally be given a waiver, but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel voted against approval of an extended-release, single-ingredient capsule formulation of hydrocodone for the treatment of chronic pain, citing the need for a tamper-proof formulation and a stronger risk mitigation strategy to address the high potential for abuse and misuse of the product.

At a Dec. 7 meeting of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee, the panelists voted 11 to 2, with 1 abstention, against approval of the product, although they agreed that the manufacturer had met the current standards for approval for the proposed indication, the management of moderate to severe chronic pain when a continuous around-the-clock opioid analgesic is needed for an extended period. However, concerns about the potential public health impact of the availability of an extended-release formulation of hydrocodone that does not contain acetaminophen – which would make it more attractive as a drug of abuse, particularly for intravenous drug abusers – or a tamper-resistant design, swayed their votes.

Panelists voting against approval also said that the Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting opioids, which was approved by the FDA in July 2012 to minimize abuse and misuse of these drugs, was not stringent enough to assure the drug would be used safely, citing the need to make prescriber education mandatory and limit distribution of the drug.

Currently, the FDA cannot require that opioids be made tamper resistant, although this is something that the agency is considering making a condition of approval for opioid products. Since 2010, OxyContin (controlled-release oxycodone) has been available in a formulation designed to prevent it from being chewed, crushed, or dissolved.

The manufacturer of the extended-release, single-ingredient hydrocodone formulation, Zogenix, has proposed that it be approved at doses of 10 to 50 mg administered twice a day, with a proposed risk management strategy that goes beyond the REMS now required by the FDA for all extended-release and long-acting opioids, including features such as a locked bottle cap.

If approved, this product would be the first product that contains hydrocodone alone, and the first extended-release form of hydrocodone, according to the FDA. It would be regulated as a schedule II narcotic. Currently, marketed hydrocodone products contain limited amounts of hydrocodone and are regulated as schedule III narcotics.

The panel voted 8 to 5 with 1 abstention that the manufacturer had shown that the product was effective for the chronic pain indication, based on the pivotal phase III, randomized, double-blind, 12-week study comparing hydrocodone ER against placebo in patients with chronic low back pain. They voted 9 to 5 that it had not been shown to be safe, however.

Panelist Dr. James Ramsay, director of critical care services in the department of anesthesiology at Emory University Hospital, Duluth, Ga., said that hydrocodone is the most widely used and abused opioid, and if marketed, the extended-release product "will be the choice drug for diversion and extraction."

Making this available without an abuse deterrent would be like "opening up Pandora’s box," added another panelist, Dr. Alan Kaye, professor and chairman of the department of anesthesia at Louisiana State University, New Orleans.

In 2008, based on U.S. emergency department (ED) visits from the Drug Abuse Warning Network and retail pharmacy sales data, the FDA estimated that for hydrocodone combination products, the abuse ratio was 14 ED visits per million tablets dispensed. For oxycodone combination products, the ratio was 24 ED visits per million tablets dispensed, but for single-entity oxycodone extended-release products, the ratio increased to 85 ED visits per million tablets dispensed. This is a "substantial" difference, and "it is likely that similar patterns will be observed" between hydrocodone products and the extended-release, single-ingredient hydrocodone product, according to the FDA’s briefing documents.

During the open public hearing portion of the meeting, parents whose children died because they became addicted to prescription pain relievers, including hydrocodone, pleaded with the FDA not to approve the product.

The FDA usually follows the recommendations of its advisory panels, which are not binding. A decision is expected by March 1, 2013, according to Zogenix, which plans to market the product as Zohydro ER if approved. A statement released by Zogenix after the meeting said that the company remained confident in its plans to support safe use of the drug, and was committed to continue working with the FDA to make the product available for the proposed patient population.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may occasionally be given a waiver, but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel voted against approval of an extended-release, single-ingredient capsule formulation of hydrocodone for the treatment of chronic pain, citing the need for a tamper-proof formulation and a stronger risk mitigation strategy to address the high potential for abuse and misuse of the product.

At a Dec. 7 meeting of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee, the panelists voted 11 to 2, with 1 abstention, against approval of the product, although they agreed that the manufacturer had met the current standards for approval for the proposed indication, the management of moderate to severe chronic pain when a continuous around-the-clock opioid analgesic is needed for an extended period. However, concerns about the potential public health impact of the availability of an extended-release formulation of hydrocodone that does not contain acetaminophen – which would make it more attractive as a drug of abuse, particularly for intravenous drug abusers – or a tamper-resistant design, swayed their votes.

Panelists voting against approval also said that the Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting opioids, which was approved by the FDA in July 2012 to minimize abuse and misuse of these drugs, was not stringent enough to assure the drug would be used safely, citing the need to make prescriber education mandatory and limit distribution of the drug.

Currently, the FDA cannot require that opioids be made tamper resistant, although this is something that the agency is considering making a condition of approval for opioid products. Since 2010, OxyContin (controlled-release oxycodone) has been available in a formulation designed to prevent it from being chewed, crushed, or dissolved.

The manufacturer of the extended-release, single-ingredient hydrocodone formulation, Zogenix, has proposed that it be approved at doses of 10 to 50 mg administered twice a day, with a proposed risk management strategy that goes beyond the REMS now required by the FDA for all extended-release and long-acting opioids, including features such as a locked bottle cap.

If approved, this product would be the first product that contains hydrocodone alone, and the first extended-release form of hydrocodone, according to the FDA. It would be regulated as a schedule II narcotic. Currently, marketed hydrocodone products contain limited amounts of hydrocodone and are regulated as schedule III narcotics.

The panel voted 8 to 5 with 1 abstention that the manufacturer had shown that the product was effective for the chronic pain indication, based on the pivotal phase III, randomized, double-blind, 12-week study comparing hydrocodone ER against placebo in patients with chronic low back pain. They voted 9 to 5 that it had not been shown to be safe, however.

Panelist Dr. James Ramsay, director of critical care services in the department of anesthesiology at Emory University Hospital, Duluth, Ga., said that hydrocodone is the most widely used and abused opioid, and if marketed, the extended-release product "will be the choice drug for diversion and extraction."

Making this available without an abuse deterrent would be like "opening up Pandora’s box," added another panelist, Dr. Alan Kaye, professor and chairman of the department of anesthesia at Louisiana State University, New Orleans.

In 2008, based on U.S. emergency department (ED) visits from the Drug Abuse Warning Network and retail pharmacy sales data, the FDA estimated that for hydrocodone combination products, the abuse ratio was 14 ED visits per million tablets dispensed. For oxycodone combination products, the ratio was 24 ED visits per million tablets dispensed, but for single-entity oxycodone extended-release products, the ratio increased to 85 ED visits per million tablets dispensed. This is a "substantial" difference, and "it is likely that similar patterns will be observed" between hydrocodone products and the extended-release, single-ingredient hydrocodone product, according to the FDA’s briefing documents.

During the open public hearing portion of the meeting, parents whose children died because they became addicted to prescription pain relievers, including hydrocodone, pleaded with the FDA not to approve the product.

The FDA usually follows the recommendations of its advisory panels, which are not binding. A decision is expected by March 1, 2013, according to Zogenix, which plans to market the product as Zohydro ER if approved. A statement released by Zogenix after the meeting said that the company remained confident in its plans to support safe use of the drug, and was committed to continue working with the FDA to make the product available for the proposed patient population.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may occasionally be given a waiver, but not at this meeting.

More than 40% of postoperative complications occurred after discharge and were more commonly associated with certain procedures – along with a significantly increased risk of reoperations and death – in a large retrospective study of adults who had undergone general surgery as inpatients.

The results indicate that postdischarge (PD) complications "account for a significant burden of postoperative complications and are an important avenue for quality improvement in inpatient general surgery," concluded Dr. Hadiza S. Kazaure of the department of general surgery, Stanford (Calif.) University, and her coauthors. "More research is needed to develop and explore the utility of a cost-effective and fastidious PD follow-up system for surgical patients," they added, noting that their findings "underscore the need for systematic collection of PD adverse event data to improve postoperative surgical care in the United States" (Arch. Surg. 2012;147:1000-07). The study was based on data from the American College of Surgeons National Surgical Quality Improvement Program (2005-2010) on 551,510 adult patients (mean age, 55 years) who had undergone inpatient surgery that fell into one of 21 types of general surgery procedure categories at U.S. hospitals. The authors analyzed the rates and types of PD complications, as well as associations between the types of surgical procedures, reoperations, and mortality, within 30 days of surgery.

Within 30 days of surgery, nearly 17% of these patients had a complication. Nearly 7% of those complications occurred after discharge, accounting for almost 42% of postoperative complications. Most – 75% – of the PD complications occurred within the first 14 days of discharge, indicating that this period is "a particularly vulnerable time" for patients undergoing general surgery, the authors said.

The highest rates of PD complications were among the patients who underwent a proctectomy (a 14.5% complication rate), followed by those who had an enteric fistula repair (13%) and a pancreatic procedure (11%). Complication rates after discharge were lowest among those undergoing fundoplasty (3%) or an endocrine procedure, which included thyroid, parathyroid, and adrenal procedures (1.5%).

Breast surgery patients accounted for the highest proportion of complications occurring during the PD period. Almost 80% of complications after breast surgery occurred after discharge, compared with 70% after bariatric procedures and 62% after ventral hernia repair. And almost 83% of the PD complications that occurred in surgical patients fell into one of the following 10 categories: colectomy, small bowel procedures, bariatric procedures, ventral hernia repair, appendectomy, cholecystectomy, pancreatic procedures, exploratory laparotomy, breast procedures, and gastrectomy.

Surgical site complications, infections, and thromboembolic events accounted for almost 91% of PD complications after discharge. Patients who had a PD complication were more likely to be older and male, and were more likely to have diabetes, to use steroids, and to have had a complication while in the hospital. Other factors associated with PD complications were an American Society of Anesthesiologist class higher than 3, a mean 35-minute longer operation time, and a mean 3-day longer hospital stay.

Reoperation rates and mortality rates were 18% and 7%, respectively, among those with a PD complication vs. 5% and 2% among those who did not have a complication after discharge – a significant difference.

Since the risk of postdischarge complications was associated with "baseline complexity of illness and potentially modifiable factors such as diabetes, obesity, and use of steroids, our findings could facilitate identification of patients at increased risk and allow for targeted preventive interventions," the authors said.

While they believe this is the largest study of complications occurring after discharge in general surgery patients in the United States, the authors noted some limitations, including possible coding errors and no markers of illness severity.

No conflict of interest disclosures were reported.

More than 40% of postoperative complications occurred after discharge and were more commonly associated with certain procedures – along with a significantly increased risk of reoperations and death – in a large retrospective study of adults who had undergone general surgery as inpatients.

The results indicate that postdischarge (PD) complications "account for a significant burden of postoperative complications and are an important avenue for quality improvement in inpatient general surgery," concluded Dr. Hadiza S. Kazaure of the department of general surgery, Stanford (Calif.) University, and her coauthors. "More research is needed to develop and explore the utility of a cost-effective and fastidious PD follow-up system for surgical patients," they added, noting that their findings "underscore the need for systematic collection of PD adverse event data to improve postoperative surgical care in the United States" (Arch. Surg. 2012;147:1000-07). The study was based on data from the American College of Surgeons National Surgical Quality Improvement Program (2005-2010) on 551,510 adult patients (mean age, 55 years) who had undergone inpatient surgery that fell into one of 21 types of general surgery procedure categories at U.S. hospitals. The authors analyzed the rates and types of PD complications, as well as associations between the types of surgical procedures, reoperations, and mortality, within 30 days of surgery.

Within 30 days of surgery, nearly 17% of these patients had a complication. Nearly 7% of those complications occurred after discharge, accounting for almost 42% of postoperative complications. Most – 75% – of the PD complications occurred within the first 14 days of discharge, indicating that this period is "a particularly vulnerable time" for patients undergoing general surgery, the authors said.

The highest rates of PD complications were among the patients who underwent a proctectomy (a 14.5% complication rate), followed by those who had an enteric fistula repair (13%) and a pancreatic procedure (11%). Complication rates after discharge were lowest among those undergoing fundoplasty (3%) or an endocrine procedure, which included thyroid, parathyroid, and adrenal procedures (1.5%).

Breast surgery patients accounted for the highest proportion of complications occurring during the PD period. Almost 80% of complications after breast surgery occurred after discharge, compared with 70% after bariatric procedures and 62% after ventral hernia repair. And almost 83% of the PD complications that occurred in surgical patients fell into one of the following 10 categories: colectomy, small bowel procedures, bariatric procedures, ventral hernia repair, appendectomy, cholecystectomy, pancreatic procedures, exploratory laparotomy, breast procedures, and gastrectomy.

Surgical site complications, infections, and thromboembolic events accounted for almost 91% of PD complications after discharge. Patients who had a PD complication were more likely to be older and male, and were more likely to have diabetes, to use steroids, and to have had a complication while in the hospital. Other factors associated with PD complications were an American Society of Anesthesiologist class higher than 3, a mean 35-minute longer operation time, and a mean 3-day longer hospital stay.

Reoperation rates and mortality rates were 18% and 7%, respectively, among those with a PD complication vs. 5% and 2% among those who did not have a complication after discharge – a significant difference.

Since the risk of postdischarge complications was associated with "baseline complexity of illness and potentially modifiable factors such as diabetes, obesity, and use of steroids, our findings could facilitate identification of patients at increased risk and allow for targeted preventive interventions," the authors said.

While they believe this is the largest study of complications occurring after discharge in general surgery patients in the United States, the authors noted some limitations, including possible coding errors and no markers of illness severity.

No conflict of interest disclosures were reported.

More than 40% of postoperative complications occurred after discharge and were more commonly associated with certain procedures – along with a significantly increased risk of reoperations and death – in a large retrospective study of adults who had undergone general surgery as inpatients.

The results indicate that postdischarge (PD) complications "account for a significant burden of postoperative complications and are an important avenue for quality improvement in inpatient general surgery," concluded Dr. Hadiza S. Kazaure of the department of general surgery, Stanford (Calif.) University, and her coauthors. "More research is needed to develop and explore the utility of a cost-effective and fastidious PD follow-up system for surgical patients," they added, noting that their findings "underscore the need for systematic collection of PD adverse event data to improve postoperative surgical care in the United States" (Arch. Surg. 2012;147:1000-07). The study was based on data from the American College of Surgeons National Surgical Quality Improvement Program (2005-2010) on 551,510 adult patients (mean age, 55 years) who had undergone inpatient surgery that fell into one of 21 types of general surgery procedure categories at U.S. hospitals. The authors analyzed the rates and types of PD complications, as well as associations between the types of surgical procedures, reoperations, and mortality, within 30 days of surgery.

Within 30 days of surgery, nearly 17% of these patients had a complication. Nearly 7% of those complications occurred after discharge, accounting for almost 42% of postoperative complications. Most – 75% – of the PD complications occurred within the first 14 days of discharge, indicating that this period is "a particularly vulnerable time" for patients undergoing general surgery, the authors said.

The highest rates of PD complications were among the patients who underwent a proctectomy (a 14.5% complication rate), followed by those who had an enteric fistula repair (13%) and a pancreatic procedure (11%). Complication rates after discharge were lowest among those undergoing fundoplasty (3%) or an endocrine procedure, which included thyroid, parathyroid, and adrenal procedures (1.5%).

Breast surgery patients accounted for the highest proportion of complications occurring during the PD period. Almost 80% of complications after breast surgery occurred after discharge, compared with 70% after bariatric procedures and 62% after ventral hernia repair. And almost 83% of the PD complications that occurred in surgical patients fell into one of the following 10 categories: colectomy, small bowel procedures, bariatric procedures, ventral hernia repair, appendectomy, cholecystectomy, pancreatic procedures, exploratory laparotomy, breast procedures, and gastrectomy.

Surgical site complications, infections, and thromboembolic events accounted for almost 91% of PD complications after discharge. Patients who had a PD complication were more likely to be older and male, and were more likely to have diabetes, to use steroids, and to have had a complication while in the hospital. Other factors associated with PD complications were an American Society of Anesthesiologist class higher than 3, a mean 35-minute longer operation time, and a mean 3-day longer hospital stay.

Reoperation rates and mortality rates were 18% and 7%, respectively, among those with a PD complication vs. 5% and 2% among those who did not have a complication after discharge – a significant difference.

Since the risk of postdischarge complications was associated with "baseline complexity of illness and potentially modifiable factors such as diabetes, obesity, and use of steroids, our findings could facilitate identification of patients at increased risk and allow for targeted preventive interventions," the authors said.

While they believe this is the largest study of complications occurring after discharge in general surgery patients in the United States, the authors noted some limitations, including possible coding errors and no markers of illness severity.

No conflict of interest disclosures were reported.

The 32-mg intravenous dose of the antinausea drug ondansetron will no longer be marketed because it has been linked to a risk of QT prolongation, the Food and Drug Administration announced.

A statement on the agency’s MedWatch website said that the withdrawal of the 32-mg dose, available in premixed solutions of dextrose or sodium chloride, is expected to last through early 2013. Since this dose accounts for a "very small percentage" of the market, the voluntary withdrawal is not expected to contribute to a shortage of intravenous ondansetron, the Dec. 4 statement said.

The drug is marketed as Zofran and is available in generic formulations for preventing chemotherapy-induced nausea and vomiting. The FDA is recommending three doses of IV ondansetron at a dose of 0.15 mg/kg administered every 4 hours for three doses to prevent chemotherapy-induced nausea and vomiting but added: "If the calculated weight-based dose were to exceed 16 mg, the potential for prolonged QT interval would be greater; therefore, no single intravenous dose should exceed 16 mg." QT prolongation can result in the potentially fatal arrhythmia, torsades de pointes.

The FDA also stated that, currently, there is not enough information to recommend another single-dose intravenous regimen and that oral ondansetron "remains effective for the prevention of chemotherapy-induced nausea and vomiting."

Ondansetron also is approved for postoperative nausea and vomiting.

The announcement follows a previous FDA notice in June 2012 that the 32-mg single-IV dose of ondansetron should be avoided, citing preliminary results from a study suggesting that the 32-mg dose may cause QT prolongation. The agency first announced that it was conducting a safety review of ondansetron in September 2011.

At the time of the June 2012 statement, GlaxoSmithKline, the manufacturer of Zofran, which conducted the QT study, announced that it was removing the 32-mg single-IV dose from the drug’s label. In November, the labeling was revised and no longer includes the 32-mg IV dose; it includes information about QT prolongation and dosing information that no single-IV weight-based dose should exceed 16 mg.

Manufacturers of ondansetron intravenous products are Baxter Healthcare, Hospira, Teva, Bedford Labs, and Claris Lifesciences.

Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or http://www.fda.gov/Safety/MedWatch/default.htm.

The 32-mg intravenous dose of the antinausea drug ondansetron will no longer be marketed because it has been linked to a risk of QT prolongation, the Food and Drug Administration announced.

A statement on the agency’s MedWatch website said that the withdrawal of the 32-mg dose, available in premixed solutions of dextrose or sodium chloride, is expected to last through early 2013. Since this dose accounts for a "very small percentage" of the market, the voluntary withdrawal is not expected to contribute to a shortage of intravenous ondansetron, the Dec. 4 statement said.

The drug is marketed as Zofran and is available in generic formulations for preventing chemotherapy-induced nausea and vomiting. The FDA is recommending three doses of IV ondansetron at a dose of 0.15 mg/kg administered every 4 hours for three doses to prevent chemotherapy-induced nausea and vomiting but added: "If the calculated weight-based dose were to exceed 16 mg, the potential for prolonged QT interval would be greater; therefore, no single intravenous dose should exceed 16 mg." QT prolongation can result in the potentially fatal arrhythmia, torsades de pointes.

The FDA also stated that, currently, there is not enough information to recommend another single-dose intravenous regimen and that oral ondansetron "remains effective for the prevention of chemotherapy-induced nausea and vomiting."

Ondansetron also is approved for postoperative nausea and vomiting.

The announcement follows a previous FDA notice in June 2012 that the 32-mg single-IV dose of ondansetron should be avoided, citing preliminary results from a study suggesting that the 32-mg dose may cause QT prolongation. The agency first announced that it was conducting a safety review of ondansetron in September 2011.

At the time of the June 2012 statement, GlaxoSmithKline, the manufacturer of Zofran, which conducted the QT study, announced that it was removing the 32-mg single-IV dose from the drug’s label. In November, the labeling was revised and no longer includes the 32-mg IV dose; it includes information about QT prolongation and dosing information that no single-IV weight-based dose should exceed 16 mg.

Manufacturers of ondansetron intravenous products are Baxter Healthcare, Hospira, Teva, Bedford Labs, and Claris Lifesciences.

Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or http://www.fda.gov/Safety/MedWatch/default.htm.

The 32-mg intravenous dose of the antinausea drug ondansetron will no longer be marketed because it has been linked to a risk of QT prolongation, the Food and Drug Administration announced.

A statement on the agency’s MedWatch website said that the withdrawal of the 32-mg dose, available in premixed solutions of dextrose or sodium chloride, is expected to last through early 2013. Since this dose accounts for a "very small percentage" of the market, the voluntary withdrawal is not expected to contribute to a shortage of intravenous ondansetron, the Dec. 4 statement said.

The drug is marketed as Zofran and is available in generic formulations for preventing chemotherapy-induced nausea and vomiting. The FDA is recommending three doses of IV ondansetron at a dose of 0.15 mg/kg administered every 4 hours for three doses to prevent chemotherapy-induced nausea and vomiting but added: "If the calculated weight-based dose were to exceed 16 mg, the potential for prolonged QT interval would be greater; therefore, no single intravenous dose should exceed 16 mg." QT prolongation can result in the potentially fatal arrhythmia, torsades de pointes.

The FDA also stated that, currently, there is not enough information to recommend another single-dose intravenous regimen and that oral ondansetron "remains effective for the prevention of chemotherapy-induced nausea and vomiting."

Ondansetron also is approved for postoperative nausea and vomiting.

The announcement follows a previous FDA notice in June 2012 that the 32-mg single-IV dose of ondansetron should be avoided, citing preliminary results from a study suggesting that the 32-mg dose may cause QT prolongation. The agency first announced that it was conducting a safety review of ondansetron in September 2011.

At the time of the June 2012 statement, GlaxoSmithKline, the manufacturer of Zofran, which conducted the QT study, announced that it was removing the 32-mg single-IV dose from the drug’s label. In November, the labeling was revised and no longer includes the 32-mg IV dose; it includes information about QT prolongation and dosing information that no single-IV weight-based dose should exceed 16 mg.

Manufacturers of ondansetron intravenous products are Baxter Healthcare, Hospira, Teva, Bedford Labs, and Claris Lifesciences.

Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or http://www.fda.gov/Safety/MedWatch/default.htm.