Elizabeth Mechcatie

More information from a large clinical trial of apixaban is needed before the Food and Drug Administration can move forward in reviewing the oral anticoagulant for preventing stroke and systemic embolism for approval in patients with nonvalvular atrial fibrillation, according to a statement issued by Bristol-Myers Squibb on June 25.

Apixaban, a factor Xa inhibitor, is being reviewed by the FDA for this indication, but the agency has issued a complete response letter requesting "additional information on data management and verification from the ARISTOTLE trial," one of the two large studies submitted to the FDA for the approval of this indication, the statement said. No other details were provided.

The other large clinical trial submitted in support of this indication is the AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) study, which along with the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, compared apixaban to warfarin or aspirin in almost 24,000 patients with atrial fibrillation. The results of both trials were published last year in the New England Journal of Medicine.

The FDA issues complete response letters to companies when there are outstanding issues that need to be resolved before the drug is approved. The FDA does not announce when these letters are issued, but the manufacturers often do.

The FDA has not asked for any new studies, and Bristol-Myers Squibb and Pfizer, which are collaborating to develop and commercialize apixaban in the United States and internationally, plan to work closely with the FDA on the next steps for the application, the statement said.

If approved in the United States, apixaban will be marketed as Eliquis, its trade name in the European Union, where it was approved in May 2011 for the prevention of venous thromboembolic events (VTEs) in adult patients who have undergone elective hip or knee replacement surgery. It is also under review for the atrial fibrillation indication in the European Union and Japan, the statement said.

In the ARISTOTLE study of patients with atrial fibrillation and at least one other stroke risk factor, apixaban was superior to warfarin in preventing stroke or systemic embolism, and was associated with less bleeding and lower mortality (N. Engl. J. Med. 2011;365:981-92). In the AVERROES study, apixaban was associated with a reduced risk of stroke or systemic embolism, but it did not significantly increase the risk of major bleeding or intracranial hemorrhage (N. Engl. J. Med. 2011;364:806-17).

The statement adds that the companies plan to conduct studies of almost 60,000 patients worldwide for different indications and patient populations, including nine phase III studies that have either been completed or are still underway. It is being studied as a treatment for VTE in the phase III studies.

More information from a large clinical trial of apixaban is needed before the Food and Drug Administration can move forward in reviewing the oral anticoagulant for preventing stroke and systemic embolism for approval in patients with nonvalvular atrial fibrillation, according to a statement issued by Bristol-Myers Squibb on June 25.

Apixaban, a factor Xa inhibitor, is being reviewed by the FDA for this indication, but the agency has issued a complete response letter requesting "additional information on data management and verification from the ARISTOTLE trial," one of the two large studies submitted to the FDA for the approval of this indication, the statement said. No other details were provided.

The other large clinical trial submitted in support of this indication is the AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) study, which along with the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, compared apixaban to warfarin or aspirin in almost 24,000 patients with atrial fibrillation. The results of both trials were published last year in the New England Journal of Medicine.

The FDA issues complete response letters to companies when there are outstanding issues that need to be resolved before the drug is approved. The FDA does not announce when these letters are issued, but the manufacturers often do.

The FDA has not asked for any new studies, and Bristol-Myers Squibb and Pfizer, which are collaborating to develop and commercialize apixaban in the United States and internationally, plan to work closely with the FDA on the next steps for the application, the statement said.

If approved in the United States, apixaban will be marketed as Eliquis, its trade name in the European Union, where it was approved in May 2011 for the prevention of venous thromboembolic events (VTEs) in adult patients who have undergone elective hip or knee replacement surgery. It is also under review for the atrial fibrillation indication in the European Union and Japan, the statement said.

In the ARISTOTLE study of patients with atrial fibrillation and at least one other stroke risk factor, apixaban was superior to warfarin in preventing stroke or systemic embolism, and was associated with less bleeding and lower mortality (N. Engl. J. Med. 2011;365:981-92). In the AVERROES study, apixaban was associated with a reduced risk of stroke or systemic embolism, but it did not significantly increase the risk of major bleeding or intracranial hemorrhage (N. Engl. J. Med. 2011;364:806-17).

The statement adds that the companies plan to conduct studies of almost 60,000 patients worldwide for different indications and patient populations, including nine phase III studies that have either been completed or are still underway. It is being studied as a treatment for VTE in the phase III studies.

More information from a large clinical trial of apixaban is needed before the Food and Drug Administration can move forward in reviewing the oral anticoagulant for preventing stroke and systemic embolism for approval in patients with nonvalvular atrial fibrillation, according to a statement issued by Bristol-Myers Squibb on June 25.

Apixaban, a factor Xa inhibitor, is being reviewed by the FDA for this indication, but the agency has issued a complete response letter requesting "additional information on data management and verification from the ARISTOTLE trial," one of the two large studies submitted to the FDA for the approval of this indication, the statement said. No other details were provided.

The other large clinical trial submitted in support of this indication is the AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) study, which along with the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, compared apixaban to warfarin or aspirin in almost 24,000 patients with atrial fibrillation. The results of both trials were published last year in the New England Journal of Medicine.

The FDA issues complete response letters to companies when there are outstanding issues that need to be resolved before the drug is approved. The FDA does not announce when these letters are issued, but the manufacturers often do.

The FDA has not asked for any new studies, and Bristol-Myers Squibb and Pfizer, which are collaborating to develop and commercialize apixaban in the United States and internationally, plan to work closely with the FDA on the next steps for the application, the statement said.

If approved in the United States, apixaban will be marketed as Eliquis, its trade name in the European Union, where it was approved in May 2011 for the prevention of venous thromboembolic events (VTEs) in adult patients who have undergone elective hip or knee replacement surgery. It is also under review for the atrial fibrillation indication in the European Union and Japan, the statement said.

In the ARISTOTLE study of patients with atrial fibrillation and at least one other stroke risk factor, apixaban was superior to warfarin in preventing stroke or systemic embolism, and was associated with less bleeding and lower mortality (N. Engl. J. Med. 2011;365:981-92). In the AVERROES study, apixaban was associated with a reduced risk of stroke or systemic embolism, but it did not significantly increase the risk of major bleeding or intracranial hemorrhage (N. Engl. J. Med. 2011;364:806-17).

The statement adds that the companies plan to conduct studies of almost 60,000 patients worldwide for different indications and patient populations, including nine phase III studies that have either been completed or are still underway. It is being studied as a treatment for VTE in the phase III studies.

The Food and Drug Administration has declined to approve the oral anticoagulant rivaroxaban as a treatment for patients with acute coronary syndrome, according to a statement issued by Johnson & Johnson.

The agency has issued a complete response letter regarding the supplemental indication for rivaroxaban for use in reducing the risk of secondary cardiovascular events in patients with acute coronary syndrome (ACS) that has been under review at the agency, the statement said.

The FDA issues complete response letters for a drug when there are outstanding issues that need to be resolved before approval; the FDA does not make these letters public, and the company statement did not provide any details about the issues raised in the letter.

Rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals, a Johnson & Johnson subsidiary, was initially approved in July 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery; and in November 2011 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In December of last year, Janssen submitted the ACS application for rivaroxaban at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with ACS [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA)] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine."

But at a meeting in May, the majority of the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against approval of this indication, with those voting no citing a large amount of missing data in ATLAS ACS, the pivotal study, as well as safety concerns, among the reasons for their votes (6 to 4 with one abstention).

In the study of 15,526 people with recent ACS, the risk of the combined end point of a composite of cardiovascular death, MI, or stroke, the primary efficacy end point, was reduced by 15% among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths). This was a statistically significant difference but with a marginal P value of .039. Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%). Intracranial hemorrhage and hemorrhagic stroke rates were also higher in those on rivaroxaban than in those on placebo (N. Engl. J. Med. 2012;366:9-19).

In an interview, Dr. Sanjay Kaul, one of the panel members who voted against approval, referred to the degree of missing data and the lack of robust data in favor of rivaroxaban in this study, pointing out that fewer than 10 excess events in the treatment arm would have negated the statistically significant treatment advantage. He also referred to the lack of a dose response (there was a greater benefit with the lower dose), a differential impact of the two doses on cardiovascular mortality and MI that was difficult to explain, and the lack of external evidence supporting an incremental advantage of anticoagulant therapy over antiplatelet therapy.

Although the contents of the FDA’s letter are not made public, "I suspect some, if not all, of these issues likely contributed to the unfavorable verdict," said Dr. Kaul, director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles. "I hope that with proper due diligence, which might involve additional trials, the sponsor will be able to respond satisfactorily to the FDA’s concerns," he added.

In the Johnson & Johnson statement, Dr. Paul Burton, vice president and cardiovascular franchise medical leader at Janssen R&D, said that the company "will continue to work with the FDA to fully address their questions as quickly as possible."

Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for reducing the risk of thrombotic CV events in patients with ACS.

Dr. Kaul holds stock in Johnson & Johnson, but less than the amount for which a waiver to be on an FDA panel is required.

The Food and Drug Administration has declined to approve the oral anticoagulant rivaroxaban as a treatment for patients with acute coronary syndrome, according to a statement issued by Johnson & Johnson.

The agency has issued a complete response letter regarding the supplemental indication for rivaroxaban for use in reducing the risk of secondary cardiovascular events in patients with acute coronary syndrome (ACS) that has been under review at the agency, the statement said.

The FDA issues complete response letters for a drug when there are outstanding issues that need to be resolved before approval; the FDA does not make these letters public, and the company statement did not provide any details about the issues raised in the letter.

Rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals, a Johnson & Johnson subsidiary, was initially approved in July 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery; and in November 2011 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In December of last year, Janssen submitted the ACS application for rivaroxaban at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with ACS [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA)] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine."

But at a meeting in May, the majority of the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against approval of this indication, with those voting no citing a large amount of missing data in ATLAS ACS, the pivotal study, as well as safety concerns, among the reasons for their votes (6 to 4 with one abstention).

In the study of 15,526 people with recent ACS, the risk of the combined end point of a composite of cardiovascular death, MI, or stroke, the primary efficacy end point, was reduced by 15% among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths). This was a statistically significant difference but with a marginal P value of .039. Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%). Intracranial hemorrhage and hemorrhagic stroke rates were also higher in those on rivaroxaban than in those on placebo (N. Engl. J. Med. 2012;366:9-19).

In an interview, Dr. Sanjay Kaul, one of the panel members who voted against approval, referred to the degree of missing data and the lack of robust data in favor of rivaroxaban in this study, pointing out that fewer than 10 excess events in the treatment arm would have negated the statistically significant treatment advantage. He also referred to the lack of a dose response (there was a greater benefit with the lower dose), a differential impact of the two doses on cardiovascular mortality and MI that was difficult to explain, and the lack of external evidence supporting an incremental advantage of anticoagulant therapy over antiplatelet therapy.

Although the contents of the FDA’s letter are not made public, "I suspect some, if not all, of these issues likely contributed to the unfavorable verdict," said Dr. Kaul, director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles. "I hope that with proper due diligence, which might involve additional trials, the sponsor will be able to respond satisfactorily to the FDA’s concerns," he added.

In the Johnson & Johnson statement, Dr. Paul Burton, vice president and cardiovascular franchise medical leader at Janssen R&D, said that the company "will continue to work with the FDA to fully address their questions as quickly as possible."

Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for reducing the risk of thrombotic CV events in patients with ACS.

Dr. Kaul holds stock in Johnson & Johnson, but less than the amount for which a waiver to be on an FDA panel is required.

The Food and Drug Administration has declined to approve the oral anticoagulant rivaroxaban as a treatment for patients with acute coronary syndrome, according to a statement issued by Johnson & Johnson.

The agency has issued a complete response letter regarding the supplemental indication for rivaroxaban for use in reducing the risk of secondary cardiovascular events in patients with acute coronary syndrome (ACS) that has been under review at the agency, the statement said.

The FDA issues complete response letters for a drug when there are outstanding issues that need to be resolved before approval; the FDA does not make these letters public, and the company statement did not provide any details about the issues raised in the letter.

Rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals, a Johnson & Johnson subsidiary, was initially approved in July 2011 for the prophylaxis of deep vein thrombosis in patients undergoing knee or hip replacement surgery; and in November 2011 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In December of last year, Janssen submitted the ACS application for rivaroxaban at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with ACS [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA)] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine."

But at a meeting in May, the majority of the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against approval of this indication, with those voting no citing a large amount of missing data in ATLAS ACS, the pivotal study, as well as safety concerns, among the reasons for their votes (6 to 4 with one abstention).

In the study of 15,526 people with recent ACS, the risk of the combined end point of a composite of cardiovascular death, MI, or stroke, the primary efficacy end point, was reduced by 15% among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths). This was a statistically significant difference but with a marginal P value of .039. Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%). Intracranial hemorrhage and hemorrhagic stroke rates were also higher in those on rivaroxaban than in those on placebo (N. Engl. J. Med. 2012;366:9-19).

In an interview, Dr. Sanjay Kaul, one of the panel members who voted against approval, referred to the degree of missing data and the lack of robust data in favor of rivaroxaban in this study, pointing out that fewer than 10 excess events in the treatment arm would have negated the statistically significant treatment advantage. He also referred to the lack of a dose response (there was a greater benefit with the lower dose), a differential impact of the two doses on cardiovascular mortality and MI that was difficult to explain, and the lack of external evidence supporting an incremental advantage of anticoagulant therapy over antiplatelet therapy.

Although the contents of the FDA’s letter are not made public, "I suspect some, if not all, of these issues likely contributed to the unfavorable verdict," said Dr. Kaul, director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles. "I hope that with proper due diligence, which might involve additional trials, the sponsor will be able to respond satisfactorily to the FDA’s concerns," he added.

In the Johnson & Johnson statement, Dr. Paul Burton, vice president and cardiovascular franchise medical leader at Janssen R&D, said that the company "will continue to work with the FDA to fully address their questions as quickly as possible."

Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for reducing the risk of thrombotic CV events in patients with ACS.

Dr. Kaul holds stock in Johnson & Johnson, but less than the amount for which a waiver to be on an FDA panel is required.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

SILVER SPRING, MD. – A new molecular weight heparin for preventing deep vein thromboses and pulmonary emboli in select cancer patients on chemotherapy failed to pass muster with a Food and Drug Administration panel on June 20.

The FDA’s Oncologic Drugs Advisory Committee voted 14 to 1, with 1 abstention, that semuloparin sodium lacked a favorable risk-benefit profile when used to prevent venous thromboembolic events (VTEs) in patients receiving chemotherapy for locally advanced or metastatic lung or pancreatic cancer, or for patients receiving chemotherapy for locally advanced or metastatic solid tumors who are determined to be at a high risk of VTEs – the indication proposed for approval by the drug’s manufacturer, Sanofi-Aventis U.S.

Semuloparin sodium, administered subcutaneously once a day, has not been approved anywhere, and if approved for this indication, it would be the first low-molecular-weight heparin (LMWH) – and the first anticoagulant – approved for preventing VTEs in cancer patients. One of the FDA reviewers pointed out that approval of the drug would "set a new standard of care" that would affect a large proportion of patients with cancer in the United States.

Current guidelines from the American Society of Clinical Oncology recommend anticoagulants for the treatment and prevention of recurrent VTE. The routine use of VTE prophylaxis is not advised for patients with cancer, except for those who are hospitalized, scheduled for major oncologic surgery, or receiving thalidomide or lenalidomide-based treatment.

In the SAVE-ONCO study, an international phase III trial of 3,212 patients undergoing chemotherapy for locally advanced cancers (most had lung or colorectal cancer; the rest had stomach, ovarian, pancreatic, or bladder cancer), participants were randomized to 20 mg of semuloparin daily or placebo for at least 3 months during chemotherapy.

The primary end point – a composite of symptomatic DVT, nonfatal pulmonary embolism, or VTE-related deaths from the time the patients were randomized until 3 days after the last study drug injection – was 1.2% in those on semuloparin, compared with 3.4% of those on placebo, a highly significant difference that represented a 64% reduced risk (N. Engl. J. Med. 2012;366:601-9).

But the absolute risk reduction was a modest 2.2%, and overall survival at 1 year, a secondary end point, was similar between the two groups. At 1 year, about 40% of patients in each group had died. The rate of VTE-related deaths was also similar between the two groups.

While the rates of major bleeding events were similar in the two groups (1.2% in the semuloparin arm and 1.1% in the placebo arm), seven patients who received semuloparin had a major bleeding event into a critical area or organ, which included one fatal intracranial bleed, compared with none of those on placebo. Compared with the placebo group, patients on semuloparin had more bleeding events overall (20% vs. 16%), more clinically relevant bleeding events (2.8% vs. 2.0%), and more cases of bleeding that led to discontinuation of treatment (2.3% vs. 1.6%).

Members of the panel pointed out that there were many unresolved issues, including the need for more information about the types of patients who would benefit from preventive treatment, uncertainty over how long patients should be treated with the drug for prophylaxis, problems with the single clinical trial that did not have robust results, uncertainty about how the drug would be used, and the lack of a clear benefit and toxic effects of the treatment.

Several panelists noted that there was a need for such a treatment, and encouraged the company to continue studying the drug and determine the types of patients with cancer who could benefit from the agent.

The FDA usually follows advisory panel recommendations, which are not binding. The panelists had been cleared of potential conflicts of interest related to the topic of the meeting.

SILVER SPRING, MD. – A new molecular weight heparin for preventing deep vein thromboses and pulmonary emboli in select cancer patients on chemotherapy failed to pass muster with a Food and Drug Administration panel on June 20.

The FDA’s Oncologic Drugs Advisory Committee voted 14 to 1, with 1 abstention, that semuloparin sodium lacked a favorable risk-benefit profile when used to prevent venous thromboembolic events (VTEs) in patients receiving chemotherapy for locally advanced or metastatic lung or pancreatic cancer, or for patients receiving chemotherapy for locally advanced or metastatic solid tumors who are determined to be at a high risk of VTEs – the indication proposed for approval by the drug’s manufacturer, Sanofi-Aventis U.S.

Semuloparin sodium, administered subcutaneously once a day, has not been approved anywhere, and if approved for this indication, it would be the first low-molecular-weight heparin (LMWH) – and the first anticoagulant – approved for preventing VTEs in cancer patients. One of the FDA reviewers pointed out that approval of the drug would "set a new standard of care" that would affect a large proportion of patients with cancer in the United States.

Current guidelines from the American Society of Clinical Oncology recommend anticoagulants for the treatment and prevention of recurrent VTE. The routine use of VTE prophylaxis is not advised for patients with cancer, except for those who are hospitalized, scheduled for major oncologic surgery, or receiving thalidomide or lenalidomide-based treatment.

In the SAVE-ONCO study, an international phase III trial of 3,212 patients undergoing chemotherapy for locally advanced cancers (most had lung or colorectal cancer; the rest had stomach, ovarian, pancreatic, or bladder cancer), participants were randomized to 20 mg of semuloparin daily or placebo for at least 3 months during chemotherapy.

The primary end point – a composite of symptomatic DVT, nonfatal pulmonary embolism, or VTE-related deaths from the time the patients were randomized until 3 days after the last study drug injection – was 1.2% in those on semuloparin, compared with 3.4% of those on placebo, a highly significant difference that represented a 64% reduced risk (N. Engl. J. Med. 2012;366:601-9).

But the absolute risk reduction was a modest 2.2%, and overall survival at 1 year, a secondary end point, was similar between the two groups. At 1 year, about 40% of patients in each group had died. The rate of VTE-related deaths was also similar between the two groups.

While the rates of major bleeding events were similar in the two groups (1.2% in the semuloparin arm and 1.1% in the placebo arm), seven patients who received semuloparin had a major bleeding event into a critical area or organ, which included one fatal intracranial bleed, compared with none of those on placebo. Compared with the placebo group, patients on semuloparin had more bleeding events overall (20% vs. 16%), more clinically relevant bleeding events (2.8% vs. 2.0%), and more cases of bleeding that led to discontinuation of treatment (2.3% vs. 1.6%).

Members of the panel pointed out that there were many unresolved issues, including the need for more information about the types of patients who would benefit from preventive treatment, uncertainty over how long patients should be treated with the drug for prophylaxis, problems with the single clinical trial that did not have robust results, uncertainty about how the drug would be used, and the lack of a clear benefit and toxic effects of the treatment.

Several panelists noted that there was a need for such a treatment, and encouraged the company to continue studying the drug and determine the types of patients with cancer who could benefit from the agent.

The FDA usually follows advisory panel recommendations, which are not binding. The panelists had been cleared of potential conflicts of interest related to the topic of the meeting.

SILVER SPRING, MD. – A new molecular weight heparin for preventing deep vein thromboses and pulmonary emboli in select cancer patients on chemotherapy failed to pass muster with a Food and Drug Administration panel on June 20.

The FDA’s Oncologic Drugs Advisory Committee voted 14 to 1, with 1 abstention, that semuloparin sodium lacked a favorable risk-benefit profile when used to prevent venous thromboembolic events (VTEs) in patients receiving chemotherapy for locally advanced or metastatic lung or pancreatic cancer, or for patients receiving chemotherapy for locally advanced or metastatic solid tumors who are determined to be at a high risk of VTEs – the indication proposed for approval by the drug’s manufacturer, Sanofi-Aventis U.S.

Semuloparin sodium, administered subcutaneously once a day, has not been approved anywhere, and if approved for this indication, it would be the first low-molecular-weight heparin (LMWH) – and the first anticoagulant – approved for preventing VTEs in cancer patients. One of the FDA reviewers pointed out that approval of the drug would "set a new standard of care" that would affect a large proportion of patients with cancer in the United States.

Current guidelines from the American Society of Clinical Oncology recommend anticoagulants for the treatment and prevention of recurrent VTE. The routine use of VTE prophylaxis is not advised for patients with cancer, except for those who are hospitalized, scheduled for major oncologic surgery, or receiving thalidomide or lenalidomide-based treatment.

In the SAVE-ONCO study, an international phase III trial of 3,212 patients undergoing chemotherapy for locally advanced cancers (most had lung or colorectal cancer; the rest had stomach, ovarian, pancreatic, or bladder cancer), participants were randomized to 20 mg of semuloparin daily or placebo for at least 3 months during chemotherapy.

The primary end point – a composite of symptomatic DVT, nonfatal pulmonary embolism, or VTE-related deaths from the time the patients were randomized until 3 days after the last study drug injection – was 1.2% in those on semuloparin, compared with 3.4% of those on placebo, a highly significant difference that represented a 64% reduced risk (N. Engl. J. Med. 2012;366:601-9).

But the absolute risk reduction was a modest 2.2%, and overall survival at 1 year, a secondary end point, was similar between the two groups. At 1 year, about 40% of patients in each group had died. The rate of VTE-related deaths was also similar between the two groups.

While the rates of major bleeding events were similar in the two groups (1.2% in the semuloparin arm and 1.1% in the placebo arm), seven patients who received semuloparin had a major bleeding event into a critical area or organ, which included one fatal intracranial bleed, compared with none of those on placebo. Compared with the placebo group, patients on semuloparin had more bleeding events overall (20% vs. 16%), more clinically relevant bleeding events (2.8% vs. 2.0%), and more cases of bleeding that led to discontinuation of treatment (2.3% vs. 1.6%).

Members of the panel pointed out that there were many unresolved issues, including the need for more information about the types of patients who would benefit from preventive treatment, uncertainty over how long patients should be treated with the drug for prophylaxis, problems with the single clinical trial that did not have robust results, uncertainty about how the drug would be used, and the lack of a clear benefit and toxic effects of the treatment.

Several panelists noted that there was a need for such a treatment, and encouraged the company to continue studying the drug and determine the types of patients with cancer who could benefit from the agent.

The FDA usually follows advisory panel recommendations, which are not binding. The panelists had been cleared of potential conflicts of interest related to the topic of the meeting.

No major safety problems were identified in the Food and Drug Administration’s review of compounded formulations of hydroxyprogesterone caproate, but the agency continues to emphasize that the approved version of the product, known as Makena, used to reduce the risk of preterm birth in certain patients, is more reliable.

A statement issued by the FDA on June 15 says that the agency’s analyses of a "limited sample" of compounded formulations of hydroxyprogesterone caproate and samples of the active ingredient used to make these formulations – obtained from compounding pharmacies, physician’s offices, distributors of the active pharmaceutical ingredient (API) and imported APIs – found that most had met potency and purity standards. However, approved products such as Makena, the FDA-approved version of hydroxyprogesterone caproate, "provide a greater assurance of safety and effectiveness than do compounded products," the statement said.

Hydroxyprogesterone caproate, a progestin, is the active ingredient in Makena, which was approved by the FDA in February 2011, for reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth; it is administered intramuscularly once a week. Before the approval of Makena, formulations of hydroxyprogesterone caproate compounded by pharmacists had been used for years, and the availability of a reliable approved version was welcomed, but enthusiasm was quickly tempered by the high price tag of the approved version.

In November 2011, the FDA announced that it had started to conduct analyses of compounded hydroxyprogesterone caproate products and bulk APIs, and that it would review data submitted by K-V Pharmaceuticals, the sponsor of Makena, which had found "variability" in their purity and potency.

In the June 15 statement, the FDA provided the final results of its testing and analyses: All 16 samples of the hydroxyprogesterone caproate API passed the tests for potency as specified by the United States Pharmacopeia (USP), and passed the potency tests used in the approval application for Makena. All 16 of these samples also passed the standard for total purity that was used in the Makena application, but "failed" to meet the limit for unidentified impurities used in the Makena application. The FDA also identified four impurities that exceeded the levels allowed in the Makena application, but they "do not raise safety concerns," the statement said,

Of the 13 compounded hydroxyprogesterone caproate products from eight pharmacies, one was subpotent, at about 80% of declared potency. All samples met the standard for total purity in the Makena application, and 2 of the 13 samples did not meet the standard for unidentified impurities used in the Makena application.

In the FDA’s analysis of the 26 samples of the compounded product from the laboratories that had conducted the testing for K-V, 3 failed to meet the potency standard with the method used in the Makena new drug application (NDA), and 7 of these samples failed the standard for unidentified purities that were used in the Makena NDA.

"Although the analysis of this limited sample of compounded hydroxyprogesterone caproate products and APIs did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products," the FDA statement said. "Before approving the Makena NDA, FDA reviewed manufacturing information, such as the source of the API used by its manufacturer, proposed manufacturing processes, and the firm’s adherence to current good manufacturing practice."

Compounded products are not FDA approved, and compounding of any drug "should not exceed the scope of traditional pharmacy compounding," according to the FDA.

The full FDA statement is available.

No major safety problems were identified in the Food and Drug Administration’s review of compounded formulations of hydroxyprogesterone caproate, but the agency continues to emphasize that the approved version of the product, known as Makena, used to reduce the risk of preterm birth in certain patients, is more reliable.

A statement issued by the FDA on June 15 says that the agency’s analyses of a "limited sample" of compounded formulations of hydroxyprogesterone caproate and samples of the active ingredient used to make these formulations – obtained from compounding pharmacies, physician’s offices, distributors of the active pharmaceutical ingredient (API) and imported APIs – found that most had met potency and purity standards. However, approved products such as Makena, the FDA-approved version of hydroxyprogesterone caproate, "provide a greater assurance of safety and effectiveness than do compounded products," the statement said.

Hydroxyprogesterone caproate, a progestin, is the active ingredient in Makena, which was approved by the FDA in February 2011, for reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth; it is administered intramuscularly once a week. Before the approval of Makena, formulations of hydroxyprogesterone caproate compounded by pharmacists had been used for years, and the availability of a reliable approved version was welcomed, but enthusiasm was quickly tempered by the high price tag of the approved version.

In November 2011, the FDA announced that it had started to conduct analyses of compounded hydroxyprogesterone caproate products and bulk APIs, and that it would review data submitted by K-V Pharmaceuticals, the sponsor of Makena, which had found "variability" in their purity and potency.

In the June 15 statement, the FDA provided the final results of its testing and analyses: All 16 samples of the hydroxyprogesterone caproate API passed the tests for potency as specified by the United States Pharmacopeia (USP), and passed the potency tests used in the approval application for Makena. All 16 of these samples also passed the standard for total purity that was used in the Makena application, but "failed" to meet the limit for unidentified impurities used in the Makena application. The FDA also identified four impurities that exceeded the levels allowed in the Makena application, but they "do not raise safety concerns," the statement said,

Of the 13 compounded hydroxyprogesterone caproate products from eight pharmacies, one was subpotent, at about 80% of declared potency. All samples met the standard for total purity in the Makena application, and 2 of the 13 samples did not meet the standard for unidentified impurities used in the Makena application.

In the FDA’s analysis of the 26 samples of the compounded product from the laboratories that had conducted the testing for K-V, 3 failed to meet the potency standard with the method used in the Makena new drug application (NDA), and 7 of these samples failed the standard for unidentified purities that were used in the Makena NDA.

"Although the analysis of this limited sample of compounded hydroxyprogesterone caproate products and APIs did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products," the FDA statement said. "Before approving the Makena NDA, FDA reviewed manufacturing information, such as the source of the API used by its manufacturer, proposed manufacturing processes, and the firm’s adherence to current good manufacturing practice."

Compounded products are not FDA approved, and compounding of any drug "should not exceed the scope of traditional pharmacy compounding," according to the FDA.

The full FDA statement is available.

No major safety problems were identified in the Food and Drug Administration’s review of compounded formulations of hydroxyprogesterone caproate, but the agency continues to emphasize that the approved version of the product, known as Makena, used to reduce the risk of preterm birth in certain patients, is more reliable.

A statement issued by the FDA on June 15 says that the agency’s analyses of a "limited sample" of compounded formulations of hydroxyprogesterone caproate and samples of the active ingredient used to make these formulations – obtained from compounding pharmacies, physician’s offices, distributors of the active pharmaceutical ingredient (API) and imported APIs – found that most had met potency and purity standards. However, approved products such as Makena, the FDA-approved version of hydroxyprogesterone caproate, "provide a greater assurance of safety and effectiveness than do compounded products," the statement said.

Hydroxyprogesterone caproate, a progestin, is the active ingredient in Makena, which was approved by the FDA in February 2011, for reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth; it is administered intramuscularly once a week. Before the approval of Makena, formulations of hydroxyprogesterone caproate compounded by pharmacists had been used for years, and the availability of a reliable approved version was welcomed, but enthusiasm was quickly tempered by the high price tag of the approved version.

In November 2011, the FDA announced that it had started to conduct analyses of compounded hydroxyprogesterone caproate products and bulk APIs, and that it would review data submitted by K-V Pharmaceuticals, the sponsor of Makena, which had found "variability" in their purity and potency.

In the June 15 statement, the FDA provided the final results of its testing and analyses: All 16 samples of the hydroxyprogesterone caproate API passed the tests for potency as specified by the United States Pharmacopeia (USP), and passed the potency tests used in the approval application for Makena. All 16 of these samples also passed the standard for total purity that was used in the Makena application, but "failed" to meet the limit for unidentified impurities used in the Makena application. The FDA also identified four impurities that exceeded the levels allowed in the Makena application, but they "do not raise safety concerns," the statement said,

Of the 13 compounded hydroxyprogesterone caproate products from eight pharmacies, one was subpotent, at about 80% of declared potency. All samples met the standard for total purity in the Makena application, and 2 of the 13 samples did not meet the standard for unidentified impurities used in the Makena application.

In the FDA’s analysis of the 26 samples of the compounded product from the laboratories that had conducted the testing for K-V, 3 failed to meet the potency standard with the method used in the Makena new drug application (NDA), and 7 of these samples failed the standard for unidentified purities that were used in the Makena NDA.

"Although the analysis of this limited sample of compounded hydroxyprogesterone caproate products and APIs did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products," the FDA statement said. "Before approving the Makena NDA, FDA reviewed manufacturing information, such as the source of the API used by its manufacturer, proposed manufacturing processes, and the firm’s adherence to current good manufacturing practice."

Compounded products are not FDA approved, and compounding of any drug "should not exceed the scope of traditional pharmacy compounding," according to the FDA.

The full FDA statement is available.

The risk of major bleeding events in Italians taking low-dose aspirin was more than 50% higher than in those not on the regimen in a large population-based cohort study.

However, those with diabetes had showed no increase in bleeding risk.

"Weighing the benefits of aspirin therapy against the potential harms is of particular relevance in the primary prevention setting, in which benefits seem to be lower than expected based on results in high risk populations," concluded Giorgia De Berardis of the department of clinical pharmacology and epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy, and her associates. The study was published online on June 6 (JAMA 2012;307:2286-94).

Although low-dose aspirin was associated with an increased risk of major bleeding in people with hypertension and most other subgroups they identified, it was not independently associated with such a risk in people with diabetes, a finding that indicates that "diabetes might represent a different population in terms of both expected benefits and risks associated with antiplatelet therapy," they wrote.

In the study, the investigators used administrative data on people living in 12 local health authorities in Puglia, Italy, which is in the southeastern part of the country, linking data from hospital discharge records, prescription databases (including information on aspirin, which in Italy is prescribed for CV prevention), and the civil registry. They compared hospitalizations for major gastrointestinal bleeding or cerebral hemorrhage among 186,425 users of low-dose aspirin (300 mg or less) during 2003-2008, to matched controls who had never used aspirin. A little over half were women; the mean age was about 69 years.

Over a median follow-up of almost 6 years, 5.58 hemorrhagic events/1,000 person-years occurred in persons on aspirin, compared with 3.60 events/1,000 person-years in those who had never used aspirin, for an increased risk of 55%. Among those on aspirin, the risk of GI bleeding was increased by 55% and the risk of intracranial bleed was increased by 54%, compared with those who had never used aspirin.

Among those on aspirin, the risk of bleeding was increased in most of the subgroups evaluated, and was "particularly high" among those younger than age 50 years(an incidence rate ratio of 1.93 – about a threefold greater risk when compared with people under 50 years who were not on aspirin). It was also increased in aspirin users who had not been treated for hypertension. They pointed out that this increased risk was seen in most of the subgroups they evaluated, except for patients with diabetes and those who had previously been admitted to the hospital for GI or CV problems, which they said could be "partially" attributed to the use of proton pump inhibitors (PPIs).

Those with diabetes who were not taking aspirin had a 59% increased risk for GI bleeding and a 64% increase risk for intracranial bleeding. But among those with diabetes who were on aspirin, the risk of bleeding was only slightly elevated. "Our study shows, for the first time, to our knowledge, that aspirin therapy only marginally increases the risk of bleeding in individuals with diabetes," the authors wrote, adding that these results "can represent indirect evidence that the efficacy of aspirin in suppressing platelet function is reduced in this population."

A notable finding, they said, was that the use of statins was associated with a significant reduction of gastrointestinal bleeding (35%) and intracranial bleeding (31%).

The authors said that the incidence of major bleeding events associated with aspirin identified in their study was "much higher" than reported in randomized prospective studies. The 55% increase in the relative risk of major bleeding, over no aspirin, "translates to 2 excess cases for 1,000 patients treated per year," they said. "In other words, the excess number of major bleeding events associated with the use of aspirin is of the same magnitude of the number of major cardiovascular events avoided in the primary prevention setting for individuals with a 10-year risk of between 10% and 20%."

Limitations of their study include the not being able to adjust for all potential factors that can affect bleeding, including over-the-counter aspirin use, although in Italy, low-dose aspirin for CV prevention in high-risk individuals is available by prescription and is fully covered.

Four of the seven authors, including the lead author, reported no disclosures. One author reported receiving a research grant from Bristol-Myers Squibb, another reported receiving a research grant from Bayer, and another reported receiving a research grant and lecture fees, including service on speakers bureaus from Bayer.

The risk of major bleeding events in Italians taking low-dose aspirin was more than 50% higher than in those not on the regimen in a large population-based cohort study.

However, those with diabetes had showed no increase in bleeding risk.

"Weighing the benefits of aspirin therapy against the potential harms is of particular relevance in the primary prevention setting, in which benefits seem to be lower than expected based on results in high risk populations," concluded Giorgia De Berardis of the department of clinical pharmacology and epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy, and her associates. The study was published online on June 6 (JAMA 2012;307:2286-94).

Although low-dose aspirin was associated with an increased risk of major bleeding in people with hypertension and most other subgroups they identified, it was not independently associated with such a risk in people with diabetes, a finding that indicates that "diabetes might represent a different population in terms of both expected benefits and risks associated with antiplatelet therapy," they wrote.

In the study, the investigators used administrative data on people living in 12 local health authorities in Puglia, Italy, which is in the southeastern part of the country, linking data from hospital discharge records, prescription databases (including information on aspirin, which in Italy is prescribed for CV prevention), and the civil registry. They compared hospitalizations for major gastrointestinal bleeding or cerebral hemorrhage among 186,425 users of low-dose aspirin (300 mg or less) during 2003-2008, to matched controls who had never used aspirin. A little over half were women; the mean age was about 69 years.

Over a median follow-up of almost 6 years, 5.58 hemorrhagic events/1,000 person-years occurred in persons on aspirin, compared with 3.60 events/1,000 person-years in those who had never used aspirin, for an increased risk of 55%. Among those on aspirin, the risk of GI bleeding was increased by 55% and the risk of intracranial bleed was increased by 54%, compared with those who had never used aspirin.

Among those on aspirin, the risk of bleeding was increased in most of the subgroups evaluated, and was "particularly high" among those younger than age 50 years(an incidence rate ratio of 1.93 – about a threefold greater risk when compared with people under 50 years who were not on aspirin). It was also increased in aspirin users who had not been treated for hypertension. They pointed out that this increased risk was seen in most of the subgroups they evaluated, except for patients with diabetes and those who had previously been admitted to the hospital for GI or CV problems, which they said could be "partially" attributed to the use of proton pump inhibitors (PPIs).

Those with diabetes who were not taking aspirin had a 59% increased risk for GI bleeding and a 64% increase risk for intracranial bleeding. But among those with diabetes who were on aspirin, the risk of bleeding was only slightly elevated. "Our study shows, for the first time, to our knowledge, that aspirin therapy only marginally increases the risk of bleeding in individuals with diabetes," the authors wrote, adding that these results "can represent indirect evidence that the efficacy of aspirin in suppressing platelet function is reduced in this population."

A notable finding, they said, was that the use of statins was associated with a significant reduction of gastrointestinal bleeding (35%) and intracranial bleeding (31%).

The authors said that the incidence of major bleeding events associated with aspirin identified in their study was "much higher" than reported in randomized prospective studies. The 55% increase in the relative risk of major bleeding, over no aspirin, "translates to 2 excess cases for 1,000 patients treated per year," they said. "In other words, the excess number of major bleeding events associated with the use of aspirin is of the same magnitude of the number of major cardiovascular events avoided in the primary prevention setting for individuals with a 10-year risk of between 10% and 20%."

Limitations of their study include the not being able to adjust for all potential factors that can affect bleeding, including over-the-counter aspirin use, although in Italy, low-dose aspirin for CV prevention in high-risk individuals is available by prescription and is fully covered.

Four of the seven authors, including the lead author, reported no disclosures. One author reported receiving a research grant from Bristol-Myers Squibb, another reported receiving a research grant from Bayer, and another reported receiving a research grant and lecture fees, including service on speakers bureaus from Bayer.

The risk of major bleeding events in Italians taking low-dose aspirin was more than 50% higher than in those not on the regimen in a large population-based cohort study.

However, those with diabetes had showed no increase in bleeding risk.

"Weighing the benefits of aspirin therapy against the potential harms is of particular relevance in the primary prevention setting, in which benefits seem to be lower than expected based on results in high risk populations," concluded Giorgia De Berardis of the department of clinical pharmacology and epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy, and her associates. The study was published online on June 6 (JAMA 2012;307:2286-94).

Although low-dose aspirin was associated with an increased risk of major bleeding in people with hypertension and most other subgroups they identified, it was not independently associated with such a risk in people with diabetes, a finding that indicates that "diabetes might represent a different population in terms of both expected benefits and risks associated with antiplatelet therapy," they wrote.

In the study, the investigators used administrative data on people living in 12 local health authorities in Puglia, Italy, which is in the southeastern part of the country, linking data from hospital discharge records, prescription databases (including information on aspirin, which in Italy is prescribed for CV prevention), and the civil registry. They compared hospitalizations for major gastrointestinal bleeding or cerebral hemorrhage among 186,425 users of low-dose aspirin (300 mg or less) during 2003-2008, to matched controls who had never used aspirin. A little over half were women; the mean age was about 69 years.

Over a median follow-up of almost 6 years, 5.58 hemorrhagic events/1,000 person-years occurred in persons on aspirin, compared with 3.60 events/1,000 person-years in those who had never used aspirin, for an increased risk of 55%. Among those on aspirin, the risk of GI bleeding was increased by 55% and the risk of intracranial bleed was increased by 54%, compared with those who had never used aspirin.

Among those on aspirin, the risk of bleeding was increased in most of the subgroups evaluated, and was "particularly high" among those younger than age 50 years(an incidence rate ratio of 1.93 – about a threefold greater risk when compared with people under 50 years who were not on aspirin). It was also increased in aspirin users who had not been treated for hypertension. They pointed out that this increased risk was seen in most of the subgroups they evaluated, except for patients with diabetes and those who had previously been admitted to the hospital for GI or CV problems, which they said could be "partially" attributed to the use of proton pump inhibitors (PPIs).

Those with diabetes who were not taking aspirin had a 59% increased risk for GI bleeding and a 64% increase risk for intracranial bleeding. But among those with diabetes who were on aspirin, the risk of bleeding was only slightly elevated. "Our study shows, for the first time, to our knowledge, that aspirin therapy only marginally increases the risk of bleeding in individuals with diabetes," the authors wrote, adding that these results "can represent indirect evidence that the efficacy of aspirin in suppressing platelet function is reduced in this population."

A notable finding, they said, was that the use of statins was associated with a significant reduction of gastrointestinal bleeding (35%) and intracranial bleeding (31%).

The authors said that the incidence of major bleeding events associated with aspirin identified in their study was "much higher" than reported in randomized prospective studies. The 55% increase in the relative risk of major bleeding, over no aspirin, "translates to 2 excess cases for 1,000 patients treated per year," they said. "In other words, the excess number of major bleeding events associated with the use of aspirin is of the same magnitude of the number of major cardiovascular events avoided in the primary prevention setting for individuals with a 10-year risk of between 10% and 20%."

Limitations of their study include the not being able to adjust for all potential factors that can affect bleeding, including over-the-counter aspirin use, although in Italy, low-dose aspirin for CV prevention in high-risk individuals is available by prescription and is fully covered.

Four of the seven authors, including the lead author, reported no disclosures. One author reported receiving a research grant from Bristol-Myers Squibb, another reported receiving a research grant from Bayer, and another reported receiving a research grant and lecture fees, including service on speakers bureaus from Bayer.

A counterfeit version of a generic Adderall product that contains pain medications is being sold on the Internet, according to a warning issued by the Food and Drug Administration on May 29.

The counterfeit product – 30-mg tablets of the Adderall formulation manufactured by Teva Pharmaceutical Industries – contains tramadol and acetaminophen, not the active ingredients in Adderall, which are dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate.

Courtesy of the U.S. Food and Drug Administration

Adderall – a controlled substance that also is on the FDA’s list of current drug shortages – is approved for treating attention-deficit/hyperactivity disorder and for narcolepsy.

"The counterfeit versions of Adderall should be considered as unsafe, ineffective, and potentially harmful," and consumers should be "extra cautious when buying their medicines from online sources," the FDA said in a statement. "Rogue websites and distributors may especially target medicines in short supply for counterfeiting," the statement added.

The authentic Adderall 30-mg tablets manufactured by Teva are round, orange/peach, and scored with "dp" embossed on one side and "30" on the other side. They are only packaged in a 100-count bottle with the National Drug Code (NDC) 0555-0768-02 listed.

The FDA described the counterfeit Adderall, however, as round, white tablets that do not have any markings with letters or numbers. Another sign that it may be counterfeit is that it comes in a blister pack and the package includes misspellings ("NDS" instead of NDC, "aspartrte" instead of aspartate, and "singel" instead of single).

The FDA is advising consumers who think they have the counterfeit Adderall not to take it or to stop taking it.

Health care professionals and consumers should report adverse events associated with Adderall thought to be counterfeit to the agency’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/. Those who believe they have received counterfeit Adderall also should contact the FDA’s Office of Criminal Investigations (OCI) at 800-551-3989 or http://www.fda.gov/OCI.

A counterfeit version of a generic Adderall product that contains pain medications is being sold on the Internet, according to a warning issued by the Food and Drug Administration on May 29.

The counterfeit product – 30-mg tablets of the Adderall formulation manufactured by Teva Pharmaceutical Industries – contains tramadol and acetaminophen, not the active ingredients in Adderall, which are dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate.

Courtesy of the U.S. Food and Drug Administration

Adderall – a controlled substance that also is on the FDA’s list of current drug shortages – is approved for treating attention-deficit/hyperactivity disorder and for narcolepsy.

"The counterfeit versions of Adderall should be considered as unsafe, ineffective, and potentially harmful," and consumers should be "extra cautious when buying their medicines from online sources," the FDA said in a statement. "Rogue websites and distributors may especially target medicines in short supply for counterfeiting," the statement added.

The authentic Adderall 30-mg tablets manufactured by Teva are round, orange/peach, and scored with "dp" embossed on one side and "30" on the other side. They are only packaged in a 100-count bottle with the National Drug Code (NDC) 0555-0768-02 listed.

The FDA described the counterfeit Adderall, however, as round, white tablets that do not have any markings with letters or numbers. Another sign that it may be counterfeit is that it comes in a blister pack and the package includes misspellings ("NDS" instead of NDC, "aspartrte" instead of aspartate, and "singel" instead of single).

The FDA is advising consumers who think they have the counterfeit Adderall not to take it or to stop taking it.

Health care professionals and consumers should report adverse events associated with Adderall thought to be counterfeit to the agency’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/. Those who believe they have received counterfeit Adderall also should contact the FDA’s Office of Criminal Investigations (OCI) at 800-551-3989 or http://www.fda.gov/OCI.

A counterfeit version of a generic Adderall product that contains pain medications is being sold on the Internet, according to a warning issued by the Food and Drug Administration on May 29.

The counterfeit product – 30-mg tablets of the Adderall formulation manufactured by Teva Pharmaceutical Industries – contains tramadol and acetaminophen, not the active ingredients in Adderall, which are dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate.

Courtesy of the U.S. Food and Drug Administration

Adderall – a controlled substance that also is on the FDA’s list of current drug shortages – is approved for treating attention-deficit/hyperactivity disorder and for narcolepsy.

"The counterfeit versions of Adderall should be considered as unsafe, ineffective, and potentially harmful," and consumers should be "extra cautious when buying their medicines from online sources," the FDA said in a statement. "Rogue websites and distributors may especially target medicines in short supply for counterfeiting," the statement added.

The authentic Adderall 30-mg tablets manufactured by Teva are round, orange/peach, and scored with "dp" embossed on one side and "30" on the other side. They are only packaged in a 100-count bottle with the National Drug Code (NDC) 0555-0768-02 listed.

The FDA described the counterfeit Adderall, however, as round, white tablets that do not have any markings with letters or numbers. Another sign that it may be counterfeit is that it comes in a blister pack and the package includes misspellings ("NDS" instead of NDC, "aspartrte" instead of aspartate, and "singel" instead of single).

The FDA is advising consumers who think they have the counterfeit Adderall not to take it or to stop taking it.

Health care professionals and consumers should report adverse events associated with Adderall thought to be counterfeit to the agency’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/. Those who believe they have received counterfeit Adderall also should contact the FDA’s Office of Criminal Investigations (OCI) at 800-551-3989 or http://www.fda.gov/OCI.

SILVER SPRING, MD. – A single study of the investigational drug tafamidis provided enough evidence of its effectiveness as a treatment for polyneuropathy in patients with a rare form of hereditary amyloidosis to meet Food and Drug Administration criteria for an accelerated approval of a drug, the majority of an advisory panel has agreed.

At a May 24th meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, the panel voted 13-4 that the results of a small placebo-controlled study of tafamidis provided enough evidence that it was effective, based on surrogate end points that were considered "reasonably likely" to predict a clinical benefit in patients with this disease. That is the basis of an accelerated approval the FDA grants to drugs for diseases for which there is an unmet need, under the condition that the company conduct another study to confirm the clinical benefit, before full approval. If follow-up studies fail to confirm a benefit, the FDA can rescind approval.

The panel also voted 13-4 that the results of the study were not strong enough to provide evidence that was comparable to the evidence required for a full approval of a drug, two studies with evidence of effectiveness on clinical end points.

The proposed indication for tafamidis – a capsule formulation taken once daily – is for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adults with symptomatic polyneuropathy, with the aim of delaying neurologic impairment. Tafamidis is thought to prevent the formation of abnormal amyloid protein that is deposited on peripheral nerves, which causes polyneuropathy in patients with the progressive neurodegenerative disease. There are no approved treatments for the disease; the only treatment option is a liver transplant, since TTR is primarily synthesized in the liver. An autosomal dominant disease, FAP is one of the two types of familial amyloidosis (the other is familial amyloid cardiomyopathy), which affects fewer than 10,000 people worldwide, including about 2,500 cases in the United States. Cases are clustered in Portugal, Sweden, and Japan.

The randomized, placebo-controlled study, conducted by FoldRx Pharmaceuticals, a subsidiary of Pfizer, enrolled patients in relatively early stages of the disease outside the United States, comparing treatment with 20 mg once a day of tafamidis in 65 patients with placebo in 63 patients. At 18 months, 45% of those on the drug had less than a two-point change in neuropathy impairment scores from baseline (the primary efficacy end point), compared with 29.5% of those on placebo, which was not statistically significant. There was also evidence that those patients on tafamidis experienced less deterioration in quality of life over 18 months, compared with those on placebo.

About 20% of the patients in the study dropped out early to undergo a liver transplant, and more than half the study patients were treated at one site in Portugal, which were limitations of the study. The most common adverse events affecting at least 10% of patients on the drug were urinary tract infections, diarrhea, extremity pain, and upper abdominal pain.

Major issues raised by FDA reviewers and panelists included the lack of statistical significance of the primary end point, the lack of a beneficial effect when the patients at the Portuguese site were excluded, generalizability to the U.S. population, and lower baseline neuropathy scores in the treatment group.

But panelists supporting the accelerated approval cited evidence of efficacy on some surrogate end points, including evidence of improvements in muscle strength, although they had concerns about the strength of the data. Panelists had no particular safety concerns, but they pointed out the number of patients studied was small, and one panelist noted that the duration of treatment for patients would be much longer than the time in the study.

Tafamidis was approved in Europe for this indication in November 2011, under an "exceptional circumstances" provision. If approved in the United States, the drug will be marketed as Vyndaquel; it would be the first pharmacologic treatment approved in the United States and the first treatment that would be available immediately after a patient is diagnosed, according to Pfizer.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A single study of the investigational drug tafamidis provided enough evidence of its effectiveness as a treatment for polyneuropathy in patients with a rare form of hereditary amyloidosis to meet Food and Drug Administration criteria for an accelerated approval of a drug, the majority of an advisory panel has agreed.

At a May 24th meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, the panel voted 13-4 that the results of a small placebo-controlled study of tafamidis provided enough evidence that it was effective, based on surrogate end points that were considered "reasonably likely" to predict a clinical benefit in patients with this disease. That is the basis of an accelerated approval the FDA grants to drugs for diseases for which there is an unmet need, under the condition that the company conduct another study to confirm the clinical benefit, before full approval. If follow-up studies fail to confirm a benefit, the FDA can rescind approval.

The panel also voted 13-4 that the results of the study were not strong enough to provide evidence that was comparable to the evidence required for a full approval of a drug, two studies with evidence of effectiveness on clinical end points.

The proposed indication for tafamidis – a capsule formulation taken once daily – is for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adults with symptomatic polyneuropathy, with the aim of delaying neurologic impairment. Tafamidis is thought to prevent the formation of abnormal amyloid protein that is deposited on peripheral nerves, which causes polyneuropathy in patients with the progressive neurodegenerative disease. There are no approved treatments for the disease; the only treatment option is a liver transplant, since TTR is primarily synthesized in the liver. An autosomal dominant disease, FAP is one of the two types of familial amyloidosis (the other is familial amyloid cardiomyopathy), which affects fewer than 10,000 people worldwide, including about 2,500 cases in the United States. Cases are clustered in Portugal, Sweden, and Japan.

The randomized, placebo-controlled study, conducted by FoldRx Pharmaceuticals, a subsidiary of Pfizer, enrolled patients in relatively early stages of the disease outside the United States, comparing treatment with 20 mg once a day of tafamidis in 65 patients with placebo in 63 patients. At 18 months, 45% of those on the drug had less than a two-point change in neuropathy impairment scores from baseline (the primary efficacy end point), compared with 29.5% of those on placebo, which was not statistically significant. There was also evidence that those patients on tafamidis experienced less deterioration in quality of life over 18 months, compared with those on placebo.

About 20% of the patients in the study dropped out early to undergo a liver transplant, and more than half the study patients were treated at one site in Portugal, which were limitations of the study. The most common adverse events affecting at least 10% of patients on the drug were urinary tract infections, diarrhea, extremity pain, and upper abdominal pain.

Major issues raised by FDA reviewers and panelists included the lack of statistical significance of the primary end point, the lack of a beneficial effect when the patients at the Portuguese site were excluded, generalizability to the U.S. population, and lower baseline neuropathy scores in the treatment group.

But panelists supporting the accelerated approval cited evidence of efficacy on some surrogate end points, including evidence of improvements in muscle strength, although they had concerns about the strength of the data. Panelists had no particular safety concerns, but they pointed out the number of patients studied was small, and one panelist noted that the duration of treatment for patients would be much longer than the time in the study.

Tafamidis was approved in Europe for this indication in November 2011, under an "exceptional circumstances" provision. If approved in the United States, the drug will be marketed as Vyndaquel; it would be the first pharmacologic treatment approved in the United States and the first treatment that would be available immediately after a patient is diagnosed, according to Pfizer.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A single study of the investigational drug tafamidis provided enough evidence of its effectiveness as a treatment for polyneuropathy in patients with a rare form of hereditary amyloidosis to meet Food and Drug Administration criteria for an accelerated approval of a drug, the majority of an advisory panel has agreed.

At a May 24th meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, the panel voted 13-4 that the results of a small placebo-controlled study of tafamidis provided enough evidence that it was effective, based on surrogate end points that were considered "reasonably likely" to predict a clinical benefit in patients with this disease. That is the basis of an accelerated approval the FDA grants to drugs for diseases for which there is an unmet need, under the condition that the company conduct another study to confirm the clinical benefit, before full approval. If follow-up studies fail to confirm a benefit, the FDA can rescind approval.

The panel also voted 13-4 that the results of the study were not strong enough to provide evidence that was comparable to the evidence required for a full approval of a drug, two studies with evidence of effectiveness on clinical end points.

The proposed indication for tafamidis – a capsule formulation taken once daily – is for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adults with symptomatic polyneuropathy, with the aim of delaying neurologic impairment. Tafamidis is thought to prevent the formation of abnormal amyloid protein that is deposited on peripheral nerves, which causes polyneuropathy in patients with the progressive neurodegenerative disease. There are no approved treatments for the disease; the only treatment option is a liver transplant, since TTR is primarily synthesized in the liver. An autosomal dominant disease, FAP is one of the two types of familial amyloidosis (the other is familial amyloid cardiomyopathy), which affects fewer than 10,000 people worldwide, including about 2,500 cases in the United States. Cases are clustered in Portugal, Sweden, and Japan.

The randomized, placebo-controlled study, conducted by FoldRx Pharmaceuticals, a subsidiary of Pfizer, enrolled patients in relatively early stages of the disease outside the United States, comparing treatment with 20 mg once a day of tafamidis in 65 patients with placebo in 63 patients. At 18 months, 45% of those on the drug had less than a two-point change in neuropathy impairment scores from baseline (the primary efficacy end point), compared with 29.5% of those on placebo, which was not statistically significant. There was also evidence that those patients on tafamidis experienced less deterioration in quality of life over 18 months, compared with those on placebo.

About 20% of the patients in the study dropped out early to undergo a liver transplant, and more than half the study patients were treated at one site in Portugal, which were limitations of the study. The most common adverse events affecting at least 10% of patients on the drug were urinary tract infections, diarrhea, extremity pain, and upper abdominal pain.

Major issues raised by FDA reviewers and panelists included the lack of statistical significance of the primary end point, the lack of a beneficial effect when the patients at the Portuguese site were excluded, generalizability to the U.S. population, and lower baseline neuropathy scores in the treatment group.

But panelists supporting the accelerated approval cited evidence of efficacy on some surrogate end points, including evidence of improvements in muscle strength, although they had concerns about the strength of the data. Panelists had no particular safety concerns, but they pointed out the number of patients studied was small, and one panelist noted that the duration of treatment for patients would be much longer than the time in the study.

Tafamidis was approved in Europe for this indication in November 2011, under an "exceptional circumstances" provision. If approved in the United States, the drug will be marketed as Vyndaquel; it would be the first pharmacologic treatment approved in the United States and the first treatment that would be available immediately after a patient is diagnosed, according to Pfizer.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel on May 23 voted 6 to 4, with 1 abstention, against approving the oral anticoagulant rivaroxaban as a treatment for acute coronary syndrome, for reasons that included a large amount of missing data in the pivotal study and safety concerns.

At the meeting, the FDA’s Cardiovascular and Renal Drugs Advisory Committee considered the proposed indication for rivaroxaban, at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA)] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine." If approved, it would be the third approved indication for rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals.

Rivaroxaban was initially approved in July 2011, at a dosage of 10 mg once daily, for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. It was then approved in November 2011 at a dosage of 30 mg or 15 mg once daily for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In an international study of 15,526 people with recent ACS, patients (mean age 62 years, about two-thirds were male and about two-thirds were white) were randomized to treatment with 2.5 mg or 5 mg of rivaroxaban twice a day or placebo, plus standard care (dual antiplatelet therapy with low-dose aspirin plus a thienopyridine in most patients, and in about 7% of patients, low-dose aspirin only). The company proposed the 2.5-mg dose for approval because of its more favorable safety profile.

Among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine – the patient group the FDA said most closely reflected the U.S. population – the risk of the combined end point of a composite of cardiovascular death, MI, or stroke, the primary efficacy end point, was reduced by 15% over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths). This was statistically significant (P = .039).

As expected, treatment with rivaroxaban was associated with increased rates of bleeding events compared with placebo: Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%), a statistically significant difference. Intracranial hemorrhage (ICH) and hemorrhagic stroke rates were also higher among those on rivaroxaban compared with those on placebo, but the incidence of fatal ICH was similar between those on the 2.5-mg dose of rivaroxaban (five cases) and those on placebo (four cases).

A major issue discussed during the meeting was the possible impact of missing data for almost 1,300 study patients on the final results, which several panelists voting against approval pointed out was a particular concern because the primary efficacy end point for the 2.5-mg dose was only marginally significant.

"The incomplete data are very worrisome," said one of the panelists voting against approval, Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, Washington, D.C. One of the implications of approving another drug for ACS is that it then becomes the standard of treatment for everyone who has one of the three components of ACS, "and this seems like a major, major leap forward given the fragility of the data."

The other reasons cited by panelists voting against approval included the significance of intracranial hemorrhages from the patient perspective.

If approved for the ACS indication, rivaroxaban would be the first factor Xa inhibitor approved for reducing the risk of thrombotic CV events in patients with ACS. Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for this indication.

The results of the ATLAS trial were published in January 2012 (N. Engl. J. Med. 2012;366:9-19).

The FDA is expected to make its decision by June 29.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel on May 23 voted 6 to 4, with 1 abstention, against approving the oral anticoagulant rivaroxaban as a treatment for acute coronary syndrome, for reasons that included a large amount of missing data in the pivotal study and safety concerns.

At the meeting, the FDA’s Cardiovascular and Renal Drugs Advisory Committee considered the proposed indication for rivaroxaban, at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA)] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine." If approved, it would be the third approved indication for rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals.

Rivaroxaban was initially approved in July 2011, at a dosage of 10 mg once daily, for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. It was then approved in November 2011 at a dosage of 30 mg or 15 mg once daily for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In an international study of 15,526 people with recent ACS, patients (mean age 62 years, about two-thirds were male and about two-thirds were white) were randomized to treatment with 2.5 mg or 5 mg of rivaroxaban twice a day or placebo, plus standard care (dual antiplatelet therapy with low-dose aspirin plus a thienopyridine in most patients, and in about 7% of patients, low-dose aspirin only). The company proposed the 2.5-mg dose for approval because of its more favorable safety profile.

Among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine – the patient group the FDA said most closely reflected the U.S. population – the risk of the combined end point of a composite of cardiovascular death, MI, or stroke, the primary efficacy end point, was reduced by 15% over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths). This was statistically significant (P = .039).

As expected, treatment with rivaroxaban was associated with increased rates of bleeding events compared with placebo: Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%), a statistically significant difference. Intracranial hemorrhage (ICH) and hemorrhagic stroke rates were also higher among those on rivaroxaban compared with those on placebo, but the incidence of fatal ICH was similar between those on the 2.5-mg dose of rivaroxaban (five cases) and those on placebo (four cases).

A major issue discussed during the meeting was the possible impact of missing data for almost 1,300 study patients on the final results, which several panelists voting against approval pointed out was a particular concern because the primary efficacy end point for the 2.5-mg dose was only marginally significant.

"The incomplete data are very worrisome," said one of the panelists voting against approval, Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, Washington, D.C. One of the implications of approving another drug for ACS is that it then becomes the standard of treatment for everyone who has one of the three components of ACS, "and this seems like a major, major leap forward given the fragility of the data."

The other reasons cited by panelists voting against approval included the significance of intracranial hemorrhages from the patient perspective.

If approved for the ACS indication, rivaroxaban would be the first factor Xa inhibitor approved for reducing the risk of thrombotic CV events in patients with ACS. Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for this indication.

The results of the ATLAS trial were published in January 2012 (N. Engl. J. Med. 2012;366:9-19).

The FDA is expected to make its decision by June 29.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel on May 23 voted 6 to 4, with 1 abstention, against approving the oral anticoagulant rivaroxaban as a treatment for acute coronary syndrome, for reasons that included a large amount of missing data in the pivotal study and safety concerns.

At the meeting, the FDA’s Cardiovascular and Renal Drugs Advisory Committee considered the proposed indication for rivaroxaban, at a dose of 2.5 mg twice a day, to "reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA)] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine." If approved, it would be the third approved indication for rivaroxaban, an oral factor Xa inhibitor marketed as Xarelto by Janssen Pharmaceuticals.

Rivaroxaban was initially approved in July 2011, at a dosage of 10 mg once daily, for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. It was then approved in November 2011 at a dosage of 30 mg or 15 mg once daily for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

In an international study of 15,526 people with recent ACS, patients (mean age 62 years, about two-thirds were male and about two-thirds were white) were randomized to treatment with 2.5 mg or 5 mg of rivaroxaban twice a day or placebo, plus standard care (dual antiplatelet therapy with low-dose aspirin plus a thienopyridine in most patients, and in about 7% of patients, low-dose aspirin only). The company proposed the 2.5-mg dose for approval because of its more favorable safety profile.

Among those on the 2.5-mg twice-daily dosage who were also on aspirin plus a thienopyridine – the patient group the FDA said most closely reflected the U.S. population – the risk of the combined end point of a composite of cardiovascular death, MI, or stroke, the primary efficacy end point, was reduced by 15% over those on placebo plus dual therapy (primarily driven by a reduction in CV deaths). This was statistically significant (P = .039).

As expected, treatment with rivaroxaban was associated with increased rates of bleeding events compared with placebo: Among those on 2.5 mg twice a day, major bleeding was significantly higher (1.3%) than in those on placebo (0.4%), a statistically significant difference. Intracranial hemorrhage (ICH) and hemorrhagic stroke rates were also higher among those on rivaroxaban compared with those on placebo, but the incidence of fatal ICH was similar between those on the 2.5-mg dose of rivaroxaban (five cases) and those on placebo (four cases).

A major issue discussed during the meeting was the possible impact of missing data for almost 1,300 study patients on the final results, which several panelists voting against approval pointed out was a particular concern because the primary efficacy end point for the 2.5-mg dose was only marginally significant.

"The incomplete data are very worrisome," said one of the panelists voting against approval, Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, Washington, D.C. One of the implications of approving another drug for ACS is that it then becomes the standard of treatment for everyone who has one of the three components of ACS, "and this seems like a major, major leap forward given the fragility of the data."

The other reasons cited by panelists voting against approval included the significance of intracranial hemorrhages from the patient perspective.

If approved for the ACS indication, rivaroxaban would be the first factor Xa inhibitor approved for reducing the risk of thrombotic CV events in patients with ACS. Warfarin and three P2Y12 inhibitors – ticagrelor (Brilinta), prasugrel (Effient), and ticlopidine (Ticlid) – are approved for this indication.

The results of the ATLAS trial were published in January 2012 (N. Engl. J. Med. 2012;366:9-19).

The FDA is expected to make its decision by June 29.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

The long-acting recombinant human insulin analog marketed as Levemir has been approved for children aged 2-5 years with type 1 diabetes, the manufacturer has announced.

Levemir (insulin detemir [rDNA origin] injection) was previously approved for people with type 1 diabetes aged 6 years through adulthood and for the treatment of type 2 diabetes in adults.

The approval of the expanded pediatric indication was based on a study comparing Levemir with NPH insulin, which found that the two were as effective as was treatment with NPH insulin in terms of mean hemoglobain A_1c values achieved at 1 year, according to the manufacturer, Novo Nordisk.

In patients with type 1 diabetes, Levemir is always used in combination with a rapid-acting insulin.

The updated prescribing information for Levemir is available at www.novo-pi.com/levemir.pdf and on the FDA's website.

The long-acting recombinant human insulin analog marketed as Levemir has been approved for children aged 2-5 years with type 1 diabetes, the manufacturer has announced.

Levemir (insulin detemir [rDNA origin] injection) was previously approved for people with type 1 diabetes aged 6 years through adulthood and for the treatment of type 2 diabetes in adults.

The approval of the expanded pediatric indication was based on a study comparing Levemir with NPH insulin, which found that the two were as effective as was treatment with NPH insulin in terms of mean hemoglobain A_1c values achieved at 1 year, according to the manufacturer, Novo Nordisk.

In patients with type 1 diabetes, Levemir is always used in combination with a rapid-acting insulin.

The updated prescribing information for Levemir is available at www.novo-pi.com/levemir.pdf and on the FDA's website.

The long-acting recombinant human insulin analog marketed as Levemir has been approved for children aged 2-5 years with type 1 diabetes, the manufacturer has announced.

Levemir (insulin detemir [rDNA origin] injection) was previously approved for people with type 1 diabetes aged 6 years through adulthood and for the treatment of type 2 diabetes in adults.

The approval of the expanded pediatric indication was based on a study comparing Levemir with NPH insulin, which found that the two were as effective as was treatment with NPH insulin in terms of mean hemoglobain A_1c values achieved at 1 year, according to the manufacturer, Novo Nordisk.

In patients with type 1 diabetes, Levemir is always used in combination with a rapid-acting insulin.

The updated prescribing information for Levemir is available at www.novo-pi.com/levemir.pdf and on the FDA's website.