Elizabeth Mechcatie

Regorafenib, an oral multikinase inhibitor, has been approved to treat metastatic colorectal cancer, the Food and Drug Administration announced on Sept. 27.

The approved indication is for the treatment of patients with metastatic colorectal cancer, "who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy."

Approval was based on the results of one study of 760 patients with metastatic colorectal cancer, who had been treated previously. Among those randomized to treatment with regorafenib and best supportive care, median overall survival was 6.4 months, compared with a median of 5 months among those who received placebo and best supportive care. Median progression-free survival was 2 months among those on regorafenib, compared with 1.7 months among those on placebo, according to the FDA statement announcing the approval.

In June, CORRECT trial investigator Dr. Eric Van Cutsem of University Hospital Leuven in Gasthuisberg, Belgium, reported that regorafenib improved survival in patients with KRAS mutations as well as those with wild-type KRAS. "Regorafenib increases overall survival and progression-free survival in patients with metastatic colorectal cancer who have failed current standard therapies. The benefit is shown across prespecified subgroups," he said at the American Society of Clinical Oncology annual meeting.

Bayer HealthCare Pharmaceuticals will market the drug as Stivarga. The recommended dose is 160 mg, once daily for the first 21 days of each 28-day cycle.

Regorafenib "is the latest colorectal cancer treatment to demonstrate an ability to extend patients’ lives and is the second drug approved for patients with colorectal cancer in the past 2 months," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in the statement.

In August, the FDA approved ziv-aflibercept (Zaltrap) for use in combination with a FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy regimen for metastatic colorectal cancer. .

The most common adverse effects associated with regorafenib treatment included weakness or fatigue, loss of appetite, palmar-plantar erythrodysesthesia, diarrhea, mucositis, weight loss, infection, hypertension, and dysphonia, the FDA said.

In clinical trials, there were severe and fatal cases of hepatotoxicity associated with treatment, which will be highlighted in the boxed warning in the drug’s label, the FDA said.

Regorafenib was approved within 6 months of the company’s application for approval, under the FDA’s review program for drugs that provide a major advance in treatment or provide a treatment for a disease for which there is no adequate treatment.

Click here to view the drug’s label.

Regorafenib, an oral multikinase inhibitor, has been approved to treat metastatic colorectal cancer, the Food and Drug Administration announced on Sept. 27.

The approved indication is for the treatment of patients with metastatic colorectal cancer, "who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy."

Approval was based on the results of one study of 760 patients with metastatic colorectal cancer, who had been treated previously. Among those randomized to treatment with regorafenib and best supportive care, median overall survival was 6.4 months, compared with a median of 5 months among those who received placebo and best supportive care. Median progression-free survival was 2 months among those on regorafenib, compared with 1.7 months among those on placebo, according to the FDA statement announcing the approval.

In June, CORRECT trial investigator Dr. Eric Van Cutsem of University Hospital Leuven in Gasthuisberg, Belgium, reported that regorafenib improved survival in patients with KRAS mutations as well as those with wild-type KRAS. "Regorafenib increases overall survival and progression-free survival in patients with metastatic colorectal cancer who have failed current standard therapies. The benefit is shown across prespecified subgroups," he said at the American Society of Clinical Oncology annual meeting.

Bayer HealthCare Pharmaceuticals will market the drug as Stivarga. The recommended dose is 160 mg, once daily for the first 21 days of each 28-day cycle.

Regorafenib "is the latest colorectal cancer treatment to demonstrate an ability to extend patients’ lives and is the second drug approved for patients with colorectal cancer in the past 2 months," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in the statement.

In August, the FDA approved ziv-aflibercept (Zaltrap) for use in combination with a FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy regimen for metastatic colorectal cancer. .

The most common adverse effects associated with regorafenib treatment included weakness or fatigue, loss of appetite, palmar-plantar erythrodysesthesia, diarrhea, mucositis, weight loss, infection, hypertension, and dysphonia, the FDA said.

In clinical trials, there were severe and fatal cases of hepatotoxicity associated with treatment, which will be highlighted in the boxed warning in the drug’s label, the FDA said.

Regorafenib was approved within 6 months of the company’s application for approval, under the FDA’s review program for drugs that provide a major advance in treatment or provide a treatment for a disease for which there is no adequate treatment.

Click here to view the drug’s label.

Regorafenib, an oral multikinase inhibitor, has been approved to treat metastatic colorectal cancer, the Food and Drug Administration announced on Sept. 27.

The approved indication is for the treatment of patients with metastatic colorectal cancer, "who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy."

Approval was based on the results of one study of 760 patients with metastatic colorectal cancer, who had been treated previously. Among those randomized to treatment with regorafenib and best supportive care, median overall survival was 6.4 months, compared with a median of 5 months among those who received placebo and best supportive care. Median progression-free survival was 2 months among those on regorafenib, compared with 1.7 months among those on placebo, according to the FDA statement announcing the approval.

In June, CORRECT trial investigator Dr. Eric Van Cutsem of University Hospital Leuven in Gasthuisberg, Belgium, reported that regorafenib improved survival in patients with KRAS mutations as well as those with wild-type KRAS. "Regorafenib increases overall survival and progression-free survival in patients with metastatic colorectal cancer who have failed current standard therapies. The benefit is shown across prespecified subgroups," he said at the American Society of Clinical Oncology annual meeting.

Bayer HealthCare Pharmaceuticals will market the drug as Stivarga. The recommended dose is 160 mg, once daily for the first 21 days of each 28-day cycle.

Regorafenib "is the latest colorectal cancer treatment to demonstrate an ability to extend patients’ lives and is the second drug approved for patients with colorectal cancer in the past 2 months," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in the statement.

In August, the FDA approved ziv-aflibercept (Zaltrap) for use in combination with a FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy regimen for metastatic colorectal cancer. .

The most common adverse effects associated with regorafenib treatment included weakness or fatigue, loss of appetite, palmar-plantar erythrodysesthesia, diarrhea, mucositis, weight loss, infection, hypertension, and dysphonia, the FDA said.

In clinical trials, there were severe and fatal cases of hepatotoxicity associated with treatment, which will be highlighted in the boxed warning in the drug’s label, the FDA said.

Regorafenib was approved within 6 months of the company’s application for approval, under the FDA’s review program for drugs that provide a major advance in treatment or provide a treatment for a disease for which there is no adequate treatment.

Click here to view the drug’s label.

Post-trauma deep vein thrombosis and pulmonary embolism diagnoses in severely injured blunt trauma patients were associated with different clinical risk factors, leading researchers to consider that the two "may represent distinct pathophysiologic entities."

At the meeting, Dr. Scott C. Brakenridge also pointed to other recent findings, including a study that found that more than half of pulmonary embolism (PE) cases are diagnosed within the first few days of injury (Am. J. Surg. 2011;201:209-15).

"We believe these findings bring into question whether the conventional wisdom of peripheral thrombosis and subsequent embolism is an oversimplification of thromboembolic pathophysiology after injury," said Dr. Brakenridge, a trauma/surgical critical care and vascular surgery fellow, at Harborview Medical Center and the University of Washington, Seattle.

In the multicenter prospective observational study, he and his coinvestigators compared clinical risk factors for deep vein thrombosis (DVT) and PE in 1,822 severely injured blunt trauma patients with evidence of hemorrhagic shock, treated at one of five urban trauma centers from 2002 to 2011. Most were male, their median age was 41 years, and the median injury severity score was 33; they received a mean of 6 U of packed red blood cells and 12 L crystalloid resuscitation over the first 24 hours.

Within 28 days of injury, 95 patients (5.1%) were diagnosed with a DVT and 83 (3.9%) were diagnosed with a PE; the total number of patients diagnosed with the traditional composite end point of venous thromboembolism (VTE) was 159 (8.5%). Of the 159 patients with VTE, only 6% (9 patients) were diagnosed with both DVT and PE.

Risk factors for the composite end point VTE resembled those from other studies. However, when analyzed individually, DVT and PE exhibited differences in their risk-factor profiles. The independent risk factors identified among those diagnosed with a DVT were failure to initiate prophylaxis within the first 48 hours, a thoracic abbreviated injury score of 3 or more, and body mass index above 28 kg/m². Independent risk factors for PE were serum lactate greater than 5 mmol/L and male gender. The median times to diagnosis of DVT and PE were similar at approximately 10 days.

These results indicate that the risk factors for a clinical DVT diagnosis after severe blunt trauma "appear to represent the inability to initiate prompt pharmacologic prophylaxis, overall injury burden and obesity, while risk factors for PE are gender specific and consistent with a severe shock state." Dr. Brakenridge said.

Mechanistically, he and his associates are suggesting that while a predisposition to DVT and PE may share "a postinjury hypercoagulopathic state ... their discordance may be secondary to differences in local factors such as tissue injury, stasis, and endothelial damage, as well as systemic influences such as a severe shock state," he added.

The study had limitations, including a lack of standardized DVT screening protocols, and more prospective studies that evaluate the pathophysiology, diagnosis, and treatment of DVT and PE early after injury are needed, Dr. Brakenridge said. "If borne out in future prospective studies, this could have significant implications for the diagnosis, and treatment of postinjury DVT and PE," he added.

Dr. Brakenridge and his coinvestigators reported having no disclosures.

Post-trauma deep vein thrombosis and pulmonary embolism diagnoses in severely injured blunt trauma patients were associated with different clinical risk factors, leading researchers to consider that the two "may represent distinct pathophysiologic entities."

At the meeting, Dr. Scott C. Brakenridge also pointed to other recent findings, including a study that found that more than half of pulmonary embolism (PE) cases are diagnosed within the first few days of injury (Am. J. Surg. 2011;201:209-15).

"We believe these findings bring into question whether the conventional wisdom of peripheral thrombosis and subsequent embolism is an oversimplification of thromboembolic pathophysiology after injury," said Dr. Brakenridge, a trauma/surgical critical care and vascular surgery fellow, at Harborview Medical Center and the University of Washington, Seattle.

In the multicenter prospective observational study, he and his coinvestigators compared clinical risk factors for deep vein thrombosis (DVT) and PE in 1,822 severely injured blunt trauma patients with evidence of hemorrhagic shock, treated at one of five urban trauma centers from 2002 to 2011. Most were male, their median age was 41 years, and the median injury severity score was 33; they received a mean of 6 U of packed red blood cells and 12 L crystalloid resuscitation over the first 24 hours.

Within 28 days of injury, 95 patients (5.1%) were diagnosed with a DVT and 83 (3.9%) were diagnosed with a PE; the total number of patients diagnosed with the traditional composite end point of venous thromboembolism (VTE) was 159 (8.5%). Of the 159 patients with VTE, only 6% (9 patients) were diagnosed with both DVT and PE.

Risk factors for the composite end point VTE resembled those from other studies. However, when analyzed individually, DVT and PE exhibited differences in their risk-factor profiles. The independent risk factors identified among those diagnosed with a DVT were failure to initiate prophylaxis within the first 48 hours, a thoracic abbreviated injury score of 3 or more, and body mass index above 28 kg/m². Independent risk factors for PE were serum lactate greater than 5 mmol/L and male gender. The median times to diagnosis of DVT and PE were similar at approximately 10 days.

These results indicate that the risk factors for a clinical DVT diagnosis after severe blunt trauma "appear to represent the inability to initiate prompt pharmacologic prophylaxis, overall injury burden and obesity, while risk factors for PE are gender specific and consistent with a severe shock state." Dr. Brakenridge said.

Mechanistically, he and his associates are suggesting that while a predisposition to DVT and PE may share "a postinjury hypercoagulopathic state ... their discordance may be secondary to differences in local factors such as tissue injury, stasis, and endothelial damage, as well as systemic influences such as a severe shock state," he added.

The study had limitations, including a lack of standardized DVT screening protocols, and more prospective studies that evaluate the pathophysiology, diagnosis, and treatment of DVT and PE early after injury are needed, Dr. Brakenridge said. "If borne out in future prospective studies, this could have significant implications for the diagnosis, and treatment of postinjury DVT and PE," he added.

Dr. Brakenridge and his coinvestigators reported having no disclosures.

Post-trauma deep vein thrombosis and pulmonary embolism diagnoses in severely injured blunt trauma patients were associated with different clinical risk factors, leading researchers to consider that the two "may represent distinct pathophysiologic entities."

At the meeting, Dr. Scott C. Brakenridge also pointed to other recent findings, including a study that found that more than half of pulmonary embolism (PE) cases are diagnosed within the first few days of injury (Am. J. Surg. 2011;201:209-15).

"We believe these findings bring into question whether the conventional wisdom of peripheral thrombosis and subsequent embolism is an oversimplification of thromboembolic pathophysiology after injury," said Dr. Brakenridge, a trauma/surgical critical care and vascular surgery fellow, at Harborview Medical Center and the University of Washington, Seattle.

In the multicenter prospective observational study, he and his coinvestigators compared clinical risk factors for deep vein thrombosis (DVT) and PE in 1,822 severely injured blunt trauma patients with evidence of hemorrhagic shock, treated at one of five urban trauma centers from 2002 to 2011. Most were male, their median age was 41 years, and the median injury severity score was 33; they received a mean of 6 U of packed red blood cells and 12 L crystalloid resuscitation over the first 24 hours.

Within 28 days of injury, 95 patients (5.1%) were diagnosed with a DVT and 83 (3.9%) were diagnosed with a PE; the total number of patients diagnosed with the traditional composite end point of venous thromboembolism (VTE) was 159 (8.5%). Of the 159 patients with VTE, only 6% (9 patients) were diagnosed with both DVT and PE.

Risk factors for the composite end point VTE resembled those from other studies. However, when analyzed individually, DVT and PE exhibited differences in their risk-factor profiles. The independent risk factors identified among those diagnosed with a DVT were failure to initiate prophylaxis within the first 48 hours, a thoracic abbreviated injury score of 3 or more, and body mass index above 28 kg/m². Independent risk factors for PE were serum lactate greater than 5 mmol/L and male gender. The median times to diagnosis of DVT and PE were similar at approximately 10 days.

These results indicate that the risk factors for a clinical DVT diagnosis after severe blunt trauma "appear to represent the inability to initiate prompt pharmacologic prophylaxis, overall injury burden and obesity, while risk factors for PE are gender specific and consistent with a severe shock state." Dr. Brakenridge said.

Mechanistically, he and his associates are suggesting that while a predisposition to DVT and PE may share "a postinjury hypercoagulopathic state ... their discordance may be secondary to differences in local factors such as tissue injury, stasis, and endothelial damage, as well as systemic influences such as a severe shock state," he added.

The study had limitations, including a lack of standardized DVT screening protocols, and more prospective studies that evaluate the pathophysiology, diagnosis, and treatment of DVT and PE early after injury are needed, Dr. Brakenridge said. "If borne out in future prospective studies, this could have significant implications for the diagnosis, and treatment of postinjury DVT and PE," he added.

Dr. Brakenridge and his coinvestigators reported having no disclosures.

An approach to sedating intubated patients in the intensive care unit, designed to minimize continuous analgesic and sedative infusions, was associated with better outcomes than was the sedation interruption regimen previously used, according to a retrospective study of almost 1,500 patients.

The new approach resulted in a nearly 80% reduction in the overall use of sedatives and narcotics, as well as fewer infections and days spent on a ventilator – with no increase in patient discomfort, falls, or unintended extubations, Brenton J. LaRiccia, RPA, lead physician assistant in the Kessler Family Burn Trauma Intensive Care Unit (BTICU) at Strong Memorial Hospital, Rochester, N.Y., reported at the annual meeting of the American Association for the Surgery of Trauma.

Courtesy Kessler Trauma Center

Protocols that address the worse outcomes associated with oversedation of mechanically ventilated patients include sedation interruption (SI) regimens. While the interruption regimens have been shown to reduce sedation use in medical ICUs, their regimens in trauma ICUs have been unclear, said Mr. LaRiccia, who is also in the division of acute care surgery at the University of Rochester (N.Y.).

In 2011, a protocol designed to minimize the use of continuous infusions was implemented at the BTICU at Strong Memorial Hospital, which he described as "aggressive upfront bolus dosing" of analgesic and sedative medications during the first hour of admission, continuous infusions if the bolus dosing was not effective, followed by "nursing-driven regimented weaning of all medications," both intermittently dosed and continuous medications.

The study compared outcomes associated with this approach among 749 patients admitted to the trauma ICU in 2011 with outcomes among 743 patients in 2009, when the SI protocol was still used. The patients (average age 55-57 years) were all ventilated and had similar APACHE II scores; burn patients and those who required hourly neurologic checks were not included.

Compared with the SI regimen, the new regimen was associated with significantly fewer sedation days (a total of 344 vs. 1,784 days) and significantly fewer days on a ventilator (an average of 6.2 vs. 8.4 days ). In addition, about one-fourth of those on the new protocol never required a continuous infusion of a sedative or analgesic, which "was in stark contrast to our prior sedation interruption–based practice where almost all intubated patients were placed on continuous infusions on arrival to the BTICU," Mr. LaRiccia said. (Among those on the SI protocol, 11% never required continuous sedatives and 13% never required continuous narcotics, compared with 25% and 27%, respectively, of those on the new protocol, statistically significant differences).

Mortality (18%-19%) and the average ICU length of stay (almost 10 days), as well as pain scores and the total number of falls and self-extubation rates, were similar between the two groups. Limitations of the study include the retrospective analysis, the single ICU setting, and the relatively small sample size and lack of long-term data, and more studies are needed to confirm these results, he pointed out.

The results indicate that an analgesia-based protocol implemented on ICU admission, which "focuses on front loading analgesia with upfront use of intermittent pain medications and sedation medications, instead of continuous infusions with sedation, greatly decreases ICU sedation use," and is well-tolerated by patients, reduces ICU infection rates and ventilator days without significant complications, Mr. LaRiccia concluded.

"By moving beyond the sedation interruption mindset, we change our goal from being ‘When can this sedation be stopped?’ to ‘Does this sedation even need to be started?’ – thereby truly optimizing patient care," he added, emphasizing that a multidisciplinary effort is needed to ensure that the protocol is implemented properly.

He and his coinvestigators reported having no relevant financial conflicts.

An approach to sedating intubated patients in the intensive care unit, designed to minimize continuous analgesic and sedative infusions, was associated with better outcomes than was the sedation interruption regimen previously used, according to a retrospective study of almost 1,500 patients.

The new approach resulted in a nearly 80% reduction in the overall use of sedatives and narcotics, as well as fewer infections and days spent on a ventilator – with no increase in patient discomfort, falls, or unintended extubations, Brenton J. LaRiccia, RPA, lead physician assistant in the Kessler Family Burn Trauma Intensive Care Unit (BTICU) at Strong Memorial Hospital, Rochester, N.Y., reported at the annual meeting of the American Association for the Surgery of Trauma.

Courtesy Kessler Trauma Center

Protocols that address the worse outcomes associated with oversedation of mechanically ventilated patients include sedation interruption (SI) regimens. While the interruption regimens have been shown to reduce sedation use in medical ICUs, their regimens in trauma ICUs have been unclear, said Mr. LaRiccia, who is also in the division of acute care surgery at the University of Rochester (N.Y.).

In 2011, a protocol designed to minimize the use of continuous infusions was implemented at the BTICU at Strong Memorial Hospital, which he described as "aggressive upfront bolus dosing" of analgesic and sedative medications during the first hour of admission, continuous infusions if the bolus dosing was not effective, followed by "nursing-driven regimented weaning of all medications," both intermittently dosed and continuous medications.

The study compared outcomes associated with this approach among 749 patients admitted to the trauma ICU in 2011 with outcomes among 743 patients in 2009, when the SI protocol was still used. The patients (average age 55-57 years) were all ventilated and had similar APACHE II scores; burn patients and those who required hourly neurologic checks were not included.

Compared with the SI regimen, the new regimen was associated with significantly fewer sedation days (a total of 344 vs. 1,784 days) and significantly fewer days on a ventilator (an average of 6.2 vs. 8.4 days ). In addition, about one-fourth of those on the new protocol never required a continuous infusion of a sedative or analgesic, which "was in stark contrast to our prior sedation interruption–based practice where almost all intubated patients were placed on continuous infusions on arrival to the BTICU," Mr. LaRiccia said. (Among those on the SI protocol, 11% never required continuous sedatives and 13% never required continuous narcotics, compared with 25% and 27%, respectively, of those on the new protocol, statistically significant differences).

Mortality (18%-19%) and the average ICU length of stay (almost 10 days), as well as pain scores and the total number of falls and self-extubation rates, were similar between the two groups. Limitations of the study include the retrospective analysis, the single ICU setting, and the relatively small sample size and lack of long-term data, and more studies are needed to confirm these results, he pointed out.

The results indicate that an analgesia-based protocol implemented on ICU admission, which "focuses on front loading analgesia with upfront use of intermittent pain medications and sedation medications, instead of continuous infusions with sedation, greatly decreases ICU sedation use," and is well-tolerated by patients, reduces ICU infection rates and ventilator days without significant complications, Mr. LaRiccia concluded.

"By moving beyond the sedation interruption mindset, we change our goal from being ‘When can this sedation be stopped?’ to ‘Does this sedation even need to be started?’ – thereby truly optimizing patient care," he added, emphasizing that a multidisciplinary effort is needed to ensure that the protocol is implemented properly.

He and his coinvestigators reported having no relevant financial conflicts.

An approach to sedating intubated patients in the intensive care unit, designed to minimize continuous analgesic and sedative infusions, was associated with better outcomes than was the sedation interruption regimen previously used, according to a retrospective study of almost 1,500 patients.

The new approach resulted in a nearly 80% reduction in the overall use of sedatives and narcotics, as well as fewer infections and days spent on a ventilator – with no increase in patient discomfort, falls, or unintended extubations, Brenton J. LaRiccia, RPA, lead physician assistant in the Kessler Family Burn Trauma Intensive Care Unit (BTICU) at Strong Memorial Hospital, Rochester, N.Y., reported at the annual meeting of the American Association for the Surgery of Trauma.

Courtesy Kessler Trauma Center

Protocols that address the worse outcomes associated with oversedation of mechanically ventilated patients include sedation interruption (SI) regimens. While the interruption regimens have been shown to reduce sedation use in medical ICUs, their regimens in trauma ICUs have been unclear, said Mr. LaRiccia, who is also in the division of acute care surgery at the University of Rochester (N.Y.).

In 2011, a protocol designed to minimize the use of continuous infusions was implemented at the BTICU at Strong Memorial Hospital, which he described as "aggressive upfront bolus dosing" of analgesic and sedative medications during the first hour of admission, continuous infusions if the bolus dosing was not effective, followed by "nursing-driven regimented weaning of all medications," both intermittently dosed and continuous medications.

The study compared outcomes associated with this approach among 749 patients admitted to the trauma ICU in 2011 with outcomes among 743 patients in 2009, when the SI protocol was still used. The patients (average age 55-57 years) were all ventilated and had similar APACHE II scores; burn patients and those who required hourly neurologic checks were not included.

Compared with the SI regimen, the new regimen was associated with significantly fewer sedation days (a total of 344 vs. 1,784 days) and significantly fewer days on a ventilator (an average of 6.2 vs. 8.4 days ). In addition, about one-fourth of those on the new protocol never required a continuous infusion of a sedative or analgesic, which "was in stark contrast to our prior sedation interruption–based practice where almost all intubated patients were placed on continuous infusions on arrival to the BTICU," Mr. LaRiccia said. (Among those on the SI protocol, 11% never required continuous sedatives and 13% never required continuous narcotics, compared with 25% and 27%, respectively, of those on the new protocol, statistically significant differences).

Mortality (18%-19%) and the average ICU length of stay (almost 10 days), as well as pain scores and the total number of falls and self-extubation rates, were similar between the two groups. Limitations of the study include the retrospective analysis, the single ICU setting, and the relatively small sample size and lack of long-term data, and more studies are needed to confirm these results, he pointed out.

The results indicate that an analgesia-based protocol implemented on ICU admission, which "focuses on front loading analgesia with upfront use of intermittent pain medications and sedation medications, instead of continuous infusions with sedation, greatly decreases ICU sedation use," and is well-tolerated by patients, reduces ICU infection rates and ventilator days without significant complications, Mr. LaRiccia concluded.

"By moving beyond the sedation interruption mindset, we change our goal from being ‘When can this sedation be stopped?’ to ‘Does this sedation even need to be started?’ – thereby truly optimizing patient care," he added, emphasizing that a multidisciplinary effort is needed to ensure that the protocol is implemented properly.

He and his coinvestigators reported having no relevant financial conflicts.

Pramipexole, the dopamine agonist approved for treating Parkinson’s disease and restless legs syndrome, may be associated with an increased risk for heart failure, according to a statement issued by the Food and Drug Administration.

"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," but the FDA has not concluded that the drug increases the risk of heart failure, the FDA said in the Sept. 19 statement.

The FDA is currently working with Boehringer Ingelheim, which markets pramipexole as Mirapex, to investigate this association further and will provide an update when more information is available.

The studies include a pooled analysis of randomized clinical trials, which found more cases of heart failure (12 of 4,157 patients) among patients treated with pramipexole than among those on placebo (4 of 2,820). The difference between groups, however, was not statistically significant.

In two epidemiologic studies using European data, though, the increased risk of heart failure associated with pramipexole was statistically significant. In one of the studies, a case control study using a database of patients aged 40-89 years treated with anti-parkinsonian drugs, the risk of heart failure associated with any use of a dopamine agonist compared with no use was increased by almost 60% (relative risk, 1.58). The heart failure risk associated with use of pramipexole (RR, 1.86) and with another dopamine agonist, cabergoline (RR, 2.07), were each higher compared with no use of these drugs.

In the other epidemiologic study, current use of pramipexole was associated with an increased risk of heart failure, compared with levodopa. The risk was increased in the first 3 months of treatment and among patients aged 80 years and older, but was no higher among people who had been treated with pramipexole for more than 3 months.

This last finding is "difficult to explain," since heart failure is a chronic condition, and the studies had limitations, which "make it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors," the FDA statement said.

The agency advises that health care professionals continue following recommendations in the pramipexole label and that patients continue to take the medication as directed.

Pramipexole was approved in July 1997.

The full FDA notice is available here. Serious adverse events associated with pramipexole should be reported to the FDA’s MedWatch program by clicking here or by calling 800-332-1088.

Pramipexole, the dopamine agonist approved for treating Parkinson’s disease and restless legs syndrome, may be associated with an increased risk for heart failure, according to a statement issued by the Food and Drug Administration.

"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," but the FDA has not concluded that the drug increases the risk of heart failure, the FDA said in the Sept. 19 statement.

The FDA is currently working with Boehringer Ingelheim, which markets pramipexole as Mirapex, to investigate this association further and will provide an update when more information is available.

The studies include a pooled analysis of randomized clinical trials, which found more cases of heart failure (12 of 4,157 patients) among patients treated with pramipexole than among those on placebo (4 of 2,820). The difference between groups, however, was not statistically significant.

In two epidemiologic studies using European data, though, the increased risk of heart failure associated with pramipexole was statistically significant. In one of the studies, a case control study using a database of patients aged 40-89 years treated with anti-parkinsonian drugs, the risk of heart failure associated with any use of a dopamine agonist compared with no use was increased by almost 60% (relative risk, 1.58). The heart failure risk associated with use of pramipexole (RR, 1.86) and with another dopamine agonist, cabergoline (RR, 2.07), were each higher compared with no use of these drugs.

In the other epidemiologic study, current use of pramipexole was associated with an increased risk of heart failure, compared with levodopa. The risk was increased in the first 3 months of treatment and among patients aged 80 years and older, but was no higher among people who had been treated with pramipexole for more than 3 months.

This last finding is "difficult to explain," since heart failure is a chronic condition, and the studies had limitations, which "make it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors," the FDA statement said.

The agency advises that health care professionals continue following recommendations in the pramipexole label and that patients continue to take the medication as directed.

Pramipexole was approved in July 1997.

The full FDA notice is available here. Serious adverse events associated with pramipexole should be reported to the FDA’s MedWatch program by clicking here or by calling 800-332-1088.

Pramipexole, the dopamine agonist approved for treating Parkinson’s disease and restless legs syndrome, may be associated with an increased risk for heart failure, according to a statement issued by the Food and Drug Administration.

"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," but the FDA has not concluded that the drug increases the risk of heart failure, the FDA said in the Sept. 19 statement.

The FDA is currently working with Boehringer Ingelheim, which markets pramipexole as Mirapex, to investigate this association further and will provide an update when more information is available.

The studies include a pooled analysis of randomized clinical trials, which found more cases of heart failure (12 of 4,157 patients) among patients treated with pramipexole than among those on placebo (4 of 2,820). The difference between groups, however, was not statistically significant.

In two epidemiologic studies using European data, though, the increased risk of heart failure associated with pramipexole was statistically significant. In one of the studies, a case control study using a database of patients aged 40-89 years treated with anti-parkinsonian drugs, the risk of heart failure associated with any use of a dopamine agonist compared with no use was increased by almost 60% (relative risk, 1.58). The heart failure risk associated with use of pramipexole (RR, 1.86) and with another dopamine agonist, cabergoline (RR, 2.07), were each higher compared with no use of these drugs.

In the other epidemiologic study, current use of pramipexole was associated with an increased risk of heart failure, compared with levodopa. The risk was increased in the first 3 months of treatment and among patients aged 80 years and older, but was no higher among people who had been treated with pramipexole for more than 3 months.

This last finding is "difficult to explain," since heart failure is a chronic condition, and the studies had limitations, which "make it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors," the FDA statement said.

The agency advises that health care professionals continue following recommendations in the pramipexole label and that patients continue to take the medication as directed.

Pramipexole was approved in July 1997.

The full FDA notice is available here. Serious adverse events associated with pramipexole should be reported to the FDA’s MedWatch program by clicking here or by calling 800-332-1088.

Seasonal influenza vaccination should be required for all health care workers, according to updated seasonal and pandemic influenza principles from the Infectious Diseases Society of America.

Incorporating lessons learned during the 2009-2010 H1N1 influenza pandemic and warning against complacency about the inevitability of another pandemic, the revised IDSA principles debuted Sept. 14 in a document titled "Pandemic and Seasonal Influenza Principles for United States Action."

The society revamped its flu guidance to help U.S. Department of Health and Human Services (HHS) officials establish priorities as they implement the Pandemic and All-Hazards Preparedness Act (PAHPA), which is being reauthorized by Congress.

IDSA last released such flu preparation and response principles in January 2007, before the 2009 H1N1 influenza pandemic. The emergence of the novel influenza H1N1 strain showed that, "in addition to severe illness and death, the spread of new influenza strains can cause significant societal and economic disruption and anxiety, and, in extreme cases, may threaten economic and national security."

The document outlines 10 principles, including strengthening influenza vaccination efforts and developing strategies to communicate with the public and medical professionals during a pandemic. It also advocates improved influenza surveillance and coordination between HHS and other federal and global partners, and well as boosting the accuracy and availability of diagnostic tools.

In addition, IDSA calls for enhanced availability of current antiviral drugs, as well as the development of new, simple-to-use antiviral drugs. The document highlights the need for antibacterial drugs to treat secondary infections.

IDSA also addresses the need to protect health care workers during seasonal and pandemic influenza outbreaks, and it recommends that annual seasonal influenza vaccination be required for all health care workers "through rules, regulations, policies, or laws." During a pandemic, health care workers directly taking care of patients should be in the group with highest vaccination priority. And long-term prophylaxis with antivirals can be considered "when medically appropriate and as supplies permit."

There were almost 61 million influenza cases reported in the United States during the 2009 H1N1 pandemic, including 274,000 hospitalizations and 12,500 deaths, according to IDSA. Younger people and pregnant women were disproportionately affected, with almost 90% of deaths occurring in people under age 65.

A copy of the 2012 IDSA principles is available by clicking here.

Seasonal influenza vaccination should be required for all health care workers, according to updated seasonal and pandemic influenza principles from the Infectious Diseases Society of America.

Incorporating lessons learned during the 2009-2010 H1N1 influenza pandemic and warning against complacency about the inevitability of another pandemic, the revised IDSA principles debuted Sept. 14 in a document titled "Pandemic and Seasonal Influenza Principles for United States Action."

The society revamped its flu guidance to help U.S. Department of Health and Human Services (HHS) officials establish priorities as they implement the Pandemic and All-Hazards Preparedness Act (PAHPA), which is being reauthorized by Congress.

IDSA last released such flu preparation and response principles in January 2007, before the 2009 H1N1 influenza pandemic. The emergence of the novel influenza H1N1 strain showed that, "in addition to severe illness and death, the spread of new influenza strains can cause significant societal and economic disruption and anxiety, and, in extreme cases, may threaten economic and national security."

The document outlines 10 principles, including strengthening influenza vaccination efforts and developing strategies to communicate with the public and medical professionals during a pandemic. It also advocates improved influenza surveillance and coordination between HHS and other federal and global partners, and well as boosting the accuracy and availability of diagnostic tools.

In addition, IDSA calls for enhanced availability of current antiviral drugs, as well as the development of new, simple-to-use antiviral drugs. The document highlights the need for antibacterial drugs to treat secondary infections.

IDSA also addresses the need to protect health care workers during seasonal and pandemic influenza outbreaks, and it recommends that annual seasonal influenza vaccination be required for all health care workers "through rules, regulations, policies, or laws." During a pandemic, health care workers directly taking care of patients should be in the group with highest vaccination priority. And long-term prophylaxis with antivirals can be considered "when medically appropriate and as supplies permit."

There were almost 61 million influenza cases reported in the United States during the 2009 H1N1 pandemic, including 274,000 hospitalizations and 12,500 deaths, according to IDSA. Younger people and pregnant women were disproportionately affected, with almost 90% of deaths occurring in people under age 65.

A copy of the 2012 IDSA principles is available by clicking here.

Seasonal influenza vaccination should be required for all health care workers, according to updated seasonal and pandemic influenza principles from the Infectious Diseases Society of America.

Incorporating lessons learned during the 2009-2010 H1N1 influenza pandemic and warning against complacency about the inevitability of another pandemic, the revised IDSA principles debuted Sept. 14 in a document titled "Pandemic and Seasonal Influenza Principles for United States Action."

The society revamped its flu guidance to help U.S. Department of Health and Human Services (HHS) officials establish priorities as they implement the Pandemic and All-Hazards Preparedness Act (PAHPA), which is being reauthorized by Congress.

IDSA last released such flu preparation and response principles in January 2007, before the 2009 H1N1 influenza pandemic. The emergence of the novel influenza H1N1 strain showed that, "in addition to severe illness and death, the spread of new influenza strains can cause significant societal and economic disruption and anxiety, and, in extreme cases, may threaten economic and national security."

The document outlines 10 principles, including strengthening influenza vaccination efforts and developing strategies to communicate with the public and medical professionals during a pandemic. It also advocates improved influenza surveillance and coordination between HHS and other federal and global partners, and well as boosting the accuracy and availability of diagnostic tools.

In addition, IDSA calls for enhanced availability of current antiviral drugs, as well as the development of new, simple-to-use antiviral drugs. The document highlights the need for antibacterial drugs to treat secondary infections.

IDSA also addresses the need to protect health care workers during seasonal and pandemic influenza outbreaks, and it recommends that annual seasonal influenza vaccination be required for all health care workers "through rules, regulations, policies, or laws." During a pandemic, health care workers directly taking care of patients should be in the group with highest vaccination priority. And long-term prophylaxis with antivirals can be considered "when medically appropriate and as supplies permit."

There were almost 61 million influenza cases reported in the United States during the 2009 H1N1 pandemic, including 274,000 hospitalizations and 12,500 deaths, according to IDSA. Younger people and pregnant women were disproportionately affected, with almost 90% of deaths occurring in people under age 65.

A copy of the 2012 IDSA principles is available by clicking here.

SILVER SPRING, MD. – Intravenous phenylephrine, used widely for decades to increase blood pressure in patients who become hypotensive during anesthesia, in intensive care, and in other situations, should be approved for use to increase blood pressure in patients who become hypotensive during neuraxial anesthesia, a Food and Drug Administration advisory panel unanimously agreed at a meeting on Sept. 13.

However, at the meeting the Cardiovascular and Renal Drugs Advisory Committee voted 8 to 2 against recommending approval of IV phenylephrine as a treatment to increase blood pressure in acute hypotensive states, such as shock, because more studies are needed.

IV phenylephrine, a selective alpha₁-adrenergic receptor agonist, has been used for decades without being approved by the FDA, since it was available before the current drug approval process was established, and is one of the unapproved products that the FDA considers medically necessary.

As a result of the FDA’s Unapproved Drugs Initiative, West-Ward Pharmaceuticals submitted an application for approval of intravenous phenylephrine "to increase blood pressure in acute hypotensive states, such as shock and perioperative hypotension." The application included 50 published studies, mostly of low-risk women who had neuraxial anesthesia during cesarean delivery.

At the meeting, company officials and clinicians who spoke on behalf of the company summarized the results of these studies, published from the 1980s through 2010.

Only eight studies were in patients with sepsis or septic shock, so the benefits and risks of IV phenylephrine for this use were limited, and there were no studies on the use of IV phenylephrine as a treatment for other types of shock, according to the FDA.

For indications other than neuraxial anesthesia, more data are needed before approval, including more data on efficacy and the impact of treatment on end-organ damage, said panel chair Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic.

One of the two panelists voting in favor of approval for the full indication (including acute hypotensive episodes due to shock), Dr. Joseph Tobin, professor of anesthesiology and pediatrics at Wake Forest Baptist Health, Winston-Salem, N.C., said that he felt comfortable after 30 years of use with this drug for the full indication, as proposed by the company.

The FDA usually follows the recommendations of its advisory panels. Panel members had no conflicts to disclose.

SILVER SPRING, MD. – Intravenous phenylephrine, used widely for decades to increase blood pressure in patients who become hypotensive during anesthesia, in intensive care, and in other situations, should be approved for use to increase blood pressure in patients who become hypotensive during neuraxial anesthesia, a Food and Drug Administration advisory panel unanimously agreed at a meeting on Sept. 13.

However, at the meeting the Cardiovascular and Renal Drugs Advisory Committee voted 8 to 2 against recommending approval of IV phenylephrine as a treatment to increase blood pressure in acute hypotensive states, such as shock, because more studies are needed.

IV phenylephrine, a selective alpha₁-adrenergic receptor agonist, has been used for decades without being approved by the FDA, since it was available before the current drug approval process was established, and is one of the unapproved products that the FDA considers medically necessary.

As a result of the FDA’s Unapproved Drugs Initiative, West-Ward Pharmaceuticals submitted an application for approval of intravenous phenylephrine "to increase blood pressure in acute hypotensive states, such as shock and perioperative hypotension." The application included 50 published studies, mostly of low-risk women who had neuraxial anesthesia during cesarean delivery.

At the meeting, company officials and clinicians who spoke on behalf of the company summarized the results of these studies, published from the 1980s through 2010.

Only eight studies were in patients with sepsis or septic shock, so the benefits and risks of IV phenylephrine for this use were limited, and there were no studies on the use of IV phenylephrine as a treatment for other types of shock, according to the FDA.

For indications other than neuraxial anesthesia, more data are needed before approval, including more data on efficacy and the impact of treatment on end-organ damage, said panel chair Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic.

One of the two panelists voting in favor of approval for the full indication (including acute hypotensive episodes due to shock), Dr. Joseph Tobin, professor of anesthesiology and pediatrics at Wake Forest Baptist Health, Winston-Salem, N.C., said that he felt comfortable after 30 years of use with this drug for the full indication, as proposed by the company.

The FDA usually follows the recommendations of its advisory panels. Panel members had no conflicts to disclose.

SILVER SPRING, MD. – Intravenous phenylephrine, used widely for decades to increase blood pressure in patients who become hypotensive during anesthesia, in intensive care, and in other situations, should be approved for use to increase blood pressure in patients who become hypotensive during neuraxial anesthesia, a Food and Drug Administration advisory panel unanimously agreed at a meeting on Sept. 13.

However, at the meeting the Cardiovascular and Renal Drugs Advisory Committee voted 8 to 2 against recommending approval of IV phenylephrine as a treatment to increase blood pressure in acute hypotensive states, such as shock, because more studies are needed.

IV phenylephrine, a selective alpha₁-adrenergic receptor agonist, has been used for decades without being approved by the FDA, since it was available before the current drug approval process was established, and is one of the unapproved products that the FDA considers medically necessary.

As a result of the FDA’s Unapproved Drugs Initiative, West-Ward Pharmaceuticals submitted an application for approval of intravenous phenylephrine "to increase blood pressure in acute hypotensive states, such as shock and perioperative hypotension." The application included 50 published studies, mostly of low-risk women who had neuraxial anesthesia during cesarean delivery.

At the meeting, company officials and clinicians who spoke on behalf of the company summarized the results of these studies, published from the 1980s through 2010.

Only eight studies were in patients with sepsis or septic shock, so the benefits and risks of IV phenylephrine for this use were limited, and there were no studies on the use of IV phenylephrine as a treatment for other types of shock, according to the FDA.

For indications other than neuraxial anesthesia, more data are needed before approval, including more data on efficacy and the impact of treatment on end-organ damage, said panel chair Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic.

One of the two panelists voting in favor of approval for the full indication (including acute hypotensive episodes due to shock), Dr. Joseph Tobin, professor of anesthesiology and pediatrics at Wake Forest Baptist Health, Winston-Salem, N.C., said that he felt comfortable after 30 years of use with this drug for the full indication, as proposed by the company.

The FDA usually follows the recommendations of its advisory panels. Panel members had no conflicts to disclose.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has recommended against the approval of lixivaptan, an orally administered vasopressin-2 receptor antagonist, for treating hyponatremia in two groups of adult patients at a meeting on Sept. 13.

The manufacturer, Cardiokine Biopharma, has proposed that lixivaptan be approved for the treatment of hypervolemic hyponatremia associated with heart failure, and for the treatment of euvolemic hyponatremia associated with syndrome of inappropriate antidiuretic hormone (SIADH). The company submitted the results of three phase III placebo-controlled trials that evaluated the changes from baseline in serum sodium at day 7 of treatment, the primary efficacy end point. The company proposed that for the SIADH indication, treatment could be initiated in an outpatient setting, which would be a potential benefit over existing treatments, including the only approved orally administered vasopressin-2 receptor antagonist that is approved for hyponatremia, tolvaptan (Samsca). Tolvaptan is approved for inpatients with diagnoses that include SIADH, heart failure, and cirrhosis, and is initiated in the hospital. The other approved "vaptan" – zomivaptan (Vaprisol), approved in 2005 – is administered intravenously.

Lixivaptan acts specifically on the vasopressin-2 receptor in the kidneys, "causing water to be excreted while sparing sodium without affecting other electrolytes," according to Cardiokine. While the changes in serum sodium from baseline to day 7 among treated patients over placebo were statistically significant, the improvements were modest and were not associated with improved cognitive function, the FDA reviewers pointed out.

In the study of patients with hypervolemic hyponatremia hospitalized with New York Heart Association (NYHA) class III or IV heart failure (652 patients), the increase in serum sodium at day 7 was 1.2 mEq/L greater among treated patients, compared with those on placebo. The mortality rate was 17.7% among those who had at least one dose of lixivaptan, compared with 14.3% on placebo; most deaths were related to heart failure, according to Cardiokine, which was recently acquired by Cornerstone Therapeutics.

In the two other studies, comprising a total of 312 patients with SIADH, the increases in serum sodium at day 7 over placebo were 2.2 mEq/L and 2.4 mEq/L.

But at the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel unanimously voted against approval of lixivaptan for the heart failure indication, because its members were not convinced that the modest effect of treatment on hyponatremia observed in the study of heart failure patients provided evidence that it benefited patients. The panel also agreed that more data on how improvements in serum sodium translated to clinical benefits, such as quality of life improvements, were needed. Another concern was that mortality was higher among the patients treated with lixivaptan than in those on placebo, particularly early in treatment.

The panel voted 5 to 3 against approval for treatment of hyponatremia in patients with SIADH, with clinicians voting on both sides of this question.

Dr. Linda Fried, professor of medicine at the VA Health Care System in Pittsburgh, voted in favor of approval because she said she believed that the vaptans directly affect pathophysiology in SIADH, and because she did not see a safety signal.

But Dr. Mori Krantz, associate professor of cardiology at the University of Colorado, Denver, voted against approval, because there were not enough data to show whether the improvements with treatment were clinically meaningful. He said that a larger study evaluating the effects of improvements in serum sodium with treatment on quality of life and other measures was needed, "to at least give clinicians some sense of security that they are helping patients."

Most panelists questioned the feasibility of initiating treatment as an outpatient, in most clinical settings.

The FDA is expected to make a decision on approval by Oct. 29.

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

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has recommended against the approval of lixivaptan, an orally administered vasopressin-2 receptor antagonist, for treating hyponatremia in two groups of adult patients at a meeting on Sept. 13.

The manufacturer, Cardiokine Biopharma, has proposed that lixivaptan be approved for the treatment of hypervolemic hyponatremia associated with heart failure, and for the treatment of euvolemic hyponatremia associated with syndrome of inappropriate antidiuretic hormone (SIADH). The company submitted the results of three phase III placebo-controlled trials that evaluated the changes from baseline in serum sodium at day 7 of treatment, the primary efficacy end point. The company proposed that for the SIADH indication, treatment could be initiated in an outpatient setting, which would be a potential benefit over existing treatments, including the only approved orally administered vasopressin-2 receptor antagonist that is approved for hyponatremia, tolvaptan (Samsca). Tolvaptan is approved for inpatients with diagnoses that include SIADH, heart failure, and cirrhosis, and is initiated in the hospital. The other approved "vaptan" – zomivaptan (Vaprisol), approved in 2005 – is administered intravenously.

Lixivaptan acts specifically on the vasopressin-2 receptor in the kidneys, "causing water to be excreted while sparing sodium without affecting other electrolytes," according to Cardiokine. While the changes in serum sodium from baseline to day 7 among treated patients over placebo were statistically significant, the improvements were modest and were not associated with improved cognitive function, the FDA reviewers pointed out.

In the study of patients with hypervolemic hyponatremia hospitalized with New York Heart Association (NYHA) class III or IV heart failure (652 patients), the increase in serum sodium at day 7 was 1.2 mEq/L greater among treated patients, compared with those on placebo. The mortality rate was 17.7% among those who had at least one dose of lixivaptan, compared with 14.3% on placebo; most deaths were related to heart failure, according to Cardiokine, which was recently acquired by Cornerstone Therapeutics.

In the two other studies, comprising a total of 312 patients with SIADH, the increases in serum sodium at day 7 over placebo were 2.2 mEq/L and 2.4 mEq/L.

But at the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel unanimously voted against approval of lixivaptan for the heart failure indication, because its members were not convinced that the modest effect of treatment on hyponatremia observed in the study of heart failure patients provided evidence that it benefited patients. The panel also agreed that more data on how improvements in serum sodium translated to clinical benefits, such as quality of life improvements, were needed. Another concern was that mortality was higher among the patients treated with lixivaptan than in those on placebo, particularly early in treatment.

The panel voted 5 to 3 against approval for treatment of hyponatremia in patients with SIADH, with clinicians voting on both sides of this question.

Dr. Linda Fried, professor of medicine at the VA Health Care System in Pittsburgh, voted in favor of approval because she said she believed that the vaptans directly affect pathophysiology in SIADH, and because she did not see a safety signal.

But Dr. Mori Krantz, associate professor of cardiology at the University of Colorado, Denver, voted against approval, because there were not enough data to show whether the improvements with treatment were clinically meaningful. He said that a larger study evaluating the effects of improvements in serum sodium with treatment on quality of life and other measures was needed, "to at least give clinicians some sense of security that they are helping patients."

Most panelists questioned the feasibility of initiating treatment as an outpatient, in most clinical settings.

The FDA is expected to make a decision on approval by Oct. 29.

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

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has recommended against the approval of lixivaptan, an orally administered vasopressin-2 receptor antagonist, for treating hyponatremia in two groups of adult patients at a meeting on Sept. 13.

The manufacturer, Cardiokine Biopharma, has proposed that lixivaptan be approved for the treatment of hypervolemic hyponatremia associated with heart failure, and for the treatment of euvolemic hyponatremia associated with syndrome of inappropriate antidiuretic hormone (SIADH). The company submitted the results of three phase III placebo-controlled trials that evaluated the changes from baseline in serum sodium at day 7 of treatment, the primary efficacy end point. The company proposed that for the SIADH indication, treatment could be initiated in an outpatient setting, which would be a potential benefit over existing treatments, including the only approved orally administered vasopressin-2 receptor antagonist that is approved for hyponatremia, tolvaptan (Samsca). Tolvaptan is approved for inpatients with diagnoses that include SIADH, heart failure, and cirrhosis, and is initiated in the hospital. The other approved "vaptan" – zomivaptan (Vaprisol), approved in 2005 – is administered intravenously.

Lixivaptan acts specifically on the vasopressin-2 receptor in the kidneys, "causing water to be excreted while sparing sodium without affecting other electrolytes," according to Cardiokine. While the changes in serum sodium from baseline to day 7 among treated patients over placebo were statistically significant, the improvements were modest and were not associated with improved cognitive function, the FDA reviewers pointed out.

In the study of patients with hypervolemic hyponatremia hospitalized with New York Heart Association (NYHA) class III or IV heart failure (652 patients), the increase in serum sodium at day 7 was 1.2 mEq/L greater among treated patients, compared with those on placebo. The mortality rate was 17.7% among those who had at least one dose of lixivaptan, compared with 14.3% on placebo; most deaths were related to heart failure, according to Cardiokine, which was recently acquired by Cornerstone Therapeutics.

In the two other studies, comprising a total of 312 patients with SIADH, the increases in serum sodium at day 7 over placebo were 2.2 mEq/L and 2.4 mEq/L.

But at the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel unanimously voted against approval of lixivaptan for the heart failure indication, because its members were not convinced that the modest effect of treatment on hyponatremia observed in the study of heart failure patients provided evidence that it benefited patients. The panel also agreed that more data on how improvements in serum sodium translated to clinical benefits, such as quality of life improvements, were needed. Another concern was that mortality was higher among the patients treated with lixivaptan than in those on placebo, particularly early in treatment.

The panel voted 5 to 3 against approval for treatment of hyponatremia in patients with SIADH, with clinicians voting on both sides of this question.

Dr. Linda Fried, professor of medicine at the VA Health Care System in Pittsburgh, voted in favor of approval because she said she believed that the vaptans directly affect pathophysiology in SIADH, and because she did not see a safety signal.

But Dr. Mori Krantz, associate professor of cardiology at the University of Colorado, Denver, voted against approval, because there were not enough data to show whether the improvements with treatment were clinically meaningful. He said that a larger study evaluating the effects of improvements in serum sodium with treatment on quality of life and other measures was needed, "to at least give clinicians some sense of security that they are helping patients."

Most panelists questioned the feasibility of initiating treatment as an outpatient, in most clinical settings.

The FDA is expected to make a decision on approval by Oct. 29.

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

A live-attenuated dengue vaccine was about 30% effective in preventing dengue infections and was well tolerated in a study of healthy children in Thailand, providing evidence for the first time that a safe and effective vaccine for dengue could eventually become a reality, according to Dr. Arunee Sabchareon and her associates.

"Although the assumed high efficacy against all four serotypes of dengue virus was not shown, our study constitutes the first ever demonstration that a safe dengue vaccine is possible," concluded Dr. Sabchareon of the department of tropical pediatrics at Mahidol University, Bangkok, and her colleagues. The study was published online Sept. 11 in the Lancet (doi: 10.1016/S0140-6736(12)61428-7).

Courtesy Wikimedia Commons/Muhammad Mahdi Karim/Creative Commons License

There are four dengue virus serotypes that are pathogenic, which has been one of the main challenges in developing a vaccine against the disease, they said. There is currently no licensed dengue vaccine available despite almost 50 years of research, but several dengue vaccines are in early clinical or preclinical stages, they noted.

The "CYD-TDV" vaccine – a recombinant, live, attenuated, tetravalent dengue vaccine used in this trial – has been studied in phase I and II trials.

In this controlled, phase IIb "proof-of-concept" study, randomized healthy Thai schoolchildren aged 4-11 years living in a dengue endemic area outside Bangkok received three doses of the dengue vaccine (2,669) or a placebo or rabies vaccine (1,333 children) at 0, 6, and 12 months, between February 2009 and February 2010.

During 25 months of follow-up, 134 of the children had virologically confirmed dengue, including 4 children who had two episodes, for an overall efficacy of the vaccine of 30.2%. Dr. Sabchareon and her associates also analyzed efficacy by serotype, and found that efficacy ranged from 61.2% against the DENV1 serotype, to 81.9% against the DENV3 subtype, to 90% against the DENV4 subtype.

The researchers evaluated immune responses to the vaccine in a subset of 300 patients, and determined that mean antibody titers against dengue virus were increased after the first dose, and levels after the second and third doses were higher compared with the first dose.

During the 2 years of follow-up after the first dose, there were no serious adverse events associated with the vaccine, and no safety signals were detected.

Considering the World Health Organization’s goal of cutting dengue mortality by half and morbidity by at least 25% by 2020, "this study represents a major milestone," and the results "support the continued evaluation of this dengue vaccine," Dr. Sabchareon and her associates wrote.

The vaccine is currently being studied in phase III trials in more than 30,000 people in Latin America and Asia, they said.

About half the people in the world are at risk for dengue. The World Health Organization estimates that every year, 50-100 million people have dengue infections, and that about 500,000 are hospitalized for severe dengue.

The study was funded by Sanofi Pasteur; eight of the authors are Sanofi Pasteur employees who own stock options or shares in the company. The eight other authors, including Dr. Sabchareon, had no conflicts of interest to disclose.

A live-attenuated dengue vaccine was about 30% effective in preventing dengue infections and was well tolerated in a study of healthy children in Thailand, providing evidence for the first time that a safe and effective vaccine for dengue could eventually become a reality, according to Dr. Arunee Sabchareon and her associates.

"Although the assumed high efficacy against all four serotypes of dengue virus was not shown, our study constitutes the first ever demonstration that a safe dengue vaccine is possible," concluded Dr. Sabchareon of the department of tropical pediatrics at Mahidol University, Bangkok, and her colleagues. The study was published online Sept. 11 in the Lancet (doi: 10.1016/S0140-6736(12)61428-7).

Courtesy Wikimedia Commons/Muhammad Mahdi Karim/Creative Commons License

There are four dengue virus serotypes that are pathogenic, which has been one of the main challenges in developing a vaccine against the disease, they said. There is currently no licensed dengue vaccine available despite almost 50 years of research, but several dengue vaccines are in early clinical or preclinical stages, they noted.

The "CYD-TDV" vaccine – a recombinant, live, attenuated, tetravalent dengue vaccine used in this trial – has been studied in phase I and II trials.

In this controlled, phase IIb "proof-of-concept" study, randomized healthy Thai schoolchildren aged 4-11 years living in a dengue endemic area outside Bangkok received three doses of the dengue vaccine (2,669) or a placebo or rabies vaccine (1,333 children) at 0, 6, and 12 months, between February 2009 and February 2010.

During 25 months of follow-up, 134 of the children had virologically confirmed dengue, including 4 children who had two episodes, for an overall efficacy of the vaccine of 30.2%. Dr. Sabchareon and her associates also analyzed efficacy by serotype, and found that efficacy ranged from 61.2% against the DENV1 serotype, to 81.9% against the DENV3 subtype, to 90% against the DENV4 subtype.

The researchers evaluated immune responses to the vaccine in a subset of 300 patients, and determined that mean antibody titers against dengue virus were increased after the first dose, and levels after the second and third doses were higher compared with the first dose.

During the 2 years of follow-up after the first dose, there were no serious adverse events associated with the vaccine, and no safety signals were detected.

Considering the World Health Organization’s goal of cutting dengue mortality by half and morbidity by at least 25% by 2020, "this study represents a major milestone," and the results "support the continued evaluation of this dengue vaccine," Dr. Sabchareon and her associates wrote.

The vaccine is currently being studied in phase III trials in more than 30,000 people in Latin America and Asia, they said.

About half the people in the world are at risk for dengue. The World Health Organization estimates that every year, 50-100 million people have dengue infections, and that about 500,000 are hospitalized for severe dengue.

The study was funded by Sanofi Pasteur; eight of the authors are Sanofi Pasteur employees who own stock options or shares in the company. The eight other authors, including Dr. Sabchareon, had no conflicts of interest to disclose.

A live-attenuated dengue vaccine was about 30% effective in preventing dengue infections and was well tolerated in a study of healthy children in Thailand, providing evidence for the first time that a safe and effective vaccine for dengue could eventually become a reality, according to Dr. Arunee Sabchareon and her associates.

"Although the assumed high efficacy against all four serotypes of dengue virus was not shown, our study constitutes the first ever demonstration that a safe dengue vaccine is possible," concluded Dr. Sabchareon of the department of tropical pediatrics at Mahidol University, Bangkok, and her colleagues. The study was published online Sept. 11 in the Lancet (doi: 10.1016/S0140-6736(12)61428-7).

Courtesy Wikimedia Commons/Muhammad Mahdi Karim/Creative Commons License

There are four dengue virus serotypes that are pathogenic, which has been one of the main challenges in developing a vaccine against the disease, they said. There is currently no licensed dengue vaccine available despite almost 50 years of research, but several dengue vaccines are in early clinical or preclinical stages, they noted.

The "CYD-TDV" vaccine – a recombinant, live, attenuated, tetravalent dengue vaccine used in this trial – has been studied in phase I and II trials.

In this controlled, phase IIb "proof-of-concept" study, randomized healthy Thai schoolchildren aged 4-11 years living in a dengue endemic area outside Bangkok received three doses of the dengue vaccine (2,669) or a placebo or rabies vaccine (1,333 children) at 0, 6, and 12 months, between February 2009 and February 2010.

During 25 months of follow-up, 134 of the children had virologically confirmed dengue, including 4 children who had two episodes, for an overall efficacy of the vaccine of 30.2%. Dr. Sabchareon and her associates also analyzed efficacy by serotype, and found that efficacy ranged from 61.2% against the DENV1 serotype, to 81.9% against the DENV3 subtype, to 90% against the DENV4 subtype.

The researchers evaluated immune responses to the vaccine in a subset of 300 patients, and determined that mean antibody titers against dengue virus were increased after the first dose, and levels after the second and third doses were higher compared with the first dose.

During the 2 years of follow-up after the first dose, there were no serious adverse events associated with the vaccine, and no safety signals were detected.

Considering the World Health Organization’s goal of cutting dengue mortality by half and morbidity by at least 25% by 2020, "this study represents a major milestone," and the results "support the continued evaluation of this dengue vaccine," Dr. Sabchareon and her associates wrote.

The vaccine is currently being studied in phase III trials in more than 30,000 people in Latin America and Asia, they said.

About half the people in the world are at risk for dengue. The World Health Organization estimates that every year, 50-100 million people have dengue infections, and that about 500,000 are hospitalized for severe dengue.

The study was funded by Sanofi Pasteur; eight of the authors are Sanofi Pasteur employees who own stock options or shares in the company. The eight other authors, including Dr. Sabchareon, had no conflicts of interest to disclose.