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FDA warns about serious GI symptoms with olmesartan
Olmesartan can cause intestinal symptoms severe enough to warrant hospitalization, even years after initiating treatment with the antihypertensive drug, the Food and Drug Administration announced July 3.
In a Drug Safety Communication, the agency warns that spruelike enteropathy – with symptoms that can include severe, chronic diarrhea with significant weight loss, sometimes requiring hospitalization – has been associated with olmesartan use, months to years after starting treatment. "If patients taking olmesartan develop these symptoms and no other cause is found, the drug should be discontinued and therapy with another antihypertensive started," the statement says. Celiac disease is one of the possible causes of such symptoms that the FDA recommends should be investigated.
Spruelike enteropathy symptoms improved in all patients after they stopped taking the drug, the statement adds.
This information is being added to the olmesartan label, which currently lists diarrhea as a side effect of the drug. Olmesartan, approved in 2002 for the treatment of hypertension, is an angiotensin II receptor blocker (ARB) marketed as Benicar, Benicar HCT, Azor, and Tribenzor. The drug also is available in generic formulations. Spruelike enteropathy has not been reported with other ARBs, according to the FDA.
The warning is based on the agency’s evaluation of data that "found clear evidence of an association between olmesartan and spruelike enteropathy," the statement says. The data include the following:
• A total of 23 cases of patients reported to the FDA’s Adverse Event Reporting System, who presented with late-onset diarrhea and significant weight loss; in some patients, biopsies that showed intestinal villous atrophy. All patients improved after the drug was stopped, but 10 developed symptoms again when treatment resumed.
• A published case series of spruelike enteropathy associated with olmesartan in 22 patients, with symptoms that were similar to the cases reported to the FDA, as well as evidence of villous atrophy. These patients also improved after the drug was stopped, and in 18 patients, follow-up intestinal biopsies documented recovery or improvement of the duodenum after treatment was stopped (Mayo Clin. Proc. 2012;87:732-8).
• An analysis of claims and administrative data that identified a higher rate of celiac disease diagnoses among patients on olmesartan compared with those on other ARBs.
The mechanism for the enteropathy is "uncertain" but, based on currently available information, could be a localized, delayed hypersensitivity or cell-mediated immune response, the statement said.
In 2012, about 10.6 million prescriptions for olmesartan products were dispensed to about 1.9 million patients in U.S. outpatient retail pharmacies, according to the FDA.
Adverse events associated with olmesartan and olmesartan-containing products should be reported to the FDA’s Adverse Event Reporting System at 800-332-1088 or www.fda.gov/medwatch/.
Olmesartan can cause intestinal symptoms severe enough to warrant hospitalization, even years after initiating treatment with the antihypertensive drug, the Food and Drug Administration announced July 3.
In a Drug Safety Communication, the agency warns that spruelike enteropathy – with symptoms that can include severe, chronic diarrhea with significant weight loss, sometimes requiring hospitalization – has been associated with olmesartan use, months to years after starting treatment. "If patients taking olmesartan develop these symptoms and no other cause is found, the drug should be discontinued and therapy with another antihypertensive started," the statement says. Celiac disease is one of the possible causes of such symptoms that the FDA recommends should be investigated.
Spruelike enteropathy symptoms improved in all patients after they stopped taking the drug, the statement adds.
This information is being added to the olmesartan label, which currently lists diarrhea as a side effect of the drug. Olmesartan, approved in 2002 for the treatment of hypertension, is an angiotensin II receptor blocker (ARB) marketed as Benicar, Benicar HCT, Azor, and Tribenzor. The drug also is available in generic formulations. Spruelike enteropathy has not been reported with other ARBs, according to the FDA.
The warning is based on the agency’s evaluation of data that "found clear evidence of an association between olmesartan and spruelike enteropathy," the statement says. The data include the following:
• A total of 23 cases of patients reported to the FDA’s Adverse Event Reporting System, who presented with late-onset diarrhea and significant weight loss; in some patients, biopsies that showed intestinal villous atrophy. All patients improved after the drug was stopped, but 10 developed symptoms again when treatment resumed.
• A published case series of spruelike enteropathy associated with olmesartan in 22 patients, with symptoms that were similar to the cases reported to the FDA, as well as evidence of villous atrophy. These patients also improved after the drug was stopped, and in 18 patients, follow-up intestinal biopsies documented recovery or improvement of the duodenum after treatment was stopped (Mayo Clin. Proc. 2012;87:732-8).
• An analysis of claims and administrative data that identified a higher rate of celiac disease diagnoses among patients on olmesartan compared with those on other ARBs.
The mechanism for the enteropathy is "uncertain" but, based on currently available information, could be a localized, delayed hypersensitivity or cell-mediated immune response, the statement said.
In 2012, about 10.6 million prescriptions for olmesartan products were dispensed to about 1.9 million patients in U.S. outpatient retail pharmacies, according to the FDA.
Adverse events associated with olmesartan and olmesartan-containing products should be reported to the FDA’s Adverse Event Reporting System at 800-332-1088 or www.fda.gov/medwatch/.
Olmesartan can cause intestinal symptoms severe enough to warrant hospitalization, even years after initiating treatment with the antihypertensive drug, the Food and Drug Administration announced July 3.
In a Drug Safety Communication, the agency warns that spruelike enteropathy – with symptoms that can include severe, chronic diarrhea with significant weight loss, sometimes requiring hospitalization – has been associated with olmesartan use, months to years after starting treatment. "If patients taking olmesartan develop these symptoms and no other cause is found, the drug should be discontinued and therapy with another antihypertensive started," the statement says. Celiac disease is one of the possible causes of such symptoms that the FDA recommends should be investigated.
Spruelike enteropathy symptoms improved in all patients after they stopped taking the drug, the statement adds.
This information is being added to the olmesartan label, which currently lists diarrhea as a side effect of the drug. Olmesartan, approved in 2002 for the treatment of hypertension, is an angiotensin II receptor blocker (ARB) marketed as Benicar, Benicar HCT, Azor, and Tribenzor. The drug also is available in generic formulations. Spruelike enteropathy has not been reported with other ARBs, according to the FDA.
The warning is based on the agency’s evaluation of data that "found clear evidence of an association between olmesartan and spruelike enteropathy," the statement says. The data include the following:
• A total of 23 cases of patients reported to the FDA’s Adverse Event Reporting System, who presented with late-onset diarrhea and significant weight loss; in some patients, biopsies that showed intestinal villous atrophy. All patients improved after the drug was stopped, but 10 developed symptoms again when treatment resumed.
• A published case series of spruelike enteropathy associated with olmesartan in 22 patients, with symptoms that were similar to the cases reported to the FDA, as well as evidence of villous atrophy. These patients also improved after the drug was stopped, and in 18 patients, follow-up intestinal biopsies documented recovery or improvement of the duodenum after treatment was stopped (Mayo Clin. Proc. 2012;87:732-8).
• An analysis of claims and administrative data that identified a higher rate of celiac disease diagnoses among patients on olmesartan compared with those on other ARBs.
The mechanism for the enteropathy is "uncertain" but, based on currently available information, could be a localized, delayed hypersensitivity or cell-mediated immune response, the statement said.
In 2012, about 10.6 million prescriptions for olmesartan products were dispensed to about 1.9 million patients in U.S. outpatient retail pharmacies, according to the FDA.
Adverse events associated with olmesartan and olmesartan-containing products should be reported to the FDA’s Adverse Event Reporting System at 800-332-1088 or www.fda.gov/medwatch/.
FDA holds off approval of insomnia drug, company says
The approval of suvorexant, a novel insomnia drug, has been delayed because of issues related to the recommended doses of the drug, according to the manufacturer, Merck Research Laboratories.
The Food and Drug Administration has issued a complete response letter stating that the efficacy of doses from 10 mg to 40 mg have been established in elderly and nonelderly adults, but that the safety data do not support the approval of the 30-mg and 40-mg doses, the company said in a statement issued July 1.
In the letter, the FDA also advised Merck that 10 mg "should be the starting dose for most patients, and must be available before suvorexant can be approved," the Merck statement said. In addition, the letter states that that the 15-mg and 20-mg doses "would be appropriate" for people "in whom the 10-mg dose is well tolerated but not effective," and that a 5-mg dose would be necessary for people taking concomitant moderate CYP3A4 inhibitors.
The company had filed for approval of suvorexant, an orexin receptor antagonist, at doses of 20 mg (starting dose) up to 40 mg taken at bedtime for adults younger than 65 years, and 15 mg (starting dose) up to 30 mg for people aged 65 years and older. The company has data on the 10-mg dose, but did not file for approval of that dose.
However, at an FDA advisory panel meeting in May 2013, FDA reviewers concluded that the drug was effective, but were concerned about the potential serious side effects associated with the higher doses. Most of the panelists agreed that the drug was effective and that the starting doses were acceptably safe, but were divided on the safety of the higher doses.
The Merck statement says that an initial review of the letter indicates that clinical studies of the 10 mg dose would not be necessary, but manufacturing studies of the 10-mg dosage form would be needed. "We will evaluate the requests outlined in the complete response letter, and expect thereafter to work expeditiously with the FDA to make suvorexant available as a new treatment option," Dr. Roger M. Perlmutter, president of Merck, said in the statement.
The FDA does not announce when they send a company a complete response letter, which is issued for a drug when there are outstanding issues that need to be resolved before approval, but manufacturers can make these announcements.
Suvorexant blocks the binding of orexin A and B neuropeptides to orexin receptors, presumably inhibiting activation of neurons to the arousal system; if approved, it would be the first drug in this class to be approved.
The approval of suvorexant, a novel insomnia drug, has been delayed because of issues related to the recommended doses of the drug, according to the manufacturer, Merck Research Laboratories.
The Food and Drug Administration has issued a complete response letter stating that the efficacy of doses from 10 mg to 40 mg have been established in elderly and nonelderly adults, but that the safety data do not support the approval of the 30-mg and 40-mg doses, the company said in a statement issued July 1.
In the letter, the FDA also advised Merck that 10 mg "should be the starting dose for most patients, and must be available before suvorexant can be approved," the Merck statement said. In addition, the letter states that that the 15-mg and 20-mg doses "would be appropriate" for people "in whom the 10-mg dose is well tolerated but not effective," and that a 5-mg dose would be necessary for people taking concomitant moderate CYP3A4 inhibitors.
The company had filed for approval of suvorexant, an orexin receptor antagonist, at doses of 20 mg (starting dose) up to 40 mg taken at bedtime for adults younger than 65 years, and 15 mg (starting dose) up to 30 mg for people aged 65 years and older. The company has data on the 10-mg dose, but did not file for approval of that dose.
However, at an FDA advisory panel meeting in May 2013, FDA reviewers concluded that the drug was effective, but were concerned about the potential serious side effects associated with the higher doses. Most of the panelists agreed that the drug was effective and that the starting doses were acceptably safe, but were divided on the safety of the higher doses.
The Merck statement says that an initial review of the letter indicates that clinical studies of the 10 mg dose would not be necessary, but manufacturing studies of the 10-mg dosage form would be needed. "We will evaluate the requests outlined in the complete response letter, and expect thereafter to work expeditiously with the FDA to make suvorexant available as a new treatment option," Dr. Roger M. Perlmutter, president of Merck, said in the statement.
The FDA does not announce when they send a company a complete response letter, which is issued for a drug when there are outstanding issues that need to be resolved before approval, but manufacturers can make these announcements.
Suvorexant blocks the binding of orexin A and B neuropeptides to orexin receptors, presumably inhibiting activation of neurons to the arousal system; if approved, it would be the first drug in this class to be approved.
The approval of suvorexant, a novel insomnia drug, has been delayed because of issues related to the recommended doses of the drug, according to the manufacturer, Merck Research Laboratories.
The Food and Drug Administration has issued a complete response letter stating that the efficacy of doses from 10 mg to 40 mg have been established in elderly and nonelderly adults, but that the safety data do not support the approval of the 30-mg and 40-mg doses, the company said in a statement issued July 1.
In the letter, the FDA also advised Merck that 10 mg "should be the starting dose for most patients, and must be available before suvorexant can be approved," the Merck statement said. In addition, the letter states that that the 15-mg and 20-mg doses "would be appropriate" for people "in whom the 10-mg dose is well tolerated but not effective," and that a 5-mg dose would be necessary for people taking concomitant moderate CYP3A4 inhibitors.
The company had filed for approval of suvorexant, an orexin receptor antagonist, at doses of 20 mg (starting dose) up to 40 mg taken at bedtime for adults younger than 65 years, and 15 mg (starting dose) up to 30 mg for people aged 65 years and older. The company has data on the 10-mg dose, but did not file for approval of that dose.
However, at an FDA advisory panel meeting in May 2013, FDA reviewers concluded that the drug was effective, but were concerned about the potential serious side effects associated with the higher doses. Most of the panelists agreed that the drug was effective and that the starting doses were acceptably safe, but were divided on the safety of the higher doses.
The Merck statement says that an initial review of the letter indicates that clinical studies of the 10 mg dose would not be necessary, but manufacturing studies of the 10-mg dosage form would be needed. "We will evaluate the requests outlined in the complete response letter, and expect thereafter to work expeditiously with the FDA to make suvorexant available as a new treatment option," Dr. Roger M. Perlmutter, president of Merck, said in the statement.
The FDA does not announce when they send a company a complete response letter, which is issued for a drug when there are outstanding issues that need to be resolved before approval, but manufacturers can make these announcements.
Suvorexant blocks the binding of orexin A and B neuropeptides to orexin receptors, presumably inhibiting activation of neurons to the arousal system; if approved, it would be the first drug in this class to be approved.
Infliximab biosimilars backed for approval in EU
Two biosimilar versions of infliximab have been recommended for approval in Europe, putting them on track to become the first monoclonal antibody biosimilars to be approved by the European Medicines Agency.*
On June 28, the agency's Committee for Medicinal Products for Human Use (CHMP) announced that it had recommended marketing authorizations for Remsima and Inflectra. Both contain the monoclonal antibody infliximab and were shown to be similar to Remicade, approved in the European Union since 1999. Authorization, or approval, of the two biosimilars is for the same indications as Remicade, which include rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.
This marks "the first time that the biosimilar concept has been successfully applied to such a complex molecule," an EMA statement said.
Infliximab, a tumor necrosis factor (TNF) blocker, was approved in 1998 in the United States and is also marketed as Remicade, for similar indications.
In Europe, the first biosimilar medication was approved in 2006, and a total of 12 biosimilar medications have been approved using a regulatory framework designed specifically for approval of biosimilars. A product-specific guideline for monoclonal antibodies has been established since December 2012. For approval, studies are required to show that the medication "does not have any meaningful differences from the reference medicine in terms of its quality, safety, and efficacy," according to the statement. The applicant must also establish a risk management plan that confirms the long-term safety and efficacy of the product, and monitors unexpected rare adverse events associated with the clinical use of the product.
The United States lags behind Europe with regard to the approval of biosimilars. A specific approval pathway for such products was created in the Affordable Care Act in March 2010. In 2012, the Food and Drug Administration issued draft guidance aimed at helping the developers of biosimilar products understand the expectations for such products and to provide a clear regulatory pathway for approval.
But to date, no biosimilar product has been approved in the United States.
*CORRECTION, 7/9/2013: An earlier version of this story incorrectly described the marketing status of the two biosimilars.
Two biosimilar versions of infliximab have been recommended for approval in Europe, putting them on track to become the first monoclonal antibody biosimilars to be approved by the European Medicines Agency.*
On June 28, the agency's Committee for Medicinal Products for Human Use (CHMP) announced that it had recommended marketing authorizations for Remsima and Inflectra. Both contain the monoclonal antibody infliximab and were shown to be similar to Remicade, approved in the European Union since 1999. Authorization, or approval, of the two biosimilars is for the same indications as Remicade, which include rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.
This marks "the first time that the biosimilar concept has been successfully applied to such a complex molecule," an EMA statement said.
Infliximab, a tumor necrosis factor (TNF) blocker, was approved in 1998 in the United States and is also marketed as Remicade, for similar indications.
In Europe, the first biosimilar medication was approved in 2006, and a total of 12 biosimilar medications have been approved using a regulatory framework designed specifically for approval of biosimilars. A product-specific guideline for monoclonal antibodies has been established since December 2012. For approval, studies are required to show that the medication "does not have any meaningful differences from the reference medicine in terms of its quality, safety, and efficacy," according to the statement. The applicant must also establish a risk management plan that confirms the long-term safety and efficacy of the product, and monitors unexpected rare adverse events associated with the clinical use of the product.
The United States lags behind Europe with regard to the approval of biosimilars. A specific approval pathway for such products was created in the Affordable Care Act in March 2010. In 2012, the Food and Drug Administration issued draft guidance aimed at helping the developers of biosimilar products understand the expectations for such products and to provide a clear regulatory pathway for approval.
But to date, no biosimilar product has been approved in the United States.
*CORRECTION, 7/9/2013: An earlier version of this story incorrectly described the marketing status of the two biosimilars.
Two biosimilar versions of infliximab have been recommended for approval in Europe, putting them on track to become the first monoclonal antibody biosimilars to be approved by the European Medicines Agency.*
On June 28, the agency's Committee for Medicinal Products for Human Use (CHMP) announced that it had recommended marketing authorizations for Remsima and Inflectra. Both contain the monoclonal antibody infliximab and were shown to be similar to Remicade, approved in the European Union since 1999. Authorization, or approval, of the two biosimilars is for the same indications as Remicade, which include rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.
This marks "the first time that the biosimilar concept has been successfully applied to such a complex molecule," an EMA statement said.
Infliximab, a tumor necrosis factor (TNF) blocker, was approved in 1998 in the United States and is also marketed as Remicade, for similar indications.
In Europe, the first biosimilar medication was approved in 2006, and a total of 12 biosimilar medications have been approved using a regulatory framework designed specifically for approval of biosimilars. A product-specific guideline for monoclonal antibodies has been established since December 2012. For approval, studies are required to show that the medication "does not have any meaningful differences from the reference medicine in terms of its quality, safety, and efficacy," according to the statement. The applicant must also establish a risk management plan that confirms the long-term safety and efficacy of the product, and monitors unexpected rare adverse events associated with the clinical use of the product.
The United States lags behind Europe with regard to the approval of biosimilars. A specific approval pathway for such products was created in the Affordable Care Act in March 2010. In 2012, the Food and Drug Administration issued draft guidance aimed at helping the developers of biosimilar products understand the expectations for such products and to provide a clear regulatory pathway for approval.
But to date, no biosimilar product has been approved in the United States.
*CORRECTION, 7/9/2013: An earlier version of this story incorrectly described the marketing status of the two biosimilars.
ACS stent thrombosis indication for rivaroxaban not approved, company says
The Food and Drug Administration has decided not to approve rivaroxaban for reducing the risk of stent thrombosis in patients with acute coronary syndrome, according to the manufacturer of the anticoagulant.
In a statement issued on June 28, Janssen Research & Development announced that the FDA has issued a complete response letter regarding the company’s application to approve rivaroxaban for this indication. Janssen markets rivaroxaban, an oral factor Xa inhibitor, as Xarelto.
The FDA does not announce when they send a company a complete response letter, issued for a drug when there are outstanding issues that need to be resolved before approval, but manufacturers can make these announcements.
The company filed for approval of this indication based on the results of the ATLAS ACS 2 TIMI 51 (the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) study, of 15,526 patients with recent ACS. In the study, rivaroxaban reduced the risk of cardiovascular death, MI, or stroke in patients with ACS, with an increase in major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. The study was published in January 2012 (N. Engl. J. Med. 2012;366:9-19).
In the Janssen statement, Dr. Christopher C. Nessel, vice president and medical leader of the cardiovascular franchise at Janssen, said, "We remain confident in the results of the ATLAS ACS 2 TIMI 51 trial and are in ongoing discussions with the FDA regarding" the supplemental new drug application. The Janssen statement did not elaborate on the reasons why the FDA did not approve this indication.
The company used data from the same study to file for approval of rivaroxaban for another indication – to reduce the risk of cardiovascular events in patients with ACS – but has received two complete response letters from the FDA for this indication, most recently in March 2013. Missing data and safety concerns were cited as concerns by FDA panelists recommending against the approval of this indication at an FDA advisory panel meeting in May 2012, but the company did not specify whether this was the reason for the two complete response letters for the ACS indication.
Since it was approved in 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, rivaroxaban has been approved by the FDA for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE); and for the reduction in the risk of recurrence of DVT and of PE.
It was recently approved in the European Union for in combination with antiplatelet therapy to help prevent atherothrombotic events after acute coronary syndrome.
The Food and Drug Administration has decided not to approve rivaroxaban for reducing the risk of stent thrombosis in patients with acute coronary syndrome, according to the manufacturer of the anticoagulant.
In a statement issued on June 28, Janssen Research & Development announced that the FDA has issued a complete response letter regarding the company’s application to approve rivaroxaban for this indication. Janssen markets rivaroxaban, an oral factor Xa inhibitor, as Xarelto.
The FDA does not announce when they send a company a complete response letter, issued for a drug when there are outstanding issues that need to be resolved before approval, but manufacturers can make these announcements.
The company filed for approval of this indication based on the results of the ATLAS ACS 2 TIMI 51 (the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) study, of 15,526 patients with recent ACS. In the study, rivaroxaban reduced the risk of cardiovascular death, MI, or stroke in patients with ACS, with an increase in major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. The study was published in January 2012 (N. Engl. J. Med. 2012;366:9-19).
In the Janssen statement, Dr. Christopher C. Nessel, vice president and medical leader of the cardiovascular franchise at Janssen, said, "We remain confident in the results of the ATLAS ACS 2 TIMI 51 trial and are in ongoing discussions with the FDA regarding" the supplemental new drug application. The Janssen statement did not elaborate on the reasons why the FDA did not approve this indication.
The company used data from the same study to file for approval of rivaroxaban for another indication – to reduce the risk of cardiovascular events in patients with ACS – but has received two complete response letters from the FDA for this indication, most recently in March 2013. Missing data and safety concerns were cited as concerns by FDA panelists recommending against the approval of this indication at an FDA advisory panel meeting in May 2012, but the company did not specify whether this was the reason for the two complete response letters for the ACS indication.
Since it was approved in 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, rivaroxaban has been approved by the FDA for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE); and for the reduction in the risk of recurrence of DVT and of PE.
It was recently approved in the European Union for in combination with antiplatelet therapy to help prevent atherothrombotic events after acute coronary syndrome.
The Food and Drug Administration has decided not to approve rivaroxaban for reducing the risk of stent thrombosis in patients with acute coronary syndrome, according to the manufacturer of the anticoagulant.
In a statement issued on June 28, Janssen Research & Development announced that the FDA has issued a complete response letter regarding the company’s application to approve rivaroxaban for this indication. Janssen markets rivaroxaban, an oral factor Xa inhibitor, as Xarelto.
The FDA does not announce when they send a company a complete response letter, issued for a drug when there are outstanding issues that need to be resolved before approval, but manufacturers can make these announcements.
The company filed for approval of this indication based on the results of the ATLAS ACS 2 TIMI 51 (the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) study, of 15,526 patients with recent ACS. In the study, rivaroxaban reduced the risk of cardiovascular death, MI, or stroke in patients with ACS, with an increase in major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. The study was published in January 2012 (N. Engl. J. Med. 2012;366:9-19).
In the Janssen statement, Dr. Christopher C. Nessel, vice president and medical leader of the cardiovascular franchise at Janssen, said, "We remain confident in the results of the ATLAS ACS 2 TIMI 51 trial and are in ongoing discussions with the FDA regarding" the supplemental new drug application. The Janssen statement did not elaborate on the reasons why the FDA did not approve this indication.
The company used data from the same study to file for approval of rivaroxaban for another indication – to reduce the risk of cardiovascular events in patients with ACS – but has received two complete response letters from the FDA for this indication, most recently in March 2013. Missing data and safety concerns were cited as concerns by FDA panelists recommending against the approval of this indication at an FDA advisory panel meeting in May 2012, but the company did not specify whether this was the reason for the two complete response letters for the ACS indication.
Since it was approved in 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, rivaroxaban has been approved by the FDA for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE); and for the reduction in the risk of recurrence of DVT and of PE.
It was recently approved in the European Union for in combination with antiplatelet therapy to help prevent atherothrombotic events after acute coronary syndrome.
Telavancin approval now includes nosocomial pneumonia indication
The lipoglycopeptide antibiotic telavancin has been approved for treating patients with hospital-acquired or ventilator-associated bacterial pneumonia caused by susceptible isolates of Staphylococcus aureus, the Food and Drug Administration announced.
Telavancin, marketed as Vibativ by Theravance, "should be used for the treatment of HABP/VABP only when alternative treatments are not suitable," the FDA said in a June 21 statement announcing the approval. It is not approved to treat other bacteria that cause pneumonia, the statement pointed out. It is administered once a day.
Approval of the expanded indication was based on the safety and effectiveness of telavancin in two studies of 1,532 patients with HABP/VABP, which compared treatment with telavancin to vancomycin, according to the FDA.
In a statement, the manufacturer said that, in the two noninferiority studies, ATTAIN I and ATTAIN II, patients received either telavancin (10 mg/kg IV once a day) or vancomycin (1 g IV every 12 hours).
All-cause mortality 28 days after treatment started was comparable between the two groups, but among those patients with pre-existing kidney disease, mortality was higher for those taking telavancin – information that is now included in the boxed warning for telavancin, according to the FDA. The most common adverse effect associated with treatment in the trials was diarrhea.
Telavancin should be considered for patients with pre-existing moderate to severe renal impairment (creatinine clearance of 50 mL/min or less) "only when the anticipated benefit to the patient outweighs the potential risk," according to Theravance.
Telavancin was initially approved in 2009 as a treatment for complicated skin and skin structure infections caused by susceptible isolates of Gram-positive bacteria, including both methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains of S. aureus, with a boxed warning about the fetal risks of treatment.
In a statement, the company said that telavancin would be made available to wholesalers for purchase for the pneumonia indication in the third quarter of 2013.
The lipoglycopeptide antibiotic telavancin has been approved for treating patients with hospital-acquired or ventilator-associated bacterial pneumonia caused by susceptible isolates of Staphylococcus aureus, the Food and Drug Administration announced.
Telavancin, marketed as Vibativ by Theravance, "should be used for the treatment of HABP/VABP only when alternative treatments are not suitable," the FDA said in a June 21 statement announcing the approval. It is not approved to treat other bacteria that cause pneumonia, the statement pointed out. It is administered once a day.
Approval of the expanded indication was based on the safety and effectiveness of telavancin in two studies of 1,532 patients with HABP/VABP, which compared treatment with telavancin to vancomycin, according to the FDA.
In a statement, the manufacturer said that, in the two noninferiority studies, ATTAIN I and ATTAIN II, patients received either telavancin (10 mg/kg IV once a day) or vancomycin (1 g IV every 12 hours).
All-cause mortality 28 days after treatment started was comparable between the two groups, but among those patients with pre-existing kidney disease, mortality was higher for those taking telavancin – information that is now included in the boxed warning for telavancin, according to the FDA. The most common adverse effect associated with treatment in the trials was diarrhea.
Telavancin should be considered for patients with pre-existing moderate to severe renal impairment (creatinine clearance of 50 mL/min or less) "only when the anticipated benefit to the patient outweighs the potential risk," according to Theravance.
Telavancin was initially approved in 2009 as a treatment for complicated skin and skin structure infections caused by susceptible isolates of Gram-positive bacteria, including both methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains of S. aureus, with a boxed warning about the fetal risks of treatment.
In a statement, the company said that telavancin would be made available to wholesalers for purchase for the pneumonia indication in the third quarter of 2013.
The lipoglycopeptide antibiotic telavancin has been approved for treating patients with hospital-acquired or ventilator-associated bacterial pneumonia caused by susceptible isolates of Staphylococcus aureus, the Food and Drug Administration announced.
Telavancin, marketed as Vibativ by Theravance, "should be used for the treatment of HABP/VABP only when alternative treatments are not suitable," the FDA said in a June 21 statement announcing the approval. It is not approved to treat other bacteria that cause pneumonia, the statement pointed out. It is administered once a day.
Approval of the expanded indication was based on the safety and effectiveness of telavancin in two studies of 1,532 patients with HABP/VABP, which compared treatment with telavancin to vancomycin, according to the FDA.
In a statement, the manufacturer said that, in the two noninferiority studies, ATTAIN I and ATTAIN II, patients received either telavancin (10 mg/kg IV once a day) or vancomycin (1 g IV every 12 hours).
All-cause mortality 28 days after treatment started was comparable between the two groups, but among those patients with pre-existing kidney disease, mortality was higher for those taking telavancin – information that is now included in the boxed warning for telavancin, according to the FDA. The most common adverse effect associated with treatment in the trials was diarrhea.
Telavancin should be considered for patients with pre-existing moderate to severe renal impairment (creatinine clearance of 50 mL/min or less) "only when the anticipated benefit to the patient outweighs the potential risk," according to Theravance.
Telavancin was initially approved in 2009 as a treatment for complicated skin and skin structure infections caused by susceptible isolates of Gram-positive bacteria, including both methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains of S. aureus, with a boxed warning about the fetal risks of treatment.
In a statement, the company said that telavancin would be made available to wholesalers for purchase for the pneumonia indication in the third quarter of 2013.
FDA: No starch solutions for critically ill, cardiopulmonary bypass patients
The Food and Drug Administration is warning that hydroxyethyl starch solutions should no longer be used in the treatment of critically ill adult patients –including patients with sepsis and those admitted to an intensive care unit – after completing an analysis of data indicating that treatment with these solutions increases the risk of death and renal injury in these groups.
In a statement, the agency also recommended that the use of hydroxyethyl starch (HES) solutions, used as plasma volume expanders, be avoided in patients who are having open heart surgery with cardiopulmonary bypass, because of an increased risk of excessive bleeding.
The FDA is making these recommendations after completing an analysis of data from randomized controlled trials, meta-analyses, and observational studies in thousands of critically ill patients, and from a meta-analysis of 18 randomized controlled trials of almost 1,000 patients undergoing open heart surgery with cardiopulmonary bypass. The risks and benefits of HES products were the focus of a meeting in September 2012 convened by the FDA.
"Based on the totality of the evidence, [the] FDA considers increased mortality and renal injury requiring RRT [renal replacement therapy] in critically ill adult patients, including patients with sepsis and those admitted to the ICU, and excess bleeding in patients undergoing open heart surgery in association with cardiopulmonary bypass, to be HES class effects," according to the statement. The agency also recommended that health care professionals avoid the use of these products in patients with preexisting renal dysfunction, discontinue their use at the first sign of renal injury, and monitor renal function for at least 90 days in all patients. In addition, HES products should be discontinued "at the first sign of coagulopathy."
The data on critically ill adults included three double-blind, multicenter, randomized controlled studies published in 2012, which compared HES with saline solution or Ringer’s acetate, in patients with severe sepsis (two studies), or patients in the ICU who had sepsis, had undergone elective surgery, and had an APACHE II score of at least 25. In these studies, which monitored patients for 90 days, HES was associated with increased mortality and/or renal injury requiring RRT, the FDA statements said. The results of meta-analyses and observational studies in similar populations lend additional support to these findings, the statement added.
But there was no evidence of an increased risk of renal injury associated with these products in a review of 59 randomized controlled studies of adult and pediatric surgical patients who received HES in the operating room and were followed for less than a week. This could have been due to less exposure to the product, a relatively short follow-up, being relatively healthy, or some unknown factor, the statement said.
In the meta-analysis of studies of patients undergoing open heart surgery with cardiopulmonary bypass, the "use of different HES products, irrespective of molecular weight or degree of molar substitution, was associated with increased bleeding," according to the statement. The meta-analysis was published in 2012 (J. Thoracic Cardiovasc. Surg. 2012:144;223-30).
A boxed warning about the risk in ICU and septic patients is being added to the labels of HES products, and the information about the excessive bleeding risk in open heart surgery patients is being added to the warnings and precautions section.
There are four FDA-approved HES products for treating and preventing hypovolemia; they are used when plasma volume expansion is needed: HESPAN (6% HES 450/0.7a in sodium chloride injection) manufactured by B. Braun Medical); Hetastarch (6%) in 0.9% sodium chloride injection, a generic equivalent of Hespan, manufactured by Teva Pharmaceuticals USA; Hextend (6% HES 450/0.7 in physiologic solution), manufactured by BioTime; and Voluven (6% HES 130/0.4 in normal saline), manufactured by Fresenius Kabi USA.
The advisory is available at www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm. Adverse events associated with HES solutions should be reported to the FDA’s MedWatch program at 80-332-1088 or www.fda.gov/Safety/MedWatch/HowToReport/default.htm.
The Food and Drug Administration is warning that hydroxyethyl starch solutions should no longer be used in the treatment of critically ill adult patients –including patients with sepsis and those admitted to an intensive care unit – after completing an analysis of data indicating that treatment with these solutions increases the risk of death and renal injury in these groups.
In a statement, the agency also recommended that the use of hydroxyethyl starch (HES) solutions, used as plasma volume expanders, be avoided in patients who are having open heart surgery with cardiopulmonary bypass, because of an increased risk of excessive bleeding.
The FDA is making these recommendations after completing an analysis of data from randomized controlled trials, meta-analyses, and observational studies in thousands of critically ill patients, and from a meta-analysis of 18 randomized controlled trials of almost 1,000 patients undergoing open heart surgery with cardiopulmonary bypass. The risks and benefits of HES products were the focus of a meeting in September 2012 convened by the FDA.
"Based on the totality of the evidence, [the] FDA considers increased mortality and renal injury requiring RRT [renal replacement therapy] in critically ill adult patients, including patients with sepsis and those admitted to the ICU, and excess bleeding in patients undergoing open heart surgery in association with cardiopulmonary bypass, to be HES class effects," according to the statement. The agency also recommended that health care professionals avoid the use of these products in patients with preexisting renal dysfunction, discontinue their use at the first sign of renal injury, and monitor renal function for at least 90 days in all patients. In addition, HES products should be discontinued "at the first sign of coagulopathy."
The data on critically ill adults included three double-blind, multicenter, randomized controlled studies published in 2012, which compared HES with saline solution or Ringer’s acetate, in patients with severe sepsis (two studies), or patients in the ICU who had sepsis, had undergone elective surgery, and had an APACHE II score of at least 25. In these studies, which monitored patients for 90 days, HES was associated with increased mortality and/or renal injury requiring RRT, the FDA statements said. The results of meta-analyses and observational studies in similar populations lend additional support to these findings, the statement added.
But there was no evidence of an increased risk of renal injury associated with these products in a review of 59 randomized controlled studies of adult and pediatric surgical patients who received HES in the operating room and were followed for less than a week. This could have been due to less exposure to the product, a relatively short follow-up, being relatively healthy, or some unknown factor, the statement said.
In the meta-analysis of studies of patients undergoing open heart surgery with cardiopulmonary bypass, the "use of different HES products, irrespective of molecular weight or degree of molar substitution, was associated with increased bleeding," according to the statement. The meta-analysis was published in 2012 (J. Thoracic Cardiovasc. Surg. 2012:144;223-30).
A boxed warning about the risk in ICU and septic patients is being added to the labels of HES products, and the information about the excessive bleeding risk in open heart surgery patients is being added to the warnings and precautions section.
There are four FDA-approved HES products for treating and preventing hypovolemia; they are used when plasma volume expansion is needed: HESPAN (6% HES 450/0.7a in sodium chloride injection) manufactured by B. Braun Medical); Hetastarch (6%) in 0.9% sodium chloride injection, a generic equivalent of Hespan, manufactured by Teva Pharmaceuticals USA; Hextend (6% HES 450/0.7 in physiologic solution), manufactured by BioTime; and Voluven (6% HES 130/0.4 in normal saline), manufactured by Fresenius Kabi USA.
The advisory is available at www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm. Adverse events associated with HES solutions should be reported to the FDA’s MedWatch program at 80-332-1088 or www.fda.gov/Safety/MedWatch/HowToReport/default.htm.
The Food and Drug Administration is warning that hydroxyethyl starch solutions should no longer be used in the treatment of critically ill adult patients –including patients with sepsis and those admitted to an intensive care unit – after completing an analysis of data indicating that treatment with these solutions increases the risk of death and renal injury in these groups.
In a statement, the agency also recommended that the use of hydroxyethyl starch (HES) solutions, used as plasma volume expanders, be avoided in patients who are having open heart surgery with cardiopulmonary bypass, because of an increased risk of excessive bleeding.
The FDA is making these recommendations after completing an analysis of data from randomized controlled trials, meta-analyses, and observational studies in thousands of critically ill patients, and from a meta-analysis of 18 randomized controlled trials of almost 1,000 patients undergoing open heart surgery with cardiopulmonary bypass. The risks and benefits of HES products were the focus of a meeting in September 2012 convened by the FDA.
"Based on the totality of the evidence, [the] FDA considers increased mortality and renal injury requiring RRT [renal replacement therapy] in critically ill adult patients, including patients with sepsis and those admitted to the ICU, and excess bleeding in patients undergoing open heart surgery in association with cardiopulmonary bypass, to be HES class effects," according to the statement. The agency also recommended that health care professionals avoid the use of these products in patients with preexisting renal dysfunction, discontinue their use at the first sign of renal injury, and monitor renal function for at least 90 days in all patients. In addition, HES products should be discontinued "at the first sign of coagulopathy."
The data on critically ill adults included three double-blind, multicenter, randomized controlled studies published in 2012, which compared HES with saline solution or Ringer’s acetate, in patients with severe sepsis (two studies), or patients in the ICU who had sepsis, had undergone elective surgery, and had an APACHE II score of at least 25. In these studies, which monitored patients for 90 days, HES was associated with increased mortality and/or renal injury requiring RRT, the FDA statements said. The results of meta-analyses and observational studies in similar populations lend additional support to these findings, the statement added.
But there was no evidence of an increased risk of renal injury associated with these products in a review of 59 randomized controlled studies of adult and pediatric surgical patients who received HES in the operating room and were followed for less than a week. This could have been due to less exposure to the product, a relatively short follow-up, being relatively healthy, or some unknown factor, the statement said.
In the meta-analysis of studies of patients undergoing open heart surgery with cardiopulmonary bypass, the "use of different HES products, irrespective of molecular weight or degree of molar substitution, was associated with increased bleeding," according to the statement. The meta-analysis was published in 2012 (J. Thoracic Cardiovasc. Surg. 2012:144;223-30).
A boxed warning about the risk in ICU and septic patients is being added to the labels of HES products, and the information about the excessive bleeding risk in open heart surgery patients is being added to the warnings and precautions section.
There are four FDA-approved HES products for treating and preventing hypovolemia; they are used when plasma volume expansion is needed: HESPAN (6% HES 450/0.7a in sodium chloride injection) manufactured by B. Braun Medical); Hetastarch (6%) in 0.9% sodium chloride injection, a generic equivalent of Hespan, manufactured by Teva Pharmaceuticals USA; Hextend (6% HES 450/0.7 in physiologic solution), manufactured by BioTime; and Voluven (6% HES 130/0.4 in normal saline), manufactured by Fresenius Kabi USA.
The advisory is available at www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm. Adverse events associated with HES solutions should be reported to the FDA’s MedWatch program at 80-332-1088 or www.fda.gov/Safety/MedWatch/HowToReport/default.htm.
CDC panel recommends egg-free influenza vaccine
The recently licensed recombinant egg-free influenza vaccine is recommended for influenza vaccination in adults aged 18-49 years with egg allergy of any severity for the 2013-2014 influenza season, by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
At a meeting June 20, the committee voted 13-0 to recommend the vaccine, a trivalent recombinant hemagglutinin vaccine marketed as FluBlok, for this population.
FluBlok, manufactured by Protein Sciences, was licensed by the Food and Drug Administration in January 2013 for annual influenza vaccination for the same population. It is the first recombinant hemagglutinin protein influenza vaccine, and is manufactured without the use of influenza virus or chicken eggs, so it does not contain any egg protein.
ACIP "recommends that individuals with a severe egg allergy consult with a physician about their allergic conditions prior to vaccination if FluBlok is not available," according to a CDC statement.
FluBlok
The recently licensed recombinant egg-free influenza vaccine is recommended for influenza vaccination in adults aged 18-49 years with egg allergy of any severity for the 2013-2014 influenza season, by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
At a meeting June 20, the committee voted 13-0 to recommend the vaccine, a trivalent recombinant hemagglutinin vaccine marketed as FluBlok, for this population.
FluBlok, manufactured by Protein Sciences, was licensed by the Food and Drug Administration in January 2013 for annual influenza vaccination for the same population. It is the first recombinant hemagglutinin protein influenza vaccine, and is manufactured without the use of influenza virus or chicken eggs, so it does not contain any egg protein.
ACIP "recommends that individuals with a severe egg allergy consult with a physician about their allergic conditions prior to vaccination if FluBlok is not available," according to a CDC statement.
The recently licensed recombinant egg-free influenza vaccine is recommended for influenza vaccination in adults aged 18-49 years with egg allergy of any severity for the 2013-2014 influenza season, by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
At a meeting June 20, the committee voted 13-0 to recommend the vaccine, a trivalent recombinant hemagglutinin vaccine marketed as FluBlok, for this population.
FluBlok, manufactured by Protein Sciences, was licensed by the Food and Drug Administration in January 2013 for annual influenza vaccination for the same population. It is the first recombinant hemagglutinin protein influenza vaccine, and is manufactured without the use of influenza virus or chicken eggs, so it does not contain any egg protein.
ACIP "recommends that individuals with a severe egg allergy consult with a physician about their allergic conditions prior to vaccination if FluBlok is not available," according to a CDC statement.
FluBlok
FluBlok
FROM A CDC ADVISORY COMMITTEE MEETING
Encephalitis travel vaccine recommendation expanded to children
ATLANTA – Vaccination against Japanese encephalitis should be recommended for children aged 2 months to 16 years as a travel vaccine in certain situations, according to the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
In a unanimous 13-0 vote, the committee supported the proposed recommendation of ACIP’s Japanese encephalitis (JE) vaccine workgroup to extend the current ACIP recommendation for JE vaccine in adults aged 17 years and older to children aged 2 months to 16 years, targeting people traveling at increased risk, based on their itineraries and activities. Until May, no vaccine for JE was available for children in the United States.
The 2009 recommendation for the JE vaccine in adults states the following:
• The JE vaccine is recommended for travelers who plan to spend 1 month or more in a JE-endemic area during the JE virus transmission season.
• The vaccine "should be considered" for short-term travelers (under 1 month) to endemic areas, if they are planning to travel outside of urban areas and have an increased risk of exposure to the JE virus (such as spending a "substantial time outdoors in rural or agricultural areas," or "participating in extensive outdoor activities").
• The vaccine also should be considered for travelers to an area with an ongoing JE outbreak, and travelers to endemic areas "who are uncertain of specific destinations, activities, or duration of travel."
• The vaccine is not recommended for short-term travelers who will be staying in urban areas only, or at times that are "outside of a well-defined JE virus transmission season."
The JE virus, a mosquito-borne flavivirus closely related to dengue and West Nile viruses, is endemic in China, Japan, and other parts of Asia, with the highest risk of in rural, agricultural areas.
Although the risk for most travelers to Asia is low, that risk varies depending on the destination, the duration and season of the visit, and activities, according to Dr. Marc Fischer of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), a member of ACIP’s JE vaccine workgroup. No cases of JE have been reported for travelers who only visited urban areas for short periods.
But JE is a severe disease with substantial morbidity and mortality, with no specific treatment available, and "the work group placed a high value on preventing this life-threatening disease," he said. Another consideration was the availability of a safe and effective vaccine, which provides high levels of seroprotection in children after 2 doses.
The vaccine that is available for adults – an inactivated cell culture derived JE vaccine (JE-VC) licensed by the Food and Drug Administration for adults aged 17 years and older – was also licensed for use in children aged 2 months to 16 years in May 2013. The vaccine is marketed as Ixiaro by Intercell Biomed, a Scottish company, and is distributed in the United States by Novartis. It is indicated for active immunization to prevent disease caused by JE virus and is administered as a two-dose primary series, 28 days apart.
The previously available JE vaccine, an inactivated mouse brain–derived JE vaccine, manufactured in Japan and licensed in the United States for people aged 1 year and older in 1992, is no longer available.
Between 1973 and 2012, there were 65 cases of travel-associated JE cases in the United States reported to the CDC or in the literature, including 6 (9%) of cases in children under age 17 years. Of the 65 cases, 13 (20%) were fatal, and of those who survived, 28 (43% of the total cases) had sequelae, Dr. Fisher said. Thailand was the "probable country of acquisition in most (32%) of these cases, followed by China (14%) Indonesia (14%), the Philippines (11%), Japan (6%) and Vietnam (5%), he said. In the remaining 18%, the probable country of acquisition was unknown.
Although the vaccine is expensive (about $200 a dose) and the risk of JE is not high, Dr. Fisher cited U.S. survey data indicating that parents would be willing to pay a high price for a vaccine to prevent a serious outcome.
Several members of the panel observed that the JE-VC vaccine is not likely to be provided in most general clinical practices, and that it would more likely be found in a travel medicine clinic. Cost was another issue cited, because travel vaccines are usually not covered by medical insurers.
There are 15 members in immunization-related fields on ACIP, which develops written recommendations for the routine administration of vaccines to children and adults in the civilian population; 13 members were present at this meeting.
ATLANTA – Vaccination against Japanese encephalitis should be recommended for children aged 2 months to 16 years as a travel vaccine in certain situations, according to the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
In a unanimous 13-0 vote, the committee supported the proposed recommendation of ACIP’s Japanese encephalitis (JE) vaccine workgroup to extend the current ACIP recommendation for JE vaccine in adults aged 17 years and older to children aged 2 months to 16 years, targeting people traveling at increased risk, based on their itineraries and activities. Until May, no vaccine for JE was available for children in the United States.
The 2009 recommendation for the JE vaccine in adults states the following:
• The JE vaccine is recommended for travelers who plan to spend 1 month or more in a JE-endemic area during the JE virus transmission season.
• The vaccine "should be considered" for short-term travelers (under 1 month) to endemic areas, if they are planning to travel outside of urban areas and have an increased risk of exposure to the JE virus (such as spending a "substantial time outdoors in rural or agricultural areas," or "participating in extensive outdoor activities").
• The vaccine also should be considered for travelers to an area with an ongoing JE outbreak, and travelers to endemic areas "who are uncertain of specific destinations, activities, or duration of travel."
• The vaccine is not recommended for short-term travelers who will be staying in urban areas only, or at times that are "outside of a well-defined JE virus transmission season."
The JE virus, a mosquito-borne flavivirus closely related to dengue and West Nile viruses, is endemic in China, Japan, and other parts of Asia, with the highest risk of in rural, agricultural areas.
Although the risk for most travelers to Asia is low, that risk varies depending on the destination, the duration and season of the visit, and activities, according to Dr. Marc Fischer of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), a member of ACIP’s JE vaccine workgroup. No cases of JE have been reported for travelers who only visited urban areas for short periods.
But JE is a severe disease with substantial morbidity and mortality, with no specific treatment available, and "the work group placed a high value on preventing this life-threatening disease," he said. Another consideration was the availability of a safe and effective vaccine, which provides high levels of seroprotection in children after 2 doses.
The vaccine that is available for adults – an inactivated cell culture derived JE vaccine (JE-VC) licensed by the Food and Drug Administration for adults aged 17 years and older – was also licensed for use in children aged 2 months to 16 years in May 2013. The vaccine is marketed as Ixiaro by Intercell Biomed, a Scottish company, and is distributed in the United States by Novartis. It is indicated for active immunization to prevent disease caused by JE virus and is administered as a two-dose primary series, 28 days apart.
The previously available JE vaccine, an inactivated mouse brain–derived JE vaccine, manufactured in Japan and licensed in the United States for people aged 1 year and older in 1992, is no longer available.
Between 1973 and 2012, there were 65 cases of travel-associated JE cases in the United States reported to the CDC or in the literature, including 6 (9%) of cases in children under age 17 years. Of the 65 cases, 13 (20%) were fatal, and of those who survived, 28 (43% of the total cases) had sequelae, Dr. Fisher said. Thailand was the "probable country of acquisition in most (32%) of these cases, followed by China (14%) Indonesia (14%), the Philippines (11%), Japan (6%) and Vietnam (5%), he said. In the remaining 18%, the probable country of acquisition was unknown.
Although the vaccine is expensive (about $200 a dose) and the risk of JE is not high, Dr. Fisher cited U.S. survey data indicating that parents would be willing to pay a high price for a vaccine to prevent a serious outcome.
Several members of the panel observed that the JE-VC vaccine is not likely to be provided in most general clinical practices, and that it would more likely be found in a travel medicine clinic. Cost was another issue cited, because travel vaccines are usually not covered by medical insurers.
There are 15 members in immunization-related fields on ACIP, which develops written recommendations for the routine administration of vaccines to children and adults in the civilian population; 13 members were present at this meeting.
ATLANTA – Vaccination against Japanese encephalitis should be recommended for children aged 2 months to 16 years as a travel vaccine in certain situations, according to the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
In a unanimous 13-0 vote, the committee supported the proposed recommendation of ACIP’s Japanese encephalitis (JE) vaccine workgroup to extend the current ACIP recommendation for JE vaccine in adults aged 17 years and older to children aged 2 months to 16 years, targeting people traveling at increased risk, based on their itineraries and activities. Until May, no vaccine for JE was available for children in the United States.
The 2009 recommendation for the JE vaccine in adults states the following:
• The JE vaccine is recommended for travelers who plan to spend 1 month or more in a JE-endemic area during the JE virus transmission season.
• The vaccine "should be considered" for short-term travelers (under 1 month) to endemic areas, if they are planning to travel outside of urban areas and have an increased risk of exposure to the JE virus (such as spending a "substantial time outdoors in rural or agricultural areas," or "participating in extensive outdoor activities").
• The vaccine also should be considered for travelers to an area with an ongoing JE outbreak, and travelers to endemic areas "who are uncertain of specific destinations, activities, or duration of travel."
• The vaccine is not recommended for short-term travelers who will be staying in urban areas only, or at times that are "outside of a well-defined JE virus transmission season."
The JE virus, a mosquito-borne flavivirus closely related to dengue and West Nile viruses, is endemic in China, Japan, and other parts of Asia, with the highest risk of in rural, agricultural areas.
Although the risk for most travelers to Asia is low, that risk varies depending on the destination, the duration and season of the visit, and activities, according to Dr. Marc Fischer of the CDC’s National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), a member of ACIP’s JE vaccine workgroup. No cases of JE have been reported for travelers who only visited urban areas for short periods.
But JE is a severe disease with substantial morbidity and mortality, with no specific treatment available, and "the work group placed a high value on preventing this life-threatening disease," he said. Another consideration was the availability of a safe and effective vaccine, which provides high levels of seroprotection in children after 2 doses.
The vaccine that is available for adults – an inactivated cell culture derived JE vaccine (JE-VC) licensed by the Food and Drug Administration for adults aged 17 years and older – was also licensed for use in children aged 2 months to 16 years in May 2013. The vaccine is marketed as Ixiaro by Intercell Biomed, a Scottish company, and is distributed in the United States by Novartis. It is indicated for active immunization to prevent disease caused by JE virus and is administered as a two-dose primary series, 28 days apart.
The previously available JE vaccine, an inactivated mouse brain–derived JE vaccine, manufactured in Japan and licensed in the United States for people aged 1 year and older in 1992, is no longer available.
Between 1973 and 2012, there were 65 cases of travel-associated JE cases in the United States reported to the CDC or in the literature, including 6 (9%) of cases in children under age 17 years. Of the 65 cases, 13 (20%) were fatal, and of those who survived, 28 (43% of the total cases) had sequelae, Dr. Fisher said. Thailand was the "probable country of acquisition in most (32%) of these cases, followed by China (14%) Indonesia (14%), the Philippines (11%), Japan (6%) and Vietnam (5%), he said. In the remaining 18%, the probable country of acquisition was unknown.
Although the vaccine is expensive (about $200 a dose) and the risk of JE is not high, Dr. Fisher cited U.S. survey data indicating that parents would be willing to pay a high price for a vaccine to prevent a serious outcome.
Several members of the panel observed that the JE-VC vaccine is not likely to be provided in most general clinical practices, and that it would more likely be found in a travel medicine clinic. Cost was another issue cited, because travel vaccines are usually not covered by medical insurers.
There are 15 members in immunization-related fields on ACIP, which develops written recommendations for the routine administration of vaccines to children and adults in the civilian population; 13 members were present at this meeting.
FROM AN ACIP MEETING
CDC study finds 56% drop in HPV infections
The prevalence of infections with the human papillomavirus types included in the quadrivalent HPV vaccine dropped by almost 60% among females aged 14-19 years during the 4-year period after the vaccine became available and was recommended as a routine vaccine in females, according to a Centers for Disease Control and Prevention study.
Considering that only about one-third of younger females have received all three recommended doses of the HPV vaccine, these results are better than expected, according to Dr. Lauri Markowitz, a CDC medical epidemiologist, and her coauthors.
"Our data suggest an early impact of HPV vaccination on vaccine type prevalence among females in the United States, and a high vaccine effectiveness against vaccine type infection," the authors concluded, adding that the decline was "encouraging, given the substantial health and economic burden of HPV-associated disease." The study was published online June 19 in the Journal of Infectious Diseases (doi: 10.1093/infdis/jit192).
"These are striking results, and they should be a wake-up call that we should increase vaccination rates" to protect the next generation of females against cancer caused by HPV infection, CDC Director Dr. Thomas Frieden said during a press briefing held to announce the results of the study. Increasing the vaccination rate to 80% would prevent about 50,000 cases of cervical cancer among girls alive today. "We owe it to the next generation – our sisters, our daughters, our nieces, and to those who are our patients, to protect them against cervical cancer," he added.
A three-dose series of the quadrivalent HPV vaccine (directed against HPV-6, -11, -16, and -18) was recommended by the CDC as a routine vaccine in 2006, for females aged 11-12 years, and for females aged 13-26 years who had not been vaccinated. In 2009, the bivalent HPV vaccine (directed against HPV-16 and -18, the types responsible for about 70% of cervical cancers) was also included in the recommendation. (In 2011, the recommendation for the quadrivalent vaccine was expanded to include boys aged 11 and 12 years, and for unvaccinated males up to age 26 years, but no data are available yet on the proportion of males who have been vaccinated or the impact of vaccination on infection rates.)
The study compared data on the prevalence of HPV infections, based on cervicovaginal samples, from the National Health and Nutrition Examination Survey (NHANES) among females aged 14-59 in two time periods: during 2003-2006, before the vaccine was available, and 2007-2010, after the HPV vaccine became available.
Among females aged 14-19 years, the prevalence of infections with the HPV types in the quadrivalent vaccine dropped from 11.5% during the first period to 5.1% during the second period – a 56% drop. There were no significant differences in infection rates between the two periods for older age groups.
The 56% drop is "greater than expected," considering the vaccine history and estimates of vaccine coverage in national immunization surveys, and could be due to herd immunity from vaccination, effectiveness of fewer than three doses, and/or changes in sexual behavior not measured in the study, Dr. Markowitz and her associates said. Based on NHANES data between 2007 and 2010, only 34% of females aged 14-19 years had received at least one dose of the HPV vaccine. The investigators could not identify any other factors that could explain the reduction in HPV infection, and concluded that the results "suggest an early impact of HPV vaccination."
Among the females aged 14-19 years who were sexually active and were vaccinated, there was an 88% drop in the prevalence of HPV vaccine types between the two time periods, and a 28% drop among those who had not been vaccinated, but the authors could not conclude that herd immunity also contributed to the drop, because of other factors.
There was no change in the rate of sexual activity during the two time periods, Dr. Markowitz, of the Division of STD Prevention in the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, said at the briefing. The indication that sexual activity was more common among those who were vaccinated has to be investigated further, she noted. NHANES started collecting data on HPV in males in 2013, and the first data in males will be available in 2015, she said.
HPV is the most common STD in the United States, with about 14 million people becoming infected with HPV every year. About 79 million people who are infected with HPV are in their late teens and early 20s, according to the CDC. About 19,000 cancers in women every year are caused by HPV; most are cervical cancer. About 8,000 cancers caused by HPV occur in men in the United States, with oropharyngeal cancers the most common, according to the CDC.
None of the authors had conflicts to report. The study was supported by the CDC.
The prevalence of infections with the human papillomavirus types included in the quadrivalent HPV vaccine dropped by almost 60% among females aged 14-19 years during the 4-year period after the vaccine became available and was recommended as a routine vaccine in females, according to a Centers for Disease Control and Prevention study.
Considering that only about one-third of younger females have received all three recommended doses of the HPV vaccine, these results are better than expected, according to Dr. Lauri Markowitz, a CDC medical epidemiologist, and her coauthors.
"Our data suggest an early impact of HPV vaccination on vaccine type prevalence among females in the United States, and a high vaccine effectiveness against vaccine type infection," the authors concluded, adding that the decline was "encouraging, given the substantial health and economic burden of HPV-associated disease." The study was published online June 19 in the Journal of Infectious Diseases (doi: 10.1093/infdis/jit192).
"These are striking results, and they should be a wake-up call that we should increase vaccination rates" to protect the next generation of females against cancer caused by HPV infection, CDC Director Dr. Thomas Frieden said during a press briefing held to announce the results of the study. Increasing the vaccination rate to 80% would prevent about 50,000 cases of cervical cancer among girls alive today. "We owe it to the next generation – our sisters, our daughters, our nieces, and to those who are our patients, to protect them against cervical cancer," he added.
A three-dose series of the quadrivalent HPV vaccine (directed against HPV-6, -11, -16, and -18) was recommended by the CDC as a routine vaccine in 2006, for females aged 11-12 years, and for females aged 13-26 years who had not been vaccinated. In 2009, the bivalent HPV vaccine (directed against HPV-16 and -18, the types responsible for about 70% of cervical cancers) was also included in the recommendation. (In 2011, the recommendation for the quadrivalent vaccine was expanded to include boys aged 11 and 12 years, and for unvaccinated males up to age 26 years, but no data are available yet on the proportion of males who have been vaccinated or the impact of vaccination on infection rates.)
The study compared data on the prevalence of HPV infections, based on cervicovaginal samples, from the National Health and Nutrition Examination Survey (NHANES) among females aged 14-59 in two time periods: during 2003-2006, before the vaccine was available, and 2007-2010, after the HPV vaccine became available.
Among females aged 14-19 years, the prevalence of infections with the HPV types in the quadrivalent vaccine dropped from 11.5% during the first period to 5.1% during the second period – a 56% drop. There were no significant differences in infection rates between the two periods for older age groups.
The 56% drop is "greater than expected," considering the vaccine history and estimates of vaccine coverage in national immunization surveys, and could be due to herd immunity from vaccination, effectiveness of fewer than three doses, and/or changes in sexual behavior not measured in the study, Dr. Markowitz and her associates said. Based on NHANES data between 2007 and 2010, only 34% of females aged 14-19 years had received at least one dose of the HPV vaccine. The investigators could not identify any other factors that could explain the reduction in HPV infection, and concluded that the results "suggest an early impact of HPV vaccination."
Among the females aged 14-19 years who were sexually active and were vaccinated, there was an 88% drop in the prevalence of HPV vaccine types between the two time periods, and a 28% drop among those who had not been vaccinated, but the authors could not conclude that herd immunity also contributed to the drop, because of other factors.
There was no change in the rate of sexual activity during the two time periods, Dr. Markowitz, of the Division of STD Prevention in the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, said at the briefing. The indication that sexual activity was more common among those who were vaccinated has to be investigated further, she noted. NHANES started collecting data on HPV in males in 2013, and the first data in males will be available in 2015, she said.
HPV is the most common STD in the United States, with about 14 million people becoming infected with HPV every year. About 79 million people who are infected with HPV are in their late teens and early 20s, according to the CDC. About 19,000 cancers in women every year are caused by HPV; most are cervical cancer. About 8,000 cancers caused by HPV occur in men in the United States, with oropharyngeal cancers the most common, according to the CDC.
None of the authors had conflicts to report. The study was supported by the CDC.
The prevalence of infections with the human papillomavirus types included in the quadrivalent HPV vaccine dropped by almost 60% among females aged 14-19 years during the 4-year period after the vaccine became available and was recommended as a routine vaccine in females, according to a Centers for Disease Control and Prevention study.
Considering that only about one-third of younger females have received all three recommended doses of the HPV vaccine, these results are better than expected, according to Dr. Lauri Markowitz, a CDC medical epidemiologist, and her coauthors.
"Our data suggest an early impact of HPV vaccination on vaccine type prevalence among females in the United States, and a high vaccine effectiveness against vaccine type infection," the authors concluded, adding that the decline was "encouraging, given the substantial health and economic burden of HPV-associated disease." The study was published online June 19 in the Journal of Infectious Diseases (doi: 10.1093/infdis/jit192).
"These are striking results, and they should be a wake-up call that we should increase vaccination rates" to protect the next generation of females against cancer caused by HPV infection, CDC Director Dr. Thomas Frieden said during a press briefing held to announce the results of the study. Increasing the vaccination rate to 80% would prevent about 50,000 cases of cervical cancer among girls alive today. "We owe it to the next generation – our sisters, our daughters, our nieces, and to those who are our patients, to protect them against cervical cancer," he added.
A three-dose series of the quadrivalent HPV vaccine (directed against HPV-6, -11, -16, and -18) was recommended by the CDC as a routine vaccine in 2006, for females aged 11-12 years, and for females aged 13-26 years who had not been vaccinated. In 2009, the bivalent HPV vaccine (directed against HPV-16 and -18, the types responsible for about 70% of cervical cancers) was also included in the recommendation. (In 2011, the recommendation for the quadrivalent vaccine was expanded to include boys aged 11 and 12 years, and for unvaccinated males up to age 26 years, but no data are available yet on the proportion of males who have been vaccinated or the impact of vaccination on infection rates.)
The study compared data on the prevalence of HPV infections, based on cervicovaginal samples, from the National Health and Nutrition Examination Survey (NHANES) among females aged 14-59 in two time periods: during 2003-2006, before the vaccine was available, and 2007-2010, after the HPV vaccine became available.
Among females aged 14-19 years, the prevalence of infections with the HPV types in the quadrivalent vaccine dropped from 11.5% during the first period to 5.1% during the second period – a 56% drop. There were no significant differences in infection rates between the two periods for older age groups.
The 56% drop is "greater than expected," considering the vaccine history and estimates of vaccine coverage in national immunization surveys, and could be due to herd immunity from vaccination, effectiveness of fewer than three doses, and/or changes in sexual behavior not measured in the study, Dr. Markowitz and her associates said. Based on NHANES data between 2007 and 2010, only 34% of females aged 14-19 years had received at least one dose of the HPV vaccine. The investigators could not identify any other factors that could explain the reduction in HPV infection, and concluded that the results "suggest an early impact of HPV vaccination."
Among the females aged 14-19 years who were sexually active and were vaccinated, there was an 88% drop in the prevalence of HPV vaccine types between the two time periods, and a 28% drop among those who had not been vaccinated, but the authors could not conclude that herd immunity also contributed to the drop, because of other factors.
There was no change in the rate of sexual activity during the two time periods, Dr. Markowitz, of the Division of STD Prevention in the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, said at the briefing. The indication that sexual activity was more common among those who were vaccinated has to be investigated further, she noted. NHANES started collecting data on HPV in males in 2013, and the first data in males will be available in 2015, she said.
HPV is the most common STD in the United States, with about 14 million people becoming infected with HPV every year. About 79 million people who are infected with HPV are in their late teens and early 20s, according to the CDC. About 19,000 cancers in women every year are caused by HPV; most are cervical cancer. About 8,000 cancers caused by HPV occur in men in the United States, with oropharyngeal cancers the most common, according to the CDC.
None of the authors had conflicts to report. The study was supported by the CDC.
FROM A CDC PRESS BRIEFING
Major finding: Among females aged 14-19 years, the prevalence of HPV infections dropped from 11.5% during the period prior to HPV vaccine availability in the United States to 5.1% after it was licensed and recommended as a routine vaccination.
Data source: The data were from NHANES during 2003-2006, for about 4,100 females aged 14-59 years, before the vaccine was available, and for about 4,200 females during 2007-2010, after the quadrivalent HPV vaccine became available.
Disclosures: None of the authors had conflicts to report. The study was supported by the CDC.
FDA investigating two deaths after olanzapine injections
The unexplained deaths of two patients a few days after receiving an intramuscular olanzapine injection are being investigated by the Food and Drug Administration.
The patients died 3-4 days after the IM injection of olanzapine pamoate, marketed as Zyprexa Relprevv, "well after the 3-hour post-injection monitoring period" required under the Risk Evaluation and Mitigation Strategy (REMS) in place for the drug. Both patients were found to have "very high" blood levels of olanzapine, according to the FDA statement issued on June 18. Zyprexa Relprevv is an intramuscular, long-acting formulation of the atypical antipsychotic olanzapine, approved for schizophrenia, and administered every 2 or 4 weeks.
Under the REMS for this agent, patients who are treated with this drug must receive the injection at a facility certified under the REMS, with ready access to emergency response services, and must be monitored continuously for at least 3 hours afterward.
The REMS addresses the risk of postinjection delirium/sedation syndrome (PDSS), which can occur when olanzapine levels rapidly rise after the injection. PDSS is associated with symptoms that can include dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, "and reduced level of consciousness ranging from mild sedation to coma," according to the drug’s label.
Cases of PDSS were reported in preapproval studies of Zyprexa Relprevv and, in most cases, patients were hospitalized; several patients required supportive care, including intubation, but all had "largely recovered" by 72 hours, the label says.
While the investigation is underway, the FDA recommends that health care professionals follow the requirements under the REMS and the recommendations in the drug’s label.
Serious adverse events associated with Zyprexa Relprevv should be reported online at the FDA’s MedWatch site or by calling 800-332-1088.
The unexplained deaths of two patients a few days after receiving an intramuscular olanzapine injection are being investigated by the Food and Drug Administration.
The patients died 3-4 days after the IM injection of olanzapine pamoate, marketed as Zyprexa Relprevv, "well after the 3-hour post-injection monitoring period" required under the Risk Evaluation and Mitigation Strategy (REMS) in place for the drug. Both patients were found to have "very high" blood levels of olanzapine, according to the FDA statement issued on June 18. Zyprexa Relprevv is an intramuscular, long-acting formulation of the atypical antipsychotic olanzapine, approved for schizophrenia, and administered every 2 or 4 weeks.
Under the REMS for this agent, patients who are treated with this drug must receive the injection at a facility certified under the REMS, with ready access to emergency response services, and must be monitored continuously for at least 3 hours afterward.
The REMS addresses the risk of postinjection delirium/sedation syndrome (PDSS), which can occur when olanzapine levels rapidly rise after the injection. PDSS is associated with symptoms that can include dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, "and reduced level of consciousness ranging from mild sedation to coma," according to the drug’s label.
Cases of PDSS were reported in preapproval studies of Zyprexa Relprevv and, in most cases, patients were hospitalized; several patients required supportive care, including intubation, but all had "largely recovered" by 72 hours, the label says.
While the investigation is underway, the FDA recommends that health care professionals follow the requirements under the REMS and the recommendations in the drug’s label.
Serious adverse events associated with Zyprexa Relprevv should be reported online at the FDA’s MedWatch site or by calling 800-332-1088.
The unexplained deaths of two patients a few days after receiving an intramuscular olanzapine injection are being investigated by the Food and Drug Administration.
The patients died 3-4 days after the IM injection of olanzapine pamoate, marketed as Zyprexa Relprevv, "well after the 3-hour post-injection monitoring period" required under the Risk Evaluation and Mitigation Strategy (REMS) in place for the drug. Both patients were found to have "very high" blood levels of olanzapine, according to the FDA statement issued on June 18. Zyprexa Relprevv is an intramuscular, long-acting formulation of the atypical antipsychotic olanzapine, approved for schizophrenia, and administered every 2 or 4 weeks.
Under the REMS for this agent, patients who are treated with this drug must receive the injection at a facility certified under the REMS, with ready access to emergency response services, and must be monitored continuously for at least 3 hours afterward.
The REMS addresses the risk of postinjection delirium/sedation syndrome (PDSS), which can occur when olanzapine levels rapidly rise after the injection. PDSS is associated with symptoms that can include dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, "and reduced level of consciousness ranging from mild sedation to coma," according to the drug’s label.
Cases of PDSS were reported in preapproval studies of Zyprexa Relprevv and, in most cases, patients were hospitalized; several patients required supportive care, including intubation, but all had "largely recovered" by 72 hours, the label says.
While the investigation is underway, the FDA recommends that health care professionals follow the requirements under the REMS and the recommendations in the drug’s label.
Serious adverse events associated with Zyprexa Relprevv should be reported online at the FDA’s MedWatch site or by calling 800-332-1088.
